Pharmacogenetics in clinical practice - ISABSisabs.hr/doc/Literature/Pharmacogenetics_in_clinical_practice.pdf · Pharmacogenetics in clinical practice Experience with 16 commonly

Pharmacogeneticsin clinical practice

Experience with 16 commonly used drugs

Pharmakogenetikin der klinischen Praxis

Die Erfahrungen mit 16 häu�g verwendeten Medikamenten

Farmakogenetikau klinickoj praksi

Iskustvo s 16 lijekova korištenih u klinickoj praksi

Wolfgang Höppner and Dragan Primorac

Pharmacogenetics in clinical practice / Pharm

akogenetik in der klinischen Praxis / Farmakogenetika u klinickoj praksi

Pharmacogenetics in clinical practicePharmakogenetik in der klinischen Praxis

Farmakogenetika u kliničkoj praksi

Pharmacogenetics in clinical practiceExperience with 16 commonly used drugs

Pharmakogenetik in der klinischen PraxisDie Erfahrungen mit 16 häu�g verwendeten Medikamentenn

Farmakogenetika u klinickoj praksiIskustvo s 16 lijekova korištenih u klinickoj praksi

Edited byWolfgang Höppner

andDragan Primorac

BioGlobe GmbH - The Home of Life Sciencewww.bioglobe.net

andSt. Catherine Hospital – Member of The Leading Hospitals of The Word

www.svkatarina.com and www.svkatarina.hr

Zagreb, Hamburg, Berlin 2016.

Pha rma cog e n e t ics / Phar makog e n e t i k / Far makogenet ika4

Publisher / Herausgeber / Nakladnik

St. Catherine Hospital, Republic of Croatia

For publisher / für Verleger / Za nakladnika

Igor Boric, M.D., Ph.D., Assistant ProfessorSt. Catherine Hospital, Republic of Croatia.

Edited by / Bearbeitet von / Ureduju

Wolfgang Höppner, Ph.D. Adjunct Professor of Biochemistry and Molecular Biology, University of Hamburg,Managing Director of BioGlobe GmbH - The Home of Life Science,Managing director of Prevendo gmbh,Chairman oft he Board of Directors, Association fort he Advancement of Clinical and Expirimental Molecular Endocrinology (keme e.V.).

Dragan Primorac, M.D., Ph.D.Adjunct Professor of Forensic Science, Eberly College of Science, The Pennsylvania State University, University Park, PA, USA, Adjunct Professor of Forensic Science, The Henry C. Lee College of Criminal Justice and Forensic Sciences, University of New Haven, West Haven, CT, USA, Professor of Pediatric Medicine, University of Split, Medical School, Split and University of Osijek, Medical School, Osijek, Croatia, Professor, Department of Biotechnology, University of Rijeka, Rijeka, Croatia,President of the Board of Trustees - St. Catherine Hospital.

Reviewers / Rezensenten / Recenzenti

Stanimir Vuk-Pavlovic, Ph.D.Professor Emeritus of Biochemistry and Molecular Biology,Mayo Clinic College of Medicine,Rochester, Minnesota, USA.

Reinhard Walther, Ph.D. Professor Emeritus, University Medicine Greifswald,Institute for Medical Biochemistry and Molecular Biology, Greifswald, Germany.

Damir Erceg, M.D., Ph.D.Assistant Professor of Clinical Pharmacology, University of Osijek, School of Medicine, Children Hospital „Srebrnjak“, Zagreb, Croatia.

Elizabeta Topic, Ph.D.Professor, Faculty of Pharmacy and Biochemistry,University of Zagreb, Zagreb, Croatia.

Jefferson G. Fernandes, M.D., Ph.D.,M.B.A.Professor, Higher School of Health Education and Sciences,German Hospital Oswaldo Cruz,São Paulo, SP, Brazil.

Translator / Übersetzer / Prevoditelj

Daliborka Kopcic, profVereidigte Gerichtsdolmetscherin für Deutsch und Tschechisch

Book design by / Buchdesign von / Dizajn knjige

Ivo Mador

In collaboration with International Society For Applied Biological SciencesIn Zusammenarbeit mit International Society For Applied Biological SciencesU suradnji s International Society for Applied Biological Sciences

CIP zapis je dostupan u racunalnome katalogu Nacionalne i sveucilišne knjižnice u Zagrebu pod brojem 000935106

ISBN 978-953-59088-0-7

Pharmacogenet ics / Pharmakogenet ik / Farmakogenet ika 5

This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the authors do not have intention to replace the role of a physician in process of prescribing the drugs.

Dieses Buch enthält Informationen aus authentischen und vertrauten Quellen. Es erforderte sehr große An-strengungen um verlässliche Daten und Informationen zu veröffentlichen , aber die Autoren haben nicht die Absicht, die Rolle eines Arztes im Verfahren der Ver-schreibung der Medikamente zu ersetzen.

Ova knjiga sadrži informacije dobivene od autenticnih i pouzdanih izvora. Ucinjeni su razumni napori kako bi se objavili pouzdani podaci i informacije, no autori nemaju namjeru zamijeniti ulogu lijecnika u procesu propisivanja lijekova.


IntroductionIndividualized (personalized) medicine can add tremen-dous value to health care. The United States Food and Drug Administration views personalized medicine an in-novative approach to disease prevention and treatment that takes into account differences in patients’ genes, en-vironments and lifestyles. Pharmacogenetics is a critical component of personalized medicine. With the advances in molecular biology and genetics, pathogenesis of many diseases has been traced to variations in the genome. The ultimate goal of pharmacogenetics is to understand how genetic makeup determines drug action and adverse re-actions. Most drugs are broken down (metabolized) by enzymes. In some cases, metabolism inactivates an active drug fully or partially. In other cases, metabolism activates an inactive (or less active) drug. Different genetic variants of a par-ticular enzyme can metabolize a particular drug or group of drugs differently; hence, understanding the particular variant in the particular patient can directly affect the de-cision on the drug choice and dosage. To avoid drug-drug interactions, the decision on which drug to prescribe may also be in�uenced by other drugs taken. Understanding the genetic basis of patient’s metabolic differences (i.e., patient’s pharmacogenetics), clinicians can select the most effective drugs while keeping the likelihood of ad-verse reactions at the minimum. The likelihood of drug overdose can be decreased, as the dosage is based on the genetic constitution of the patient rather than on his/her body weight and age, as in the conventional approach. Pharmacogenetics will surely become part of standard considerations in the use of pharmaceuticals. Results of the contemporary farmacogenetics research are �nding an increasing role in clinical practice, yet the practicing physician often does not have at hand the rel-evant information in the appropriate form. For that reason in this brochure we compiled the information about the pharmacogenetic considerations on some of the most of-ten prescribed drugs according to the recommendations by the Clinical Pharmacogenetics Implementation Consor-tium and other sources. For each drug we cite the original literature that we recommend for further details.

Editors


EinführungDer individualisierte (personalisierte) Zugang zur Diagnostik und Behandlung kann die Wirksamkeit der Gesundheitsver-sorgung deutlich erhöhen. Die behördliche Lebensmittelüber-wachungs- und Arzneimittelzulassungsbehörde (Food and Drug Administration) der Vereinigten Staaten weist darauf hin, dass die personalisierte Medizin sowie innovative Ansätze zur Prävention von Krankheiten und Behandlung, auf der Untersu-chung der genetischen Vielfalt der Menschen, Umweltfaktoren und Lebensstil basieren. Als wichtiger und untrennbarer Bestandteil der personalisier-ten Medizin entwickelt sich zunehmend die Pharmakogenetik. Mit dem Fortschritt der Molekularbiologie und Genetik ist es unbestreitbar, dass die Pathogenese vieler Krankheiten besser verstanden wird, vor allem bezogen auf die Korrelation mit der Variabilität des Genoms. Das Ziel der Pharmakogenetik ist zu verstehen, wie das Genom eines Individuums die Wirkungen von Medikamenten bestimmt, aber auch die Entstehung von Nebenwirkungen.Es ist bekannt, dass die meisten Arzneimittel im Körper von Enzymen metabolisiert werden; in einigen Fällen inaktivieren sie ganz oder teilweise das Medikament und in anderen Fällen aktivieren sie den zuvor inaktiven oder weniger aktiven Wirk-stoff (Prodrug). Genetische Varianten eines bestimmten Enzyms können verschieden auf den Stoffwechsel der einzelnen Medi-kamente oder Gruppen von Medikamenten wirken. Die Kennt-niss des Gentyps eines Patienten, kann direkten Ein�uss auf die Auswahl und Dosierung des Medikaments haben. Die Entschei-dung über ein verschriebenes Medikament kann auch durch die Verwendung von anderen Medikamenten beein�usst werden. Das Ziel lautet: Arzneimittel-Wechselwirkungen, die zu schäd-lichen Nebenwirkungen führen, zu vermeiden. Zweifellos ver-ringert die Verschreibung der Medikamente, gemäß dem gene-tischem Pro�l eines Patienten, deutlich die Wahrscheinlichkeit von Nebenwirkungen, unter gleichzeitiger Berücksichtigung der korrekten Dosierung in Bezug auf das vorgeschriebene Me-dikament entsprechend Körpergewicht und Alter. Zusammen-gefasst: Pharmakogenetik hilft bei der bestmöglichen Auswahl der Medikamente und reduziert gleichzeitig das Risiko von Ne-benwirkungen, Über- oder Unterdosierung sowie die negativen Folgen der Wechselwirkungen mit anderen Medikamenten. Es besteht kein Zweifel, dass in naher Zukunft die Pharmakogene-tik Teil der Standard Pharmakotherapie werden wird. Die Ergebnisse der modernen pharmakogenetischen Forschung könnten bereits heute in der klinischen Praxis eingesetzt wer-den. Aber dem praktizierenden Arzt ist die relevante Literatur in geeigneter Form oft nicht zugänglich. Aus diesem Grund haben wir diese Broschüre vorbereitet. Sie soll den Zugriff auf Infor-mationen über häu�g verwendete Medikamente mit klinisch relevanten pharmakogenetischen Wechselwirkungen ermög-lichen. Die Informationen auf den folgenden Seiten basieren auf den neuesten Empfehlungen der Clinical Pharmacoge-netics Implementation Consortium und anderen Quellen. Für jedes Medikament führen wir die Originalliteratur auf, um einen schnellen Zugriff auf die Studien details zu ermöglichen.

Redakteure

UvodIndividualizirani (personalizirani) pristup dijagnostici i lije-cenju može znatno uvecati djelotvornost zdravstvene zaštite. Uprava za hranu i lijekove (Food and Drug Administration) Sjedinjenih Americkih Država istice da se personalizirana medicina, kao inovativni pristup prevenciji bolesti i lijecenju, temelji na istraživanju genetske raznolikosti ljudi, cinitelja okoliša i stila života. Kao važan i nedjeljiv dio personalizirane medicine posebno se istice farmakogenetika. Uz napredak molekulske biologije i genetike nedvojbeno je da patogene-za mnogih bolesti postaje jasnija pogotovo temeljem razu-mijevanja varijabilnosti genoma. Cilj farmakogenetike je ra-zumjeti kako genom pojedinca uvjetuje djelovanje lijekova, ali i nastanak popratnih pojava. Poznato je da vecinu lijekova u organizmu metaboliziraju enzimi; u nekim slucajevima potpuno ili djelomice inakti-viraju lijek, a u nekim aktiviraju dotad inaktivni ili manje aktivni lijek. Genetske inacice pojedinog enzima mogu ra-zlicito djelovati na metabolizam pojedinog lijeka ili skupi-ne lijekova pa poznavanje koja inacica djeluje u pacijentu može izravno utjecati na odluku o izboru i dozi lijeka. Odlu-ka o propisanom lijeku može biti uvjetovana i korištenjem drugih lijekova, a cilj je uvijek jedan: izbjeci interakciju lijekova koje dovode do štetnih popratnih pojava. Ned-vojbeno je da propisivanje lijekova sukladno genetskom pro�lu pojednica znatno smanjuje vjerojatnost popratnih pojava istodobno smanjujuci i vjerojatnost predoziranja u odnosu na lijek propisan prema bolesnikovoj tjelesnoj te-žini i starosti. Ukratko, farmakogenetika pomažu u izboru najboljeg moguceg lijeka i doze istodobno umanjujuci rizik popratnih pojava, predoziranja i nepovoljnih posljedica in-terakcije lijekova. Nema sumnje da ce u skoroj buducnosti farmakogenetika postati dio standardne farmakoterapije. Rezultati suvremenih farmakogenetickih istraživanja na-laze sve vecu primjenu u klinickoj praksi, ali lijecniku prakticaru relevantna literatura u prikladnom obliku cesto nije na dohvat ruke. Ovu smo brošuru priredili upravo da olakšamo pristup informaciji o najcešce primjenjivanim lijekovima. Informacija na narednim stranicama se teme-lji na najnovijim preporukama Clinical Pharmacogenetics Implementation Consortium i drugih izvora. Za svaki lijek navodimo izvornu literaturu koju preporucamo za uvid u više pojedinosti.

Urednici



ContentInhalt

Sadržaj

Abacavir / Abacavir / Abakavir 10 Allopurinol / Allopurinol / Alopurinol 14 Amitriptyline / Amitriptylin / Amitriptilin 18 Azathioprine / Azathioprin / Azatioprin 25 Carbamazepine / Carbamazepin / Karbamazepin 29 Clopidogrel / Clopidogrel / Klopidogrel 33 Codeine / Codein / Kodein 37 5-Fluorouracil and Capecitabine / 5-Fluorouracil und Capecitabine / 5-Fluorouracil i Kapecatibin 41 Ivacaftor / Ivacaftor / Ivakaftor 45 6-Mercaptopurine / 6-Mercaptopurin / 6-Merkaptopurin 49 Phenprocoumon / Phenprocoumon / Fenprokumonom (U Hrvatskoj se u iste svrhe koristi Varfarin) 53 Phenytoin / Phenitoin / Fenitoin 57 Ribavirin and PEG-interferon-α / Ribavirin und PEG-interferon-α / Ribavirin i Peginterferon alfa 64 Simvastatin / Simvastatin / Simvastatin 68 Tamoxifen / Tamoxifen / Tamoksifen 72 6-Thioguanine / 6-Thioguanin / 6-Tiogvanin 76


Abacavir Abacavir Abakavir


Gene test to minimise the risks related to therapy with abacavir

Drug

What are the indications and the mechanisms of action of abacavir?Abacavir is an antiviral active agent for the treatment of infections with the human immunodeficiency virus (HIV). Abacavir is a nucleoside analogue whose antiviral properties result from the enzyme’s reverse transcriptase which suppresses the propagation of the HIV-virus. Abacavir thus prevents the integration of the viral DNA into the host cell genome as well as the replication of the HIV-virus.

Genes

What genes influence the effect of abacavir?In individual cases, treatment with abacavir results in side effects such as pyrexia, fatigue and gastrointestinal symptoms. In 48-61 percent of the patients who carry the HLA-B*57:01 allele (HLA-B gene), however, the active agent causes severe immunological hypersensitivity reactions that can be life-threatening or fatal. The HLA-B*57:01 allele occurs in approx. 6 percent of the population.

Test

What is tested?The genotype of patients is tested with regard to the allele HLA-B*57:01 in the HLA-B gene.

Indication

When should a test be carried out?Genetic testing should be carried out before the initiation of the scheduled therapy with abacavir in order to change the active agent, as required, so that severe immunological hypersensitivity reactions can be avoided.

Consequences and test results

How does the therapy need to be adjusted to the test results?The following procedure is based on the recommendations of the Clinical Pharmacogenetics Implementation Consortium (CPIC)1 and has the highest clinical level of evidence, 1A.

Table 1: Recommendations for abacavir therapy depending on the genotype in the HLA-B gene

HLA genotype Recommended therapy

HLA-B*57:01, negative Therapy according to the summary of product characteristics

HLA-B*57:01, heterozygous or homozygous Therapy with abacavir not indicated

Costs

Costs for the determination of the HLA-B genotype are reimbursed for patients with a statutory or private health insurance if the testing is requested by a doctor. The budget of the doctor responsible for treatment is not affected.

1 Clinical Pharmacogenetics Implementation Consortium Guidelines for HLA-B Genotype and Abacavir Dosing: 2014 update. Martin MA, Hoffman JM, Freimuth RR, Klein TE, Dong BJ, Pirmohamed M, Hicks JK, Wilkinson MR, Haas DW, Kroetz DL Clin Pharmacol Ther. 2014, 95(5):499-500 PMID: 24561393


Gentest zur Risikominimierung der Therapie mit Abacavir

Arzneimittel

Wie sind die Indikationen und der Wirkmechanismus von Abacavir?Abacavir ist ein antiviraler Wirkstoff zur Behandlung von Infektionen mit dem humanen Immundefizienz-Virus (HIV). Abacavir ist ein Nucleosid-Analogon, dessen antivirale Eigenschaften auf die Hemmung des Enzyms reverse Transkriptase zurückzuführen sind, wodurch die Vermehrung des HI-Virus unterdrückt wird. Abacavir verhindert sowohl die Integration der viralen DNA in das Wirtszellgenom als auch die Replikation des HI-Virus.

Gene

Welche Gene beeinflussen die Wirkung von Abacavir?Unter der Therapie mit Abacavir treten in Einzelfällen Nebenwirkungen wie Fieber, Abgeschlagenheit und gastrointestinale Symptome auf. Demgegenüber löst der Wirkstoff bei ca. 48-61 Prozent der Patienten, die Träger des HLA-B*57:01 Allels (HLA-B-Gen) sind, schwere immunologische Überempfindlichkeitsreaktionen aus, die lebensbedrohlich oder tödlich verlaufen können. Die Häufigkeit des HLA-B*57:01-Allels in der Bevölkerung liegt bei 6 Prozent.

Test

Was wird getestet?Das Erbgut der Patienten wird auf das Allel HLA-B*57:01 (HLA-B-Gen) getestet.

Indikation

Wann sollte getestet werden?Der Gentest sollte vor Beginn einer geplanten Therapie mit Abacavir durchgeführt werden, um gegebenenfalls einen Wirkstoff vorzunehmen und schwere immunologische Überempfindlichkeitsreaktionen zu vermeiden.

Konsequenzen der Testergebnisse

Wie muss die Therapie an die Testergebnisse angepasst werden?Folgendes Vorgehen basiert auf Empfehlungen des Clinical Pharmacogenetics Implementation Consortium (CPIC)1 und hat den höchsten klinischen Evidenzlevel 1A.

Tabelle 1: Empfehlungen für die Abacavir-Therapie in Abhängigkeit vom HLA-B-Genotyps

HLA-Genotyp Therapieempfehlung

HLA-B*57:01, negativ Therapie gemäß Fachinformation

HLA-B*57:01, heterozygot oder homozygot Therapie mit Abacavir nicht indiziert

Kosten

Die Kosten für die Bestimmung des HLA-B-Genotyps werden für gesetzlich und privat versicherte Patienten erstattet, wenn die Testung durch einen Arzt angeordnet wird. Das Budget des behandelnden Arztes ist dadurch nicht belastet.

1 Clinical Pharmacogenetics Implementation Consortium Guidelines for HLA-B Genotype and Abacavir Dosing: 2014 update. Martin MA, Hoffman JM, Freimuth RR, Klein TE, Dong BJ, Pirmohamed M, Hicks JK, Wilkinson MR, Haas DW, Kroetz DL Clin Pharmacol Ther. 2014, 95(5):499-500 (PMID: 24561393)


Genski test za smanjenje rizika pri primjeni lijeka abakavir

Lijek

Koje su indikacije za primjenu i mehanizmi djelovanja abakavira?Abakavir je antivirusni lijek, primjenjuje se u lije�enju infekcija izazvanih virusom humane imunodeficijencije (HIV). Nukleozidni je analog, inhibitor reverzne transkriptaze (NRTI). Abakavir spre�ava integraciju virusne DNA u stani�ni genom doma�ina i replikaciju virusa HIV-a.

Geni

Koji geni utje�u na djelovanje abakavira?Uslijed lije�enja abakavirom u pojedina�nim slu�ajevima javljaju se nuspojave poput povišene tjelesne temperature, iznemoglosti i gastrointestinalnih simptoma. Nasuprot tome, abakavir kod 48-61 posto pacijenata, koji su nositelji alela HLA-B*57:01 alela (gen HLA-B), izaziva tešku imunološku reakciju preosjetljivosti koja može završiti i smrtnim ishodom. U�estalost alela HLA-B*57:01 (HLA-B*5701) u populaciji iznosi oko 6 posto.

Analiza

Što se analizira?Analizira se genotip pacijenta, konkretnije alel HLA-B*57:01, gena HLA-B.

Indikacije

U kojim je slu�ajevima potrebno napraviti analizu?Gensko testiranje bi trebalo napraviti prije planirane terapije abakavirom, kako bi se po potrebi ordinirala zamjenska terapija u svrhu spre�avanja teške imunološke reakcije preosjetljivosti.

Preporuke

Na koji na�in se terapija mora prilagoditi rezultatima genske analize?Postupak je utemeljen je na preporukama Clinical Pharmacogenetics Implementation Consortium (CPIC)1 te ima najvišu klini�ku razinu dokaza, 1A.

Tabela 1: Preporuke za lije�enje abakavirom ovisno o genotipu HLA-B gena

Genotip HLA Preporu�ena terapija

HLA-B*57:01, negativan Terapija sukladno uputama o lijeku (Informacijama za korisnika)

HLA-B*57:01, heterozigot ili homozigot Terapija abakavirom nije indicirana

Troškovi

Budžet nadležnog lije�nika ili institucije u kojoj lije�nik radi zbog toga ne�e biti optere�en. Priznavanje i povrat troškova za navedenu analizu varira od države do države. Ukoliko je analiza ordinirana od strane lije�nika, troškovi za odre�ivanje genotipa HLA-B bit �e priznati i refundirani za bolesnike koji imaju obvezno i privatno osiguranje, te budžet nadležnog lije�nika ili institucije u kojoj lije�nik radi zbog toga ne�e biti optere�en.

1 Clinical Pharmacogenetics Implementation Consortium Guidelines for HLA-B Genotype and Abacavir Dosing: 2014 update. Martin MA, Hoffman JM, Freimuth RR, Klein TE, Dong BJ, Pirmohamed M, Hicks JK, Wilkinson MR, Haas DW, Kroetz DL Clin Pharmacol Ther. 2014, 95(5):499-500 (PMID: 24561393)


Allopurinol Allopurinol Alopurinol


Gene test to minimise the risks related to therapy with allopurinol

Drug

What are the indications and the mechanisms of action of allopurinol?Allopurinol inhibits the breakdown of purines and is used to treat chronic gout caused by permanently elevated levels of uric acid in the blood. Further indications are connected with the treatment of uric acid concrements in the kidney and for preventing tumor lysis syndrome following chemotherapy. Due to its parasitostatic effect, allopurinol is also successfully used in combination with other drugs to treat leishmaniasis. The uricostatic properties of allopurinol are based on the inhibition of the breakdown enzyme xanthine oxidase. The enzyme blockage inhibits the breakdown of purine nucleotides to uric acid as well as the new synthesis of uric acid, reducing the uric acid concentration in the blood and urine.

Genes

What genes influence the effect of allopurinol?In patients who carry the HLA-B*58:01 allele (HLA-B gene), allopurinol can cause severe immunological hypersensitivity reactions. The HLA-B*58:01 allele occurs in 1-5 percent of the European population.

If a patient is HLA-B*58:01 allele positive, allopurinol should only be used if no therapeutic alternatives are available or if the benefits of the therapy outweigh the risks.

Test

What is tested?The genotype of patients is tested with regard to the allele HLA-B*58:01 in the HLA-B gene.

Indication

When should a test be carried out?Genetic testing should be carried out before the initiation of the scheduled therapy with allopurinol in order to change the active agent, as required, so that severe side effects can be avoided.


How does the therapy need to be adjusted to the test results?The following recommendations are based on the guidelines of the Clinical Pharmacogenetics Implementation Consortium (CPIC)1 and the American College of Rheumatology guidelines2and have the highest clinical level of evidence, 1A.

Table 1: Recommendations for allopurinol therapy depending on the genotype in the HLA-B gene

Genotype Recommended therapy

HLA-B*58:01, negative Use according to the summary of product characteristics

HLA-B*58:01, heterozygous or homozygous Allopurinol contraindicated, change of the active agent recommended

Costs

Costs for the determination of the HLA-B genotype are reimbursed for patients with a statutory or private health insurance if the testing is requested by a doctor. The budget of the doctor responsible for treatment is not affected.

1 Clinical Pharmacogenetics Implementation Consortium Guidelines for Human Leukocyte Antigen-B Genotype and Allopurinol Dosing. Hershfield MS, Callaghan JT, Tassaneeyakul W, Mushiroda T, Thorn CF, Klein TE, Lee MT. Clin Pharmacol Ther. 2013 93(2):153-8. (PMID: 23232549)2 2012 American College of Rheumatology Guidelines for Management of Gout. Part 1: Systematic Nonpharmacologic and Pharmacologic Approaches to Hyperuricemia. Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Noegi T, Pillinger MH, Merill J, Lee S, Prakash S, Kaldas M, Gogia M, Perez-Ruiz F, Taylor W, Lioté F, Choi H, Singh JA, Dalbeth N, Kaplan S, Niyyar V, Jones D, Yarows SA, Roessler B, Kerr G, King C, Levy G, Furst DE, Edwards NL, Mandell B, Schumacher HR, Robbins M, Weniger N, Terkeltaub R Arthritis Care & Research 2012 64(10): 1431-1446


Gentest zur Risikominimierung der Therapie mit Allopurinol

Arzneimittel

Wie sind die Indikationen und der Wirkmechanismus von Allopurinol?Allopurinol ist ein Purinabbauhemmer, der bei dauerhaft erhöhten Blutharnsäurespiegeln zur Behandlung der chronischen Gicht eingesetzt wird. Weitere Indikationsfelder sind die Therapie von Uratsteinen der Niere und die Prävention des Tumorlyse-Syndroms nach einer chemotherapeutischen Behandlung. Aufgrund seiner parasitostatischen Wirkung wird Allopurinol in Kombination mit anderen Arzneimitteln auch erfolgreich bei der Behandlung der Leishmaniose eingesetzt. Die urikostatischen Eigenschaften von Allopurinol beruhen auf der Inhibierung des Abbauenzyms Xanthinoxidase. Durch die Emzymblockade wird sowohl der Abbau von Purinnukleotiden zu Harnsäure als auch die Neusynthese von Harnsäure gehemmt, wodurch die Harnsäurekonzentration in Blut und Urin sinkt.

Gene

Welche Gene beeinflussen die Wirkung von Allopurinol?Bei Patienten, die Träger des HLA-B*58:01 Allels (HLA-B-Gen) sind, kann Allopurinol schwere immunologische Überempfindlichkeitsreaktionen auslösen. Das HLA-B*58:01 Allel kommt in der europäischen Bevölkerung mit einer Häufigkeit von 1-5 Prozent vor. Wird ein Patient als HLA-B*5801-Allel-positiv getestet, sollte Allopurinol nur angewendet werden, wenn keine therapeutischen Alternativen zur Verfügung stehen und der Therapienutzen die Risiken übersteigt.

Test

Was wird getestet?Das Erbgut der Patienten wird auf das HLA-B*58:01 Allel (HLA-B-Gen) getestet.

Indikation

Wann sollte getestet werden?Der Gentest sollte vor Beginn einer geplanten Therapie mit Allopurinol durchgeführt werden, um gegebenenfalls einen Wirkstoff vorzunehmen und schwere Nebenwirkungen zu vermeiden.


Wie muss die Therapie an die Testergebnisse angepasst werden?Die folgenden Empfehlungen basieren auf den Leitlinien des Clinical Pharmacogenetics Implementation Consortium (CPIC)1 und der American College of Rheumatology guidelines2 und haben den höchsten klinischen Evidenzlevel 1A.

Tabelle 1: Empfehlungen bei der Allopurinol-Therapie in Abhängigkeit vom Genotyp des HLA-B-Gens

HLA-B Genotyp Therapieempfehlung

HLA-B*58:01, negativ Anwendung gemäß Fachinformation

HLA-B*58:01, heterozygot oder homozygot Allopurinol kontraindiziert, Wirkstoffwechsel empfohlen

Kosten

Die Kosten für die Bestimmung des HLA-B-Genotyps werden für gesetzlich und privat versicherte Patienten erstattet, wenn die Testung durch einen Arzt angeordnet wird. Das Budget des behandelnden Arztes ist dadurch nicht belastet.



Genski test za smanjenje rizika kod primjene lijeka alopurinola

Lijek

Koje su indikacije za primjenu i mehanizmi djelovanja alopurinola?Alopurinol inhibira razgradnju purina i primjenjuje se u lije�enju kroni�nih uloga (gihta) koji su posljedica trajno povišene razine mokra�ne kiseline u krvi. Daljnja indikacijska podru�ja su lije�enje i prevencija bolesti nastalih zbog povišene vrijednosti mokra�ne kiseline poput bubrežnih kamenaca, te sindroma lize tumora. Urikostati�ka obilježja alopurinola temelje se na inhibiciji enzima ksantin oksidaze. Blokadom enzima zaustavlja se kako razgradnja purinskih nukleotida u mokra�nu kiselinu tako i nova sinteza mokra�ne kiseline pri �emu dolazi do pada njene koncentracije u krvi i u urinu. Na temelju njegovog parazitostati�kog djelovanja alopurinol se u kombinaciji sa drugim lijekovima uspješno primjenjuje i kod lije�enja lišmanijaze.

Geni

Koji geni utje�u na u�inkovitost alopurinola?Kod pacijenata koji su nositelji alela HLA-B*58:01 (gen HLA-B) alopurinol može izazivati tešku imunološku reakciju preosjetljivosti. U�estalost alela HLA-B*58:01 u Europskoj populaciji iznosi 1-5 posto. Ukoliko pacijent ima alel HLA-B*58:01, alopurinol se primjenjuje samo u slu�ajevima kada ne postoji niti jedan drugi alternativni oblik lije�enja te kad korist od terapije premašuje same rizike.

Analiza

Što se analizira?Analizira se genotip bolesnika, posebice postojanje alela HLA-B*58:01 (gen HLA-B).

Indikacije

U kojim je slu�ajevima potrebno napraviti analizu?Genski test potrebno je provesti prije po�etka planirane terapije alopurinolom, kako bi se po potrebi ordinirala zamjenska terapija u svrhu spre�avanja težih nuspojava.

Preporuke

Na koji na�in se terapija mora prilagoditi rezultatima genske analize?Preporuke su utemeljene na smjernicama Clinical Pharmacogenetics Implementation Consortium (CPIC)1 i American College of Rheumatology guidelines2 te imaju najvišu klini�ku razinu dokaza 1A.

Tabela 1: Preporuke za terapiju alopurinolom, ovisno o genotipu HLA-B

Genotip HLA-B Preporu�ena terapija


HLA-B*58:01, heterozigot ili homozigot Allopurinol je kontraindiciran, preporuca se promjena lijeka

Troškovi

Priznavanje i povrat troškova za navedenu analizu varira od države do države. Ukoliko je testiranje ordinirano od strane lije�nika, troškovi za odre�ivanje genotipa HLA-B biti �e priznati i refundirani za bolesnike koji imaju obvezno i privatno osiguranje, pa budžet nadležnog lije�nika ili institucije u kojoj nadležni lije�nik radi zbog toga ne�e biti optere�en.



Amitriptyline Amitriptylin Amitriptilin


Gene test to minimise the risks related to therapy with amitriptyline

Drug

What are the indications and the mechanism of action of amitriptyline?Amitriptyline belongs to the group of tricyclic antidepressants and is used for depressive disorders, prevention of migraines and treatment of neuropathic pain within the framework of an overall therapeutic concept. The effects are based on the inhibition of the reuptake of serotonin and norepinephrine in the presynaptic neuron. Amitriptyline modifies the sensitivity of various neurotransmitter receptors by means of down-regulation.

Genes

Which genes influence the effect of amitriptyline?Amitriptyline’s metabolism via the enzymes CYP2C19 and CYP2D6 plays a decisive role for its efficiency and duration of action. Several variants in the genes of these two enzymes are known in our population. These lead to a great variability in the enzymatic efficacy of CYP2C19 and CYP2D6, and can therefore be of vital importance for amitriptyline therapy.

Test

What will be tested?In order to determine the CYP2C19 as well as the CYP2D6 metabolism type, the patient’s genotype is tested for the most common activity-varying gene variants in the CYP2C19 gene (*2,*3,*17) and in the CYP2D6 gene (*1XN, *2, *2XN, 3*, *4, *5, *6, *9, *10, *41).

Indication

When should a test be performed?The genetic test should be performed before the start of planned therapy with amitriptyline in order to adjust the dosage or to make a change of active ingredient if necessary.

Consequences of test results

How does the therapy have to be adapted to the test results?The following recommendations are based on the Clinical Pharmacogenetics Implementation Consortium (CPIC)1 guideline and have the highest clinical level of evidence 1A.

Table 1: Recommendations for amitriptyline therapy subject to CYP2D6 genotype

CYP2D6 metabolism type Therapy recommendation

Ultra-rapid metabolizer (1-12%) Therapy with amitriptyline not recommended, prescribe alternative active ingredient

Extensive metabolizer (77-92%) Use in accordance with Summary of Product Characteristics

Intermediate metabolizer (2-11%) Reduction of starting dose by 25 percent

Poor metabolizer (5-10%) Therapy with amitriptyline not recommended, prescribe alternative active ingredient

1 Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Hicks JK, Swen JJ, Thorn CF, Sangkuhl K, Kharasch ED, Ellingrod VL, Skaar TC, Müller DJ, Gaedigk A, Stingl JC. Clin Pharmacol Ther. 2013 93(5):402-8. (PMID: 23486447)


Table 2: Recommendations for amitriptyline therapy subject to CYP2C19 genotype

CYP2C19 metabolism type Therapy recommendation

Ultra-rapid metabolizer (5-30%) Therapy with amitriptyline not recommended, prescribe alternative active ingredient


Intermediate metabolizer (18-45%) Use in accordance with Summary of Product Characteristics

Poor metabolizer (2-15%) Reduction of starting dose by 50 percent

Costs

Costs for genetic analyses will be reimbursed for statutory and privately insured patients if the testing is prescribed by a physician. The attending physician’s budget is not burdened as a result.


Gentest zur Risikominimierung der Therapie mit Amitriptylin

Arzneimittel

Wie sind die Indikationen und der Wirkmechanismus von Amitriptylin?Amitriptylin gehört zur Gruppe der trizyklischen Antidepressiva und wird eingesetzt bei depressiven Erkrankungen, zur Vorbeugung von Migräne und zur Behandlung von neuropathischen Schmerzen im Rahmen eines therapeutischen Gesamtkonzeptes. Die Effekte beruhen auf der Hemmung der Wiederaufnahme von Serotonin und Noradrenalin in das präsynaptische Neuron. Amitriptylin modifiziert die Empfindlichkeit verschiedener Neurotransmitter-Rezeptoren über Down-Regulation.

Gene

Welche Gene beeinflussen die Wirkung von Amitriptylin?Eine entscheidende Rolle für die Effizienz und die Wirkdauer von Amitriptylin spielt seine Verstoffwechslung über die Enzyme CYP2C19 und CYP2D6. In unserer Bevölkerung sind mehrere Varianten in den Genen dieser beiden Enzyme bekannt, die zu einer großen Variabilität in der enzymatischen Wirksamkeit von CYP2C19 und CYP2D6 führen und damit von entscheidender Bedeutung für die Amitriptylin-Therapie sein können.

Test

Was wird getestet?Um sowohl den CYP2C19- als auch den CYP2D6-Metabolisierungstyp zu ermitteln, wird das Erbgut der Patienten auf die häufigsten aktivitätsvariierenden Genvarianten im CYP2C19-Gen (*2,*3,*17) und im CYP2D6-Gen (*1XN, *2, *2XN, 3*, *4, *5, *6, 9*, *10, *41) ermittelt.

Indikation

Wann sollte getestet werden?Der Gentest sollte vor Beginn einer geplanten Therapie mit Amitriptylin durchgeführt werden, um gegebenenfalls die Dosierung anzupassen oder einen Wirkstoffwechsel vorzunehmen.


Wie muss die Therapie an die Testergebnisse angepasst werden?Die folgenden Empfehlungen basieren auf der Leitlinie des Clinical Pharmacogenetics Implementation Consortium (CPIC)1 und haben den höchsten klinischen Evidenzlevel 1A.

Tabelle 1: Empfehlungen für die Amitriptylin-Therapie in Abhängigkeit vom CYP2D6-Genotyp

CYP2D6-Metabolisierungstyp Therapieempfehlung

Ultraschnelle Metabolisierer (1-2%) Therapie mit Amitriptylin nicht empfohlen, alternativen Wirkstoff verordnen

Schnelle Metabolisierer (77-92%) Anwendung gemäß Fachinformation

Intermediäre Metabolisierer (2-11%) Reduzierung der Startdosis um 25 Prozent

Langsame Metabolisierer (5-10%) Therapie mit Amitriptylin nicht empfohlen, alternativen Wirkstoff verordnen



Tabelle 2: Empfehlungen für die Amitriptylin-Therapie in Abhängigkeit vom CYP2C19-Genotyp

CYP2C19-Metabolisierungstyp Therapieempfehlung

Ultraschnelle Metabolisierer (5-30%) Therapie mit Amitriptylin nicht empfohlen, alternativen Wirkstoff verordnen


Intermediäre Metabolisierer (18-45%) Anwendung gemäß Fachinformation

Langsame Metabolisierer (2-15%) Reduzierung der Startdosis um 50 Prozent

Kosten

Die Kosten für die Genanalysen werden für gesetzlich und privat versicherte Patienten erstattet, wenn die Testung durch einen Arzt angeordnet wird. Das Budget des behandelnden Arztes ist dadurch nicht belastet.


Genski test za smanjenje rizika povezanog s primjenom amitriptilina

Lijek

Koje su indikacije i mehanizmi djelovanja amitriptilina?Amitriptilin pripada grupi tricikli�kih antidepresiva. Primjenjuje se u lije�enju depresivnih oboljenja, u prevenciji migrene, te lije�enju neuropatske boli u sklopu cjelokupnog terapijskog koncepta. Mehanizam djelovanja amitriptilina je temeljen na blokiranju ponovne pohrane serotonina i noradrenalina u presinapti�kom neuronu. Amitriptilin modificira osjetljivost razli�itih neurotransmiterskih receptora putem sniženja osjetljivosti receptora ili i smanjenja njihova broja («down-regulation»).

Geni

Koji geni utje�u na djelovanje amitriptilina?Metabolizam amitriptilina se odvija putem enzima CYP2C19 i CYP2D6 što u kona�nici odre�uje njegovo djelovanje. Populacijske studije su utvrdile postojanje nekoliko genetskih varijanti enzima CYP2C19 i CYP2D6 što dovodi do velike varijabilnosti u djelovanju amitriptilina.

Analiza

Što se analizira?Da bi se utvrdio fenotip sposobnosti metaboliziranja lijeka, posebice s osvrtom na gene CYP2C19 i CYP2D6, analizira se genotip bolesnika na naju�estalije polimorfizme gena CYP2C19 (*2,*3,*17) te gena CYP2D6 (*1XN, *2, *2XN, 3*, *4, *5, *6, 9*, *10, *41).

Indikacije

U kojim slu�ajevima je potrebno napraviti analizu?Gensko testiranje bi se trebalo napraviti prije planirane terapije amitriptilinom, kako bi se po potrebi prilagodilo doziranje lijeka ili ordinirala zamjenska terapija.

Preporuke

Na koji na�in se terapija mora prilagoditi rezultatima genske analize?Preporuke su temeljene na smjernicama Clinical Pharmacogenetics Implementation Consortium (CPIC)1 te imaju najvišu klini�ku razinu dokaza 1A.

Tablica 1: Preporuke za lije�enje amitriptilinom ovisno o genotipu CYP2D6

CYP2D6 fenotip metaboliziranja Preporu�ena terapija

Ultra-brzi metabolizatori (UEM) (1-2%)Ne preporucuje se lijecenje amitriptilinom. Potrebno je ordinirati zamjensku terapiju

Ekstenzivni metabolizatori (EM) (77-92%) Terapija sukladno uputama o lijeku (Informacijama za korisnika)

Intermedijarni metabolizatori (IM) (2-11%) Potrebno je smanjiti pocetnu dozu za 25 posto

Spori metabolizatori (PM) (5-10%)Ne preporucuje se lijecenje amitriptilinom. Potrebno je ordinirati zamjensku terapiju.



Tablica 2: Preporuke za lije�enje amitriptilinom ovisno o CYP2C19 genotipu

CYP2C19 fenotip metaboliziranja Preporu�ena terapija

Ultra-brzi metabolizatori (UEM) (5-30%)Ne preporucuje se terapija amitriptilinom. Potrebno je ordinirati zamjensku terapiju.

Brzi metabolizatori (EM) (35-50%) Terapija sukladno uputama o lijeku (Informacijama za korisnika)

Intermedijarni metabolizatori (IM) (18-45%) Terapija sukladno uputama o lijeku (Informacijama za korisnika)

Spori metabolizatori (PM) (2-15%) Potrebno je reducirati pocetnu dozu lijeka za 50 posto

Troškovi

Priznavanje povrata troškova za navedenu analizu varira od države do države. Ukoliko je testiranje ordinirano od strane lije�nika, troškovi za odre�ivanje genotipa CYP2C19 i CYP2D6 biti �e priznati i refundirani za bolesnike koji imaju obvezno i privatno osiguranje, pa budžet nadležnog lije�nika ili institucije u kojoj nadležni lije�nik radi zbog toga ne�e biti optere�en.


Azathioprine Azathioprin

Azatioprin


Gene test to minimise the risks related to a therapy with azathioprine

Drug

What are the indications and the mechanisms of action of azathioprine?Azathioprine is a prodrug and belongs to the group of immunosuppressive drugs mainly used to prevent rejection following allogeneic organ transplantations as well as for the treatment of autoimmune diseases (e.g., rheumatoid arthritis and chronic-inflammatory bowel diseases). Azathioprine is converted to the purine anti-metabolite 6-mercaptopurine by glutathione S-transferase, which antagonistically inhibits purine synthesis as well as DNA and RNA synthesis and thus blocks the propagation of immune cells.

Genes

What genes influence the effect of azathioprine?Following the conversion of azathioprine into the active agent 6-mercaptopurine, it is inactivated by the enzyme thiopurine methyltransferase (TPMT). In case of genetically caused TPMT deficiency, toxic by-products increasingly accumulate which can lead to myelosuppression with life-threatening side effects due to their cytotoxic potential. In our population, there are known activity-reducing gene variants for the TPMT gene which require an adjustment of the dose in order to increase the tolerability with regard to azathioprine.

Test

What is tested?The genotype of patients is examined with regard to the most common clinically relevant TPMT gene variants (*2, *3A, *3B, *3C and *4) which in compound heterozygous or homozygous state lead to a complete loss of the TPMT enzyme activity.

Indication

When should a test be carried out?Genetic testing should be carried out before the initiation of the scheduled therapy with azathioprine in order to reduce the risk of myelosuppression, as required, by means of an adjustment of the initial dose or by prescribing an alternative active agent. In 30-60 percent of patients with a heterozygous TPMT risk genotype, the standard dose involves the risk of side effects.


How does the therapy need to be adjusted to the test results?The following recommendations are based on the guidelines of the Clinical Pharmacogenetics Implementation Consortium (CPIC)1 and have the highest clinical level of evidence, 1A.

Table 1: Recommendations for azathioprine therapy depending on the TPMT genotype

TPMT genotype Recommended therapy

Wild type Use according to the summary of product characteristics

Risk variant, heterozygous Initial dose should correspond to 30-70 percent of the normal dose

Risk variant, compound heterozygous or homozygous Change of the active agent or drastic reduction of the initial dose (10-fold reduction and only on 3 days / week)

Costs

Costs for the TPMT gene analysis are reimbursed for patients with a statutory or private health insurance if the testing is requested by a doctor. The budget of the doctor responsible for treatment is not affected.

1 Clinical pharmacogenetics implementation consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing: 2013 update. Relling MV, Gardner EE, Sandborn WJ, Schmiegelow K, Pui CH, Yee SW, Stein CM, Carrillo M, Evans WE, Hicks JK, Schwab M, Klein TE Clin Pharmacol Ther. 2013 93(4): pp. 324-325 (PMID: 23422873)


Gentest zur Risikominimierung der Therapie mit Azathioprin

Arzneimittel

Wie sind die Indikationen und der Wirkmechanismus von Azathioprin?Azathioprin ist ein Prodrug aus der Gruppe der Immunsuppressiva, das vorrangig zur Vorbeugung von Abstoßungsreaktionen nach allogenen Organtransplantationen sowie zur Behandlung von Autoimmunerkrankungen (u.a. rheumatoide Arthritis und chronisch-entzündliche Darmerkrankungen) eingesetzt wird. Azathioprin wird durch Glutathion-S-Transferase in den Purinantimetaboliten 6-Mercaptopurin umgewandelt, der antagonistisch sowohl die Purinsynthese als auch die DNA- und RNA-Synthese hemmt und dadurch die Vermehrung von Immunzellen blockiert.

Gene

Welche Gene beeinflussen die Wirkung von Azathioprin?Nach der Umwandlung von Azathioprin in den aktiven Wirkstoff 6-Mercatopurin wird dieser durch das Enzym Thiopurin-Methyltransferase (TPMT) inaktiviert. Bei einer genetisch bedingten TPMT-Defizienz kumulieren vermehrt toxische Nebenprodukte, die durch ihr cytotoxisches Potenzial zu einer Myelosuppression mit lebensbedrohenden Nebenwirkungen führen können. Für das TPMT-Gen sind in der Bevölkerung aktivitätsmindernde Genvarianten bekannt, die eine Dosierungsanpassung erforderlich machen, um die Verträglichkeit von Azathioprin zu erhöhen.

Test

Was wird getestet?Das Erbgut der Patienten wird auf die häufigsten klinisch relevanten TPMT-Genvarianten (*2, *3A, *3B, *3C und *4) untersucht, die compound heterozygot oder homozygot zum kompletten Verlust der TPMT-Enzymaktivität führen.

Indikation

Wann sollte getestet werden?Der Gentest sollte vor Beginn einer geplanten Therapie mit Azathioprin durchgeführt werden, um gegebenenfalls durch eine Anpassung der Startdosis oder die Verordnung eines alternativen Wirkstoffs das Risiko einer Myelosuppression zu senken. Bei 30-60 Prozent der Patienten mit einem heterozygoten TPMT-Risikogenotyp ist die Standarddosierung mit dem Risiko von Nebenwirkungen verbunden.



Tabelle1: Empfehlungen für die Azathioprin-Therapie in Abhängigkeit vom TPMT-Genotyp

TPMT-Genotyp Therapieempfehlung

Wildtyp Anwendung gemäß der Fachinformationen

Risikovariante, heterozygot Die Startdosis sollte 30-70 Prozent der normalen Dosierung entsprechen

Risikovariante, compound heterozygot oder homozygotWirkstoffwechsel oder drastisch reduzierte Startdosis (10-fach reduziert und nur an 3 Tagen/Woche)

Kosten

Die Kosten für die genetische Analyse des TPMT-Gens werden erstattet für gesetzlich und privat versicherte Patienten, wenn die Testung durch einen Arzt angeordnet wird. Das Budget des behandelnden Arztes wird dadurch nicht belastet.

1 Clinical pharmacogenetics implementation consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing: 2013 update. Relling MV, Gardner EE, Sandborn WJ, Schmiegelow K, Pui CH, Yee SW, Stein CM, Carrillo M, Evans WE, Hicks JK, Schwab M, Klein TE Clin Pharmacol Ther. 2013 93(4): S. 324-325 (PMID: 23422873)


Genski test za smanjenje rizika pri primjene azatioprina

Lijek

Koje su indikacije za primjenu i mehanizmi djelovanja azatioprina?Azatioprin je prolijek iz skupine imunosupresiva, koji se prvenstveno primjenjuju u svrhu prevencije reakcije odbacivanja nakon transplatacije alogenskih organa kao i lije�enja autoimunih bolesti (izme�u ostaloga reumatskog artritisa te kroni�nih upalnih bolesti crijeva). Azatioprin se putem glutation S-antitransferaze pretvara u purinski antimetabolit, 6-merkaptopurin (6-MP) koji zaustavlja sintezu purinskih nukleozida te posljedi�no DNA te RNA sintezu. Lijek na taj na�in blokira propagaciju stanica imunološkog sustava, izme�u ostalog i aktivacijom apoptoze.

Geni

Koji geni utje�u na djelovanje azatioprina?Nakon pretvaranje azatioprina u 6-merkaptopurin, ta se aktivna tvar putem enzima tiopurin-metiltransferaze (TPMT) inaktivira. Kod geneti�ki uvjetovanog nedostatka TPMT akumuliraju se toksi�ki nusproizvodi koji zbog svojeg citotoksi�nog potencijala mogu dovesti do ošte�enja funkcije koštane srži (mijelosupresija) s nuspojavama opasnim po život. Vezano za gen TPMT, populacijske studije su utvrdile postojanje više varijanti gena koje smanjuju aktivnost TPMT gena te je stoga nužno prilagoditi doziranje u svrhu pove�anja podnošljivosti azatioprina.

Analiza

Što se analizira?Analiziraju se naju�estalije klini�ki relevantne varijante gena TPMT (*2, *3A, *3B, *3C i *4) koje u kombinirani (združeni) heterozigot ili homozigota za posljedicu imaju potpuni gubitak aktivnosti enzima TPMT.

Indikacije

U kojim je slu�ajevima potrebno napraviti analizu?Gensko testiranje bi se trebalo napraviti prije planirane terapije s azatioprinom, kako bi se smanjio rizik ošte�enja koštane srži (mijelosupresije) putem prilagodbe po�etne doze ili po potrebi ordiniranja zamjenskog lijeka. Kod 30-60 posto pacijenata, koji su heterozigoti za rizi�ni genotip TPMT primjena standardne doze je povezana s rizikom razvoja nuspojava.

Posljedice rezultata testova

Na koji na�in treba prilagoditi terapiju rezultatima testa?Preporuke su temeljene na smjernicama Clinical Pharmacogenetics Implementation Consortium (CPIC)1 te imaju najvišu klini�ku razinu dokaza 1A.

Tabela 1: Preporuke za lije�enje azatioprinom ovisno o genotipu - TPMT

Genotip TPMT Preporu�ena terapija

Homozigoti bez mutacija wt/wt Terapija sukladno uputama o lijeku (Informacijama za korisnika)

Rizicna varijanta, heterozigot Pocetna doza trebala bi iznositi 30-70 posto prosjecne doze lijeka

Rizicna varijanta, kombinirani (združeni) heterozigot («compound heterozygous)» ili homozigot

Promjena lijeka ili drasticno smanjena pocetna doza (10-terostruko reducirana i samo 3 dana/tjedno)

Troškovi

Priznavanje i povrat troškova za navedenu analizu varira od države do države. Ukoliko je testiranje ordinirano od strane lije�nika, troškovi za analizu gena TPMT biti �e priznati i refundirani za bolesnike koji imaju obvezno i privatno osiguranje, pa budžet nadležnog lije�nika ili institucije u kojoj nadležni lije�nik radi zbog toga ne�e biti optere�en.

1 Clinical pharmacogenetics implementation consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing: 2013 update. Relling MV, Gardner EE, Sandborn WJ, Schmiegelow K, Pui CH, Yee SW, Stein CM, Carrillo M, Evans WE, Hicks JK, Schwab M, Klein TE Clin Pharmacol Ther. 2013 93(4): S. 324-325 (PMID: 23422873)


Carbamazepine Carbamazepin Karbamazepin


Gene test to minimise the risks related to therapy with carbamazepine

Drug

What are the indications and the mechanisms of action of carbamazepine?Carbamazepine is the most frequently prescribed anticonvulsant drug and is used for the treatment of different forms of epilepsy, neuropathic pain, bipolar disorders and for co-treatment during alcohol withdrawal. Carbamazepine suppresses the excitability of nerve cells by blocking the sodium channels of the cell membrane. It furthermore inhibits the release of the neurotransmitter glutamate.

Genes

What genes influence the effect of carbamazepine?Approximately 5-10 percent of patients present with different side effects under carbamazepine therapy, such as central nervous disorders, problems with the gastrointestinal tract or haematopoietic changes to mention just a few examples. On the other hand, the drug can cause severe immunological hypersensitivity reactions in patients who carry the HLA alleles HLA-A*31:01 (HLA-A gene) or HLA-B*15:02 (HLA-B gene) which manifest themselves as Stevens-Johnson syndrome (SJS) or as toxic epidermal necrolysis (TEN).

Test

What is tested?The genotype of patients is tested with regard to the alleles HLA-A*31:01 and HLA-B*15:02 in the HLA-A and HLA-B genes.

Indication

When should a test be carried out?Genetic testing should be carried out before the initiation of the scheduled therapy with carbamazepine in order to change the active agent, as required, so that severe side effects can be avoided.


How does the therapy need to be adjusted to the test results?The following recommendations are based on the guidelines of the Clinical Pharmacogenetics Implementation Consortium (CPIC)1 and of the Canadian Pharmacogenomics Network for Drug Safety (CPNDS)2. The recommendations have high clinical evidence.

Table 1: Recommendations for carbamazepine therapy depending on the HLA-gene A and B genotype

HLA genotype Recommended therapy

HLA-B*15:02 and HLA-A*31:01 negative Therapeutic dose according to the summary of product characteristics

HLA-B*15:02 or HLA-A*31:01 heterozygous, compound heterozygous or homozygous

Use alternative active agents

Costs

Costs for the determination of the HLA-A and HL-B gene are reimbursed for patients with a statutory or private health insurance if testing is requested by a doctor. The budget of the doctor responsible for treatment is not affected.

1 Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B genotype and carbamazepine dosing. Leckband SG, Kelsoe JR, Dunnenberger HM, George AL Jr, Tran E, Berger R, Müller DJ, Whirl-Carrillo M, Caudle KE, Pirmohamed M Clin Pharmacol Ther. 2013 94(3) : pp. 324-328 PMID: 236951852 Recommendations for HLA-B*15:02 and HLA-A*31:01 genetic testing to reduce the risk of carbamazepine-induced hypersensitivity reactions. Amstutz U, Shear NH, Rieder MJ, Hwang S, Fung V, Nakamura H, Connolly MB, Ito S, Carleton BC Epilepsia. 2014 55(4): pp. 496-506 PMID: 24597466


Gentest zur Risikominimierung der Therapie mit Carbamazepin

Arzneimittel

Wie sind die Indikationen und der Wirkmechanismus von Carbamazepin?Carbamazepin ist eines der am häufigsten verordneten Antikonvulsiva. Es wird zur Behandlung verschiedener Formen der Epilepsie, bei Neuralgien, der bipolaren Störung und zur Begleitung des Alkoholentzugs eingesetzt. Carbamazepin unterdrückt die Erregbarkeit von Nervenzellen durch eine Blockade der Natriumkanäle in der Zellmembran. Es inhibiert außerdem die Freisetzung des Neurotransmitters Glutamat.

Gene

Welche Gene beeinflussen die Wirkung von Carbamazepin?Ca. 5-10 Prozent der Patienten beklagen unter einer Carbamazepin-Therapie verschiedenartige Nebenwirkungen, wie zentralnervöse Störungen, Probleme im Magen-Darm-Trakt, Blutbildungsveränderungen, um einige zu nennen. Demgegenüber kann das Medikament bei Patienten, die Träger der HLA-Allele HLA-A*31:01 (HLA-A-Gen) oder HLA-B*15:02 (HLA-B-Gen) sind, schwerste immunologische Überempfindlichkeitsreaktionen auslösen, die sich als Stevens-Johnson-Syndrom (SJS) oder in einer toxischen epidermalen Nekrolyse (TEN) manifestieren.

Test

Was wird getestet?Das Erbgut der Patienten wird auf die Allele HLA-A*31:01 (HLA-A–Gen) und HLA-B*15:02 (HLA-B-Gen) getestet.

Indikation

Wann sollte getestet werden?Der Gentest sollte vor Beginn einer geplanten Therapie mit Carbamazepin durchgeführt werden, um gegebenenfalls einen Wirkstoffwechsel vorzunehmen und schwere Nebenwirkungen zu vermeiden.


Wie muss die Therapie an die Testergebnisse angepasst werden?Die folgende Empfehlung basiert auf der Leitlinie des Clinical Pharmacogenetics Implementation Consortium (CPIC)1 und der Leitlinie des Canadian Pharmacogenomics Network for Drug Safety (CPNDS)2. Die Empfehlung hat hohe klinische Evidenz.

Tabelle 1 : Empfehlungen für die Carbamazepin-Therapie in Abhängigkeit vom Genotyp der HLA-Gene A und B

HLA-Genotyp Therapieempfehlungen

HLA-B*15:02 und HLA-A*31:01, negativ Therapiedosis gemäß Fachinformation

HLA-B*15:02 oder HLA-A*31:01, heterozygot, compound heterozygot oder homozygot

alternativen Wirkstoff einsetzen

Kosten

Die Kosten für die Bestimmung der HLA-A- und HLA-B-Gene werden für gesetzlich und privat versicherte Patienten erstattet, wenn die Testung durch einen Arzt angeordnet wird. Das Budget des behandelnden Arztes ist dadurch nicht belastet.

1 Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B genotype and carbamazepine dosing. Leckband SG, Kelsoe JR, Dunnenberger HM, George AL Jr, Tran E, Berger R, Müller DJ, Whirl-Carrillo M, Caudle KE, Pirmohamed M Clin Pharmacol Ther. 2013 94(3) : S. 324-328 PMID: 236951852 Recommendations for HLA-B*15:02 and HLA-A*31:01 genetic testing to reduce the risk of carbamazepine-induced hypersensitivity reactions. Amstutz U, Shear NH, Rieder MJ, Hwang S, Fung V, Nakamura H, Connolly MB, Ito S, Carleton BC Epilepsia. 2014 55(4): S. 496-506 PMID: 24597466


Genski test za smanjenje rizika pri primjeni lijeka karbamazepina

Lijek

Koje su indikacije za primjenu i mehanizmi djelovanja karbamazepina?Karbamazepin je jedan od naj�eš�e ordiniranih antikonvulzivnih lijekova. Primjenjuje se u lije�enju razli�itih oblika epilepsije, neuropatske boli, kod bipolarnih poreme�aja te kod odvikavanja od alkohola. Karbamazepin suprimira podražljivost živ�anih stanica putem blokade natrijskih kanala unutar stani�ne membrane, te inhibira osloba�anje neurotransmitera glutamata.

Geni

Koji geni utje�u na djelovanje karbamazepina? Tijekom lije�enja karbamazepinom, 5-10 posto pacijenata žali se na razli�ite nuspojave (smetnje središnjeg živ�anog sustava, problemi s probavnim sustavom, promjena krvne slike, itd.). Nasuprot tomu ovaj lijek može kod pacijenata koji su nositelji alela HLA-A*31:01 (gen HLA-A) ili alela HLA-B*15:02 (gen HLA-B) izazvati tešku imunološku reakcije preosjetljivosti koji se manifestira kao Stevens-Johnson-sindrom (SJS) ili kao toksi�na epidermalna nekroliza (TEN).

Analiza

Što se analizira?Analizira se genotip pacijenata, prvenstveno aleli HLA-A*31:01 (gen HLA-A) i HLA-B*15:02 (gen HLA-B).

Indikacije

U kojim je slu�ajevima potrebno napraviti analizu?Gensku analizu je potrebno napraviti prije po�etka lije�enja karbamazepinom, kako bi se pravovremeno ordinirala zamjenska terapija i izbjegle teže nuspojave.

Peporuke

Na koji na�in se terapija mora prilagoditi rezultatima testa?Preporuke su temeljene na smjernicama Clinical Pharmacogenetics Implementation Consortium (CPIC)1 i smjernicama Canadian Pharmacogenomics Network for Drug Safety (CPNDS)2. Preporuke imaju visoku klini�ku razinu dokaza.

Tabela 1: Preporuke za terapiju karbamazepinom ovisno o genima HLA A i B

HLA-Genotip Preporu�ena terapija

HLA-B*15:02 i HLA-A*31:01, negativan Terapija sukladno uputama o lijeku (Informacijama za korisnika)

HLA-B*15:02 ili HLA-A*31:01, heterozigot, kombinirani (združeni) heterozigot («compound heterozygous)» ili homozigot

Primjena alternativnog lijeka

Troškovi

Priznavanje i povrat troškova za navedenu analizu varira od države do države. Ukoliko je testiranje ordinirano od strane lije�nika, troškovi za odre�ivanje HLA-A i HLA-B genotipova biti �e priznati i refundirani za pacijente koji imaju obvezno i privatno osiguranje, pa budžet nadležnog lije�nika ili institucije u kojoj nadležni lije�nik radi zbog toga ne�e biti optere�en.

1 Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B genotype and carbamazepine dosing. Leckband SG, Kelsoe JR, Dunnenberger HM, George AL Jr, Tran E, Berger R, Müller DJ, Whirl-Carrillo M, Caudle KE, Pirmohamed M Clin Pharmacol Ther. 2013 94(3) : S. 324-328 PMID: 236951852 Recommendations for HLA-B*15:02 and HLA-A*31:01 genetic testing to reduce the risk of carbamazepine-induced hypersensitivity reactions. Amstutz U, Shear NH, Rieder MJ, Hwang S, Fung V, Nakamura H, Connolly MB, Ito S, Carleton BC Epilepsia. 2014 55(4): S. 496-506 PMID: 24597466


Clopidogrel Clopidogrel Klopidogrel


Gene test to minimise the risks related to therapy with clopidogrel

Drug

What are the indications and the mechanism of action of clopidogrel?Clopidogrel is a platelet function inhibitor that is used for therapy after atherothrombotic events (among other things, heart attack and stroke) as well as for ischemia with peripheral artery disease, acute coronary syndrome and after stent implantation. As a prodrug, clopidogrel is converted in the liver into a pharmacologically active thiol derivative which irreversibly inhibits the binding of adenosine diphosphate (ADP) to the platelet receptor (P2Y12), thereby prevents ADP-dependent platelet aggregation and thus inhibits blood clotting. Blood platelets blocked by clopidogrel remain incapable of clotting throughout their entire lifespan (7-10 days).

Genes

Which genes influence the effect of clopidogrel?Clopidogrel is converted in the liver by the enzyme CYP2C19 into the active ingredient. Whether the targeted level of active ingredient in the blood is achieved is particularly dependent on the activity of the CYP2C19 enzyme. Based on which influence the CYP2C19 gene variants have on the enzyme activity, a distinction is made between poor, intermediate, extensive and ultra-rapid metabolizers for clopidogrel.

Test

What will be tested?In order to determine the CYP2C19 metabolism type, the patient’s genotype is tested for the two most common activity-reducing gene variants (*2 and *3) as well as the activity-increasing variant (*17).

Indication

When should a test be performed?The genetic test should be performed before the start of planned therapy with clopidogrel in order to consider a change of active ingredient if necessary and in order to avoid serious adverse effects.



Table 1: Recommendations for clopidogrel therapy subject to CYP2C19 metabolism type


Ultra-rapid metabolizer (5-30%) Therapy in accordance with Summary of Product Characteristics

Extensive metabolizer (35-50%) Therapy in accordance with Summary of Product Characteristics

Intermediate metabolizer (18-45%) Change of active ingredient recommended

Poor metabolizer (2-15%) Change of active ingredient recommended

Costs

Costs for the genetic analysis of the CYP2C19 gene will be reimbursed for statutory and privately insured patients if the testing is prescribed by a physician. The attending physician’s budget is not burdened as a result.

1 Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Scott SA, Sangkuhl K, Stein CM, Hulot JS, Mega JL, Roden DM, Klein TE, Sabatine MS, Johnson JA, Shuldiner AR Clin Pharmacol Ther. 2013 94(3):317-323 (PMID: 23698643)


Gentest zur Risikominimierung der Therapie mit Clopidogrel

Arzneimittel

Wie sind die Indikationen und der Wirkmechanismus von Clopidogrel?Clopidogrel ist ein Thrombozytenfunktionshemmer, der sowohl zur Therapie nach atherothrombotischen Ereignissen (u.a. Herzinfarkt, Schlaganfall), als auch zur Prävention einer Ischämie bei peripherer arterieller Verschlusskrankheit, akutem Koronarsyndrom und nach einer Stentimplantation eingesetzt wird. Als Prodrug wird Clopidogrel in der Leber in ein pharmakologisch wirksames Thiolderivat umgewandelt, welches die Bindung von Adenosindiphosphat (ADP) an den Thrombozytenrezeptor (P2Y12) irreversibel hemmt, dadurch die ADP-abhängige Thrombozytenaggregation unterbindet und so die Blutgerinnung hemmt. Durch Clopidogrel blockierte Thrombozyten bleiben während ihrer gesamten Lebensdauer (7-10 Tage) gerinnungsunfähig.

Gene

Welche Gene beeinflussen die Wirkung von Clopidogrel?Clopidogrel wird in der Leber durch das Enzym CYP2C19 in den aktiven Wirkstoff umgewandelt. Ob der angestrebte Wirkstoffspiegel im Blut erreicht wird, ist insbesondere von der Aktivität des CYP2C19-Enzyms abhängig. Ausgehend davon, welchen Einfluss die CYP2C19-Genvarianten auf die Enzymaktivität haben, unterscheidet man langsame, intermediäre, schnelle und ultraschnelle Metabolisierer für Clopidogrel.

Test

Was wird getestet?Um den CYP2C19-Metabolisierungstyp zu ermitteln, wird das Erbgut der Patienten sowohl auf die zwei häufigsten aktivitätsmindernden Genvarianten (*2 und *3) als auch auf die aktivitätssteigernde Variante (*17) untersucht.

Indikation

Wann sollte getestet werden?Der Gentest sollte vor Beginn einer geplanten Therapie mit Clopidogrel durchgeführt werden, um gegebenenfalls einen Wirkstoffwechsel in Erwägung zu ziehen, um schwere Nebenwirkungen zu vermeiden.



Tabelle 1: Empfehlungen für die Clopidogrel-Therapie in Abhängigkeit vom CYP2C19-Metabolisierungstyp


Ultraschnelle Metabolisierer (5-30%) Therapie gemäß Fachinformation

Schnelle Metabolisierer (35-50%) Therapie gemäß Fachinformation

Intermediäre Metabolisierer (18-45%) Wirkstoffwechsel empfohlen

Langsame Metabolisierer (2-15%) Wirkstoffwechsel empfohlen

Kosten

Die Kosten für die genetische Analyse des CYP2C19-Gens werden für gesetzlich und privat versicherte Patienten erstattet, wenn die Testung durch einen Arzt angeordnet wird. Das Budget des behandelnden Arztes wird dadurch nicht belastet.

1 Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Scott SA, Sangkuhl K, Stein CM, Hulot JS, Mega JL, Roden DM, Klein TE, Sabatine MS, Johnson JA, Shuldiner AR Clin Pharmacol Ther. 2013 94(3): S. 317-323 (PMID: 23698643)


Genski test za smanjenje rizika pri primjeni klopidogrela

Lijek

Koje su indikacije za primjenu i mehanizmi djelovanja klopidogrela?Klopidogrel inhibira funkciju trombocita (antitrombocitni lijek) te se primjenjuje nakon stvaranja krvnih ugrušaka (tromba) u otvrdnutim krvnim žilama (arterijama) u procesu zvanom aterotromboza, koji dovodi do moždanog i sr�anog udara ili �ak smrti. Klopidogrel se korisiti i u lije�enju ishemi�nih procesa vezanih uz bolest perifernih arterija, akutnog koronarnog sindroma te nakon implantacije stenta. Klopidogrel se u jetri pretvara u farmakološki djelotvorni (aktivni metabolit) tiol-derivat koji ireverzibilno inhibira vezivanje adenozin difosfata (ADP) za receptor trombocita (P2Y12), �ime se zaustavlja agregacija trombocita ovisna o ADP i na taj na�in sprje�avanjem agregacije trombocita zaustavlja zgrušavanje krvi. Trombociti koji su blokirani klopidogrelom, trajno su ošte�eni i za vrijeme svojeg životnog vijeka (7-10 dana) nemaju sposobnost zgrušanja krvi, a normalna funkcija zgrušavanja se obnavlja tek stvaranjem novih trombocita.

Geni

Koji geni utje�u na djelovanje klopidogrela? Klopidogrel se prvenstveno putem enzima CYP2C19 pretvara u aktivnu tvar ili aktivni metabolit. Da li �e razina aktivne tvari u krvi biti dosegnuta posebice ovisi o aktivnosti enzima CYP2C19. Drugim rije�ima, varijanta gena CYP2C19 direktno utje�e na aktivnost enzima i sukladno tome razlikujemo spore, intermedijarne, brze i ultra brze metabolizatore za klopidogrel.

Analiza

Što se analizira?Da bi se ustanovio fenotip vezan uz sposobnost metaboliziranja lijeka putem enzima CYP2C19, analiziraju se dvije naju�estalije varijante gena CYP2C19: (*2 i *3) koje dovode do smanjene aktivnosti enzima te varijanta (*17) koja dovodi do poja�ane aktivnosti enzima.

Indikacije

U kojim slu�ajevima je potrebno napraviti analizu?Gensko testiranje bi trebalo provesti prije po�etka terapije sa klopidogrelom kako bi se po potrebi ordinirala zamjenska terapija u svrhu sprje�avanja ozbiljnih nuspojava.


Na koji na�in se terapija mora prilagoditi rezultatima testa?Preporuke su temeljene na smjernicama Clinical Pharmacogenetics Implementation Consortium (CPIC)1 i imaju najvišu klini�ku razinu dokaza 1A.

Tabela 1: Preporuke za lije�enje klopidogrelom ovisno o fenotipu metaboliziranja lijeka putem CYP2C19

CYP2C19 fenotip metaboliziranja Preporu�ena terapija

Ultra-brzi metabolizatori (UEM) (5-30%) Terapija sukladno uputama o lijeku (Informacijama za korisnika)

Ekstenzivni metabolizatori (EM) (35-50%) Terapija sukladno uputama o lijeku (Informacijama za korisnika)

Intermedijarni metabolizatori (IM) (18-45%) Preporuca se promjena lijeka

Slabi metabolizatori (PM) (2-15%) Preporuca se promjena lijeka

Troškovi

Priznavanje i povrat troškova za navedenu analizu varira od države do države. Ukoliko je testiranje ordinirano od strane lije�nika, troškovi analize CYP2C19 biti �e priznati i refundirani za bolesnike koji imaju obvezno i privatno osiguranje pa budžet nadležnog lije�nika ili institucije u kojoj nadležni lije�nik radi zbog toga ne�e biti optere�en.

1 Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Scott SA, Sangkuhl K, Stein CM, Hulot JS, Mega JL, Roden DM, Klein TE, Sabatine MS, Johnson JA, Shuldiner AR Clin Pharmacol Ther. 2013 94(3): S. 317-323 (PMID: 23698643)


Codeine Codein Kodein


Gene test to minimise the risks related to therapy with codeine

Drug

What are the indications and the mechanism of action of codeine?Codeine is a morphine derivative from the class of opiates that due to its analgesic, antitussive and light sedative effects is commonly used for treatment of dry cough and in combination with other active ingredients such as paracetamol, acetylsalicylic acid or diclofenac for treatment of moderately severe to severe pain. Codeine is converted in the liver to a small proportion (approx. 10%) into the pharmacologically more active morphine. The opioid effect of both morphines is mediated through the binding to opiate receptors, whereby for codeine the affinity to the µ-receptor and therefore also the rate of binding compared to morphine is much less.

Genes

Which genes influence the effect of codeine?The enzyme CYP2D6 catalyses the demethylation reaction of codeine to morphine. Since the latter is the much stronger opiate of the two, the CYP2D6 enzyme activity determines the level of the codeine/morphine ratio and therefore also the strength of the opiate effect. A variety of activity-reducing gene variants as well as activity-increasing gene duplications which cause a large fluctuation range of enzyme activity are known for the CYP2D6 gene.

Test

What will be tested?In order to determine the CYP2D6 metabolism type, the patient’s genotype is tested for the most common activity-reducing gene variants in the CYP2D6 gene as well as for the number of active gene copies.

Indication

When should a test be performed?The genetic test should be performed before the start of planned therapy with codeine in order to make a change of therapy with the suitable active ingredient if necessary.



Table 1: Recommendations for codeine therapy subject to CYP2D6 metabolism type

CYP2D6 metabolism type Therapy recommendation

Ultra-rapid metabolizer (1-2%) Change of active ingredient recommended


Intermediate metabolizer (2-11%) Use in accordance with Summary of Product Characteristics

Poor metabolizer (5-10%) Change of active ingredient recommended

Costs

Costs for the CYP2D6 genetic analysis will be reimbursed for statutory and privately insured patients if the testing is prescribed by a physician. The attending physician’s budget is not burdened as a result.

1 Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Crews KR, Gaedigk A, Dunnenberger HM, Leeder JS, Klein TE, Caudle KE, Haidar CE, Shen DD, Callaghan JT, Sadhasivam S, Prows CA, Kharasch ED, Skaar TC; Clinical Pharmacogenetics Implementation Consortium. Clin Pharmacol Ther. 2014 95(4):376-82 (PMID: 24458010)


Gentest zur Risikominimierung der Therapie mit Codein

Arzneimittel

Wie sind die Indikationen und der Wirkmechanismus von Codein?Codein ist ein Morphinderivat aus der Klasse der Opiate, das auf Grund seiner analgetischen, antitussiven und leicht sedierenden Wirkung häufig zur Behandlung von Reizhusten und in Kombination mit anderen Wirkstoffen wie Paracetamol, Acetylsalicylsäure oder Diclofenac zur Behandlung von mäßig starken bis starken Schmerzen eingesetzt wird. Codein wird in der Leber zu einem geringen Teil (ca. 10%) in das pharmakologisch wirksamere Morphin umgewandelt. Die opioide Wirkung beider Morphine wird durch die Bindung an Opiatrezeptoren vermittelt, wobei für Codein die Affinität zum µ-Rezeptor und damit auch die Bindungsrate im Vergleich zum Morphin wesentlich geringer ist.

Gene

Welche Gene beeinflussen die Wirkung von Codein?Das Enzym CYP2D6 katalysiert die Demethylierungsreaktion von Codein zu Morphin. Da letzteres das wesentlich stärkere Opiat von beiden ist, bestimmt die CYP2D6-Enzymaktivität die Höhe des Codein/Morphin-Ratios und damit auch die Stärke der Opiatwirkung. Für das CYP2D6-Gen sind eine Vielzahl sowohl aktivitätsmindernder Genvarianten als auch aktivitätssteigernde Genduplikationen bekannt, die eine große Schwankungsbreite der Enzymaktivität bedingen.

Test

Was wird getestet?Um den CYP2D6-Metabolisierungstyp zu ermitteln, wird das Erbgut der Patienten sowohl auf die häufigsten aktivitätsmindernden Genvarianten im CYP2D6-Gen als auch auf die Anzahl der aktiven Genkopien untersucht.

Indikation

Wann sollte getestet werden?Der Gentest sollte vor Beginn einer geplanten Therapie mit Codein durchgeführt werden, um gegebenenfalls eine Therapieänderung mit dem passenden Wirkstoff vorzunehmen.



Tabelle 1: Empfehlungen für die Codein-Therapie in Abhängigkeit vom CYP2D6-Metabolisierungstyp


Ultraschnelle Metabolisierer (1-2%) Wirkstoffwechsel empfohlen


Intermediäre Metabolisierer (2-11%) Anwendung gemäß Fachinformation

Langsame Metabolisierer (5-10%) Wirkstoffwechsel empfohlen

Kosten

Die Kosten für die CYP2D6-Genanalyse werden für gesetzlich und privat versicherte Patienten erstattet, wenn die Testung durch einen Arzt angeordnet wird. Das Budget des behandelnden Arztes ist dadurch nicht belastet.



Genski test za smanjenje rizika pri primjeni kodeina

Lijek

Koje su indikacije za primjenu i mehanizmi djelovanja kodeina?Kodein je sintetski derivat morfija, spada u skupinu opiodnih lijekova. U opiodne lijekove ubrajamo potpune agoniste, parcijalne agoniste i antagoniste. Morfin je potpuni agonist µ (mi) opiodnog receptora koji je ujedno i glavni opiodni receptor. Za razliku od njega kodein je parcijalni ili slabi agonist µ receptora. U jetri se morfin u manjem dijelu (oko 10%) metabolizira preko jetrenog enzima CYP2D6 u svoj aktivni metabolit morfin s u�inkom 4-6 puta ja�im od ishodne molekule. Ima analgetski, antitusivni u�inak i lagano sediraju�e djelovanje. �esto se kombinira s drugim lijekovima kao što su paracetamol, acetilsalicilna kiselina ili diklofenak u lije�enju umjereno jake do jake boli.

Geni

Koji geni utje�u na djelovanje kodeina?Enzim CYP2D6 katalizira demetilaciju kodeina u morfin. Budu�i da se kod zadnjega radi o znatno ja�em opijatu, aktivnost enzima CYP2D6 odre�uje odnos kodeina i morfina i samim time i u�inak djelovanja opiodnih lijekova. Za gen CYP2D6 su poznate brojne varijante gena koje umanjuju aktivnost enzima, ali i varijante gena koje pove�avaju aktivnost enzima (zbog duplikacije gena) te posljedi�no doprinose velikoj varijabilnosti aktivnosti enzima

Analiza

Što se analizira?Da bi se ustanovila sposobnost metaboliziranja lijeka ovisna o genu CYP2D6, analiziraju se naju�estalije varijante gena koje dovode do smanjenja aktivnosti enzima kao i broj aktivnih kopija gena što u kona�nici dovodi do pove�ane aktivnosti enzima.

Indikacije

U kojim je slu�ajevima potrebno napraviti analizu?Gensko testiranje bi se trebao provesti prije planirane terapije kodeinom kako bi se eventualno prilagodilo doziranje ili promjena lijeka te time sprije�ile ozbiljne nuspojave.


Na koji na�in se terapija mora prilagoditi rezultatima testa?Preporuke su utemeljene na smjernicama Clinical Pharmacogenetics Implementation Consortium (CPIC)1 imaju najvišu klini�ku razinu dokaza1A.

Tabela 1: Preporuke za lije�enje kodeinom, ovisno o CYP2D6 fenotipu metaboliziranja lijeka

CYP2D6- fenotip metaboliziranja Preporu�ena terapija

Ultra-brzi metabolizatori (UEM) (1-2%) Preporuca se promjena lijeka

Brzi metabolizatori (EM) (77-92%) Terapija sukladno uputama o lijeku (Informacijama za korisnika)

Intermedijarni metabolizatori (IM) (2-11%) Terapija sukladno uputama o lijeku (Informacijama za korisnika)

Spori metabolizatori (PM) (5-10%) Preporuca se promjena lijeka

Troškovi

Priznavanje i povrat troškova za navedenu analizu varira od države do države. Ukoliko je testiranje ordinirano od strane lije�nika, troškovi za odre�ivanje genotipa CYP2D6 biti �e priznati i refundirani za bolesnike koji imaju obvezno i privatno osiguranje, pa budžet nadležnog lije�nika ili institucije u kojoj nadležni lije�nik radi zbog toga ne�e biti optere�en.



5-Fluorouracil and Capecitabine

5-Fluorouracil und Capecitabine

5-Fluorouracil i Kapecatibin


Gene test to minimise the risks related to therapy with 5-fluorouracil and capecitabine

Drug

What are the indications and the mechanisms of action of 5-fluorouracil and capecitabine?5-fluorouracil and capecitabine belong the group of cytotoxic agents mainly used to treat metastasising large intestinal carcinomas or progressed carcinomas of the breast. Capecitabine is a prodrug converted into the active agent 5-fluorouracil in the tumour. The cytostatic effect of 5-fluorouracil results from an inhibition of DNA and RNA synthesis.

Genes

What genes influence the effect of 5-fluorouracil and capecitabine?As an active agent of capecitabine, 5-fluorouracil is also broken down by the enzyme dihydropyrimidine dehydrogenase (DPYD). In our population, the DPYD gene occurs in several variants. In up to 5 percent of patients, poisoning symptoms with nausea and cardiac arrhythmia occur due to the genetically reduced enzyme activity. Some fatal cases have been reported.

Test

What is tested?The genotype of patients is tested with regard to most common genetic variants (*2, *13 and *9B) which cause a partial or complete loss of the DPYD activity.

Indication

When should a test be carried out?Genetic testing should be carried out before the initiation of the scheduled therapy with 5-fluorouracil or capecitabine in order to reduce the risk of severe side effects, as required, by means of an adjustment of the initial dose or by prescribing an alternative active agent.


How does the therapy need to be adjusted to the test results?The following recommendations are based on the guidelines of the Clinical Pharmacogenetics Implementation Consortium (CPIC)1.

Table 1: Recommendations for the therapy with 5-fluorouracil and/or capecitabine depending on the DPYD genotype

DPYD genotype Recommended therapy

Wild type Therapy according to the summary of product characteristics

Risk variant, heterozygous Reduce standard dose by 50 percent

Risk variant, compound heterozygous or homozygous Use alternative active agents

Costs

Costs for the CPYD gene analysis are reimbursed for patients with a statutory or private health insurance if the testing is requested by a doctor. The budget of the doctor responsible for treatment is not affected.

1 Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing. Caudle KE, Thorn CF, Klein TE, Swen JJ, McLeod HL, Diasio RB, Schwab M. Clin Pharmacol Ther. 2013 94(6): pp. 640-645 PMID: 23988873


Gentest zur Risikominimierung der Therapie mit 5-Fluoruracil und Capecitabin

Arzneimittel

Wie sind die Indikationen und der Wirkmechanismus von 5-Fluoruracil und Capecitabin?5-Fluoruracil und Capecitabin gehören zur Gruppe der Zytostatika, welche bevorzugt bei metastasierten Dickdarm- und fortgeschrittenen Mammakarzinomen eingesetzt werden. Capecitabin ist ein Prodrug, das im Tumor in den aktiven Wirkstoff 5-Fluoruracil umgewandelt wird. Die zytostatische Wirkung von 5-Fluoruracil beruht auf der Hemmung der DNA- und RNA-Synthese.

Gene

Welche Gene beeinflussen die Wirkung von 5-Fluoruracil und Capecitabin?5-Fluoruracil wird als aktiver Wirkstoff von Capecitabin durch das Enzym Dihydropyrimidin-Dehydrogenase (DPYD) abgebaut. Das DPYD-Gen kommt in der Bevölkerung in mehreren Varianten vor. Bei bis zu 5 Prozent der Patienten treten aufgrund einer genetisch verminderten Enzymaktivität Vergiftungserscheinungen mit Übelkeit und Herzrhythmusstörungen auf. Vereinzelt wurden Todesfälle berichtet.

Test

Was wird getestet?Das Erbgut der Patienten wird auf die häufigsten DPYD-Genvarianten (*2, *13 und *9B) getestet, die zum partiellen oder kompletten Verlust der DPYD-Aktivität führen.

Indikation

Wann sollte getestet werden?Der Gentest sollte vor Beginn einer geplanten Therapie mit 5-Fluoruracil bzw. Capecitabin durchgeführt werden, um gegebenenfalls durch eine Anpassung der Startdosis oder die Verordnung eines alternativen Wirkstoffs das Risiko für schwere Nebenwirkungen zu senken.


Wie muss die Therapie an die Testergebnisse angepasst werden?Folgende Empfehlungen basieren auf den Leitlinien des Clinical Pharmacogenetics Implementation Consortium (CPIC)1.

Tabelle 1: Empfehlungen für die Therapie mit 5-Fluoruracil bzw. Capecitapin in Abhängigkeit vom DPYD-Genotyp

DPYD-Genotyp Therapieempfehlung

Wildtyp Therapie gemäß Fachinformation

Risikovariante, heterozygot Standard-Startdosis um 50 Prozent reduzieren

Risikovariante, compound heterozygot oder homozygot alternativen Wirkstoff einsetzen

Kosten

Die Kosten für die Analyse des DPYD-Gens werden für gesetzlich und privat versicherte Patienten erstattet, wenn die Testung durch einen Arzt angeordnet wird. Das Budget des behandelnden Arztes ist dadurch nicht belastet.

1 Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing. Caudle KE, Thorn CF, Klein TE, Swen JJ, McLeod HL, Diasio RB, Schwab M. Clin Pharmacol Ther. 2013 94(6): S. 640-645 (PMID: 23988873)


Genski test za smanjenje rizika pri primjeni 5-fluorouracila i kapecitabina

Lijek

Koje su indikacije i mehanizmi djelovanja 5-fluorouracila i kapecitabina?5-fluorouracil i kapecitabin pripadaju grupi citostatika. Naj�eš�e se koriste u lije�enju metastatskog tumora debelog crijeva te kod uznapredovalog karcinoma dojke. Kapecitabin je prolijek, koji se u jetrima ili u samom tumoru pretvara u aktivni metabolit 5-fluoruracil. Citostatsko djelovanje 5-fluoruracila temelji se na inhibiciji sinteze DNA i RNA.

Geni

Koji geni utje�u na djelovanje 5-fluoruracila i kapecitabina?Kao aktivni metabolit kapecitabina 5-fluoruracil se razgra�uje putem enzima dihidropirimidin dehidrogenaze (DPD). Gen DPYD se me�u stanovništvom pojavljuje u nekoliko varijanti. Kod otprilike 5 posto pacijenata simptomi trovanja popra�eni mu�ninama i sr�anom aritmijom nastupaju zbog genetski uvjetovane smanjene aktivnosti enzima. U literaturi su opisani i smrtni slu�ajevi kao posljedica navedenog.

Analiza

Što se analizira?Analizira se genotip pacijenta na naju�estalije varijante gena DPYD (*2, *13 i *9B) gena koje dovode do parcijalnog ili potpunog gubitka aktivnosti DPD.

Indikacije

U kojim je slu�ajevima potrebno napraviti analizu?Prije zapo�injanja terapije 5-fluorouracilom odnosno kapecitabinom trebalo bi se provesti gensko testiranje da bi se prilagodbom po�etne doze ili po potrebi ordiniranjem drugog lijeka smanjio rizik ozbiljnih nuspojava.

Preporuke

Na koji na�in se terapija mora prilagoditi rezultatima genetske analize?Preporuke su temeljene na smjernicama Clinical Pharmacogenetics Implementation Consortium (CPIC)1.

Tabela 1: Preporuke za lije�enje 5-fluoruracilom i/ili kapecitabinom ovisno o genotipu DPYD

Genotip DPYD Preporu�ena terapija

wt/wt Terapija sukladno uputama o lijeku (Informacijama za korisnika

Rizicna varijanta, heterozigot Potrebno je smanjiti standardnu-pocetnu dozu za 50 posto


Primjena zamjenskog lijeka

Troškovi

Priznavanje i povrat troškova za navedenu analizu varira od države do države. Ukoliko je testiranje ordinirano od strane lije�nika, troškovi analize DPYD biti �e priznati i refundirani za bolesnike koji imaju obvezno i privatno osiguranje, pa budžet nadležnog lije�nika ili institucije u kojoj nadležni lije�nik radi zbog toga ne�e biti optere�en.

1 Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing. Caudle KE, Thorn CF, Klein TE, Swen JJ, McLeod HL, Diasio RB, Schwab M. Clin Pharmacol Ther. 2013 94(6): S. 640-645 (PMID: 23988873)


Ivacaftor Ivacaftor Ivakaftor


Gene test to minimise the risks related to therapy with ivacaftor

Drug

What are the indications and the mechanism of action of ivacaftor?Ivacaftor is used for treatment of cystic fibrosis (mucoviscidosis) among patients with certain mutations in the CFTR gene. Genetic modifications in the CFTR gene on the CFTR protein level lead to loss of function in the chloride channels in the cell membranes of certain somatic cells, whereby viscous secretions occur, including the bronchial mucosa of the lungs, as a result of the insufficient moisture content. The active ingredient ivacaftor is a CFTR potentiator and leads to an improved function of the misdirected chloride channels among patients with certain mutations in the CFTR gene, but can only alleviate the clinical symptoms.

Genes

Which genes influence the effect of ivacaftor?More than 2,000 mutations of the CFTR gene in connection with cystic fibrosis are known at present. According to the present state of knowledge, the pharmacological efficacy of ivacaftor is so far only limited to patients with one of 9 known CFTR variants (4-5% of cystic fibrosis patients). The efficacy has not yet been verified for the other mutations.

Test

What will be tested?The patient’s genotype will be tested for the CFTR gene variants which are sensitive to ivacaftor.

Indication

When should a test be performed?The genetic test should be performed before the start of planned therapy with ivacaftor in order to ensure the therapeutic efficacy of ivacaftor.



Table 1: Recommendations for ivacaftor therapy subject to CFTR genotype

CFTR genotype Therapy recommendation

Homozygosity or compound heterozygosity for following variants Gly551Asp, Gly1244Glu, Gly1349Asp, Gly178Arg, Gly551Ser, Ser1251Asn, Ser1255Pro, Ser549Asn, Ser549Arg, F508del (only compound heterozygous)

Therapy in accordance with Summary of Product Characteristics

None of the following variants exist: Gly551Asp, Gly1244Glu, Gly1349Asp, Gly178Arg, Gly551Ser, Ser1251Asn, Ser1255Pro, Ser549Asn, Ser549Arg

Ivacaftor is not recommended

F508del homozygous Ivacaftor is not recommended

Costs

Costs of genetic testing will be reimbursed for statutory and privately insured patients whose testing is prescribed by a physician. The attending physician’s budget is not burdened as a result.

1 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for ivacaftor therapy in the context of CFTR genotype. Clancy JP, Johnson SG, Yee SW, McDonagh EM, Caudle KE, Klein TE, Cannavo M, Giacomini KM Clin Pharmacol Ther. 2014 95(6): 592-597 (PMID: 24598717)


Gentest zur Risikominimierung der Therapie mit Ivacaftor

Arzneimittel

Wie sind die Indikationen und der Wirkmechanismus von Ivacaftor?Ivacaftor wird zur Behandlung der zystischen Fibrose (Mukoviszidose) bei Patienten mit bestimmten Mutationen im CFTR-Gen eingesetzt wird. Genetische Veränderungen im CFTR-Gen führen auf CFTR-Proteinebene zum Funktionsverlust der Chloridkanäle in den Zellmembranen bestimmter Körperzellen, wodurch infolge des zu geringen Wassergehaltes zähflüssige Sekrete u.a. der Bronchialschleimhaut der Lunge entstehen. Der Wirkstoff Ifacaftor ist ein CFTR-Potentiator und führt bei Patienten mit bestimmten Mutationen im CFTR-Gen zu einer verbesserten Funktion der fehlgesteuerten Chloridkanäle, kann jedoch die klinischen Symptome nur mildern.

Gene

Welche Gene beeinflussen die Wirkung von Ivacaftor?Gegenwärtig sind mehr als 2000 Mutationen des CFTR-Gen im Zusammenhang mit Mukoviszidose bekannt. Nach gegenwärtigem Wissensstand beschränkt sich die pharmakologische Wirksamkeit von Ivacaftor bisher nur auf Patienten mit einer von 9 bekannten CFTR-Varianten (4-5% der Mukoviszidose-Patienten). Für die anderen Mutationen wurde die Wirksamkeit noch nicht belegt.

Test

Was wird getestet?Das Erbgut der Patienten wird auf die für Ivacaftor sensitiven CFTR-Genvarianten getestet.

Indikation

Wann sollte getestet werden?Der Gentest sollte vor Beginn einer geplanten Therapie mit Ivacaftor durchgeführt werden, um die therapeutische Wirksamkeit von Ivacaftor abzusichern.



Tabelle 1: Empfehlungen für die Ivacaftor-Therapie in Abhängigkeit vom CFTR-Genotyp

CFTR-Genotyp Therapieempfehlung

Homo- bzw. Compound Heterozygotie für folgende Varianten Gly551Asp, Gly1244Glu, Gly1349Asp, Gly178Arg, Gly551Ser, Ser1251Asn, Ser1255Pro, Ser549Asn, Ser549Arg, F508del (nur compound heterozygot)

Therapie gemäß Fachinformation

Keine der folgenden Varianten vorhanden: Gly551Asp, Gly1244Glu, Gly1349Asp, Gly178Arg, Gly551Ser, Ser1251Asn, Ser1255Pro, Ser549Asn, Ser549Arg

Ivacaftor wird nicht empfohlen

F508del homozygot Ivacaftor wird nicht empfohlen

Kosten

Die Kosten der Genuntersuchung werden für gesetzlich und privat versicherte Patienten erstattet, deren Testung durch einen Arzt angeordnet wird. Das Budget des behandelnden Arztes ist dadurch nicht belastet.

1 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for ivacaftor therapy in the context of CFTR genotype. Clancy JP, Johnson SG, Yee SW, McDonagh EM, Caudle KE, Klein TE, Cannavo M, Giacomini KM Clin Pharmacol Ther. 2014 95(6): S. 592-597 (PMID: 24598717)


Genski test za smanjenje rizika pri primjeni ivakaftora

Lijek

Koje su indikacije za primjenu i koji su mehanizmi djelovanja lijeka ivakaftora?Ivakaftor se koristi u lije�enja cisti�ne fibroze kod pacijenata s odre�enim mutacijama u genu CFTRu. Geneti�ke promjene u genu CFTR rezultiraju na proteinskoj razini CFTR gubitkom funkcije kloridnog kanala u stani�noj membrani odre�enih tjelesnih stanica pri �emu uslijed nedostatnog sadržaja vode nastaje žilavi sekret, izme�u ostaloga i u bronhima. Aktivna tvar ivakaftor stimulira CFTR protein i kod pacijenata s odre�enim mutacijama gena CFTR (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N and S549R) dovodi do poboljšane funkcije kloridnih kanala, i time ublažava klini�ke simptome.

Geni

Koji geni utje�u na djelovanje ivakaftora?Trenutno je poznato više od 2000 mutacija gena CFTR koje su povezane s cisti�nom fibrozom. Trenutno se farmakološka djelotvornost ivakaftora ograni�ava na pacijente sa jednom od 9 poznatih mutacija CFTR (4-5% pacijenata s cisti�nom fibrozom). Za ostale mutacije do danas nije potkrijepljena djelotvornost.

Analiza

Što se analizira?Analizira se genotip bolesnika na CFTR varijante gena na koje ivakaftor djeluje.

Indikacije

U kojim slu�ajevima je potrebno napraviti analizu?Genski test potrebno je provesti prije po�etka planirane terapije sa ivakaftorom kako bi se osigurao terapijski u�inak ivakaftora.

Preporuke

Na koji na�in se terapija mora prilagoditi rezultatima genske analize?Preporuke su temeljene na smjernicama Clinical Pharmacogenetics Implementation Consortium (CPIC)1 i imaju najvišu klini�ku razinu dokaza 1A.

Tabela 1: Preporuke za lije�enjem ivakaftorom ovisno o genotipu CFTR

CFTR-genotip Preporu�ena terapija

Homozigotnost, odnosno kombinirani (združeni) heterozigot («compound heterozygous)» za sljedece varijante: Gly551Asp, Gly1244Glu, Gly1349Asp, Gly178Arg, Gly551Ser, Ser1251Asn, Ser1255Pro, Ser549Asn, Ser549Arg, F508del (kombinirani (združeni) heterozigot («compound heterozygous)»

Terapija sukladno uputama o lijeku (Informacijama za korisnika)

Odsustvo Gly551Asp, Gly1244Glu, Gly1349Asp, Gly178Arg, Gly551Ser, Ser1251Asn, Ser1255Pro, Ser549Asn, Ser549Arg

Terapija ivakaftorom se ne preporucuje

F508del homozigot Terapija ivakaftorom se ne preporucuje

Troškovi

Priznavanje i povrat troškova za navedenu analizu varira od države do države. Ukoliko je testiranje ordinirano od strane lije�nika, troškovi analize gena CFTR biti �e priznati i refundirani za bolesnike koji imaju obvezno i privatno osiguranje, pa budžet nadležnog lije�nika ili institucije u kojoj nadležni lije�nik radi zbog toga ne�e biti optere�en.

1 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for ivacaftor therapy in the context of CFTR genotype. Clancy JP, Johnson SG, Yee SW, McDonagh EM, Caudle KE, Klein TE, Cannavo M, Giacomini KM Clin Pharmacol Ther. 2014 95(6): S. 592-597 (PMID: 24598717)


6-Mercaptopurine 6-Mercaptopurin 6-Merkaptopurin


Gene test to minimise the risks related to therapy with 6-mercaptopurine

Drug

What are the indications and the mechanisms of action of 6-mercaptopurine?6-mercaptopurine is a cytotoxic, immunosuppressive active agent mainly used to treat acute and chronic myeloid leukaemia. 6-mercaptopurine is a purine analogue and inhibits purine synthesis as well as DNA and RNA synthesis.

Genes

What genes influence the effect of 6-mercaptopurine?The enzyme thiopurine methyltransferase (TPMT) is responsible for the inactivation of 6-mercaptopurine through methylation of the sulfhydryl group. In case of a TPMT deficiency, toxic metabolites develop during the breakdown process which can cause myelosuppression in the haematopoietic tissue with life-threatening side effects. In our population, there are known activity-reducing gene variants for the TPMT gene which require an adjustment of the dose in order to increase the tolerability with regard to the active agent.

Test

What is tested?The genotype of patients is examined with regard to the most frequent clinically relevant TPMT gene variants (*2, *3A, *3B, *3C and *4) which in compound heterozygous or homozygous state lead to a complete loss of the TPMT enzyme activity.

Indication

When should a test be carried out?Genetic testing should be carried out before the initiation of the scheduled therapy with 6-mercaptopurine in order to reduce the risk of myelosuppression (disturbance of haematopoiesis), as required, by means of an adjustment of the initial dose or by prescribing an alternative active agent.


How does the therapy need to be adjusted to the test results?The following recommendations are based on the guidelines of the Clinical Pharmacogenetics Implementation Consortium (CPIC)1 and have the highest clinical level of evidence, 1A.

Table 1: Recommendations for 6-mercaptopurine therapy depending on the TPMT genotype




Risk variant, compound heterozygous or homozygousChange of the active agent or drastic reduction of the initial dose for treatment of malignant diseases (10-fold reduction and only on 3 days / week)

Costs


1 Clinical Pharmacogenetics ImplementationConsortium Guidelines for ThiopurineMethyltransferase Genotype and Thiopurine Dosing: 2013 Update, Relling MV, Gardner EE, Sandborn WJ, Schmiegelow K, Pui CH, Yee SW, Stein CM, Carrillo M, Evans WE, Hicks JK, Schwab M, Klein TE. Clin Pharmacol Ther 2013 93(4):324-325 PMID:23422873


Gentest zur Risikominimierung der Therapie mit 6-Mercaptopurin

Arzneimittel

Wie sind die Indikationen und der Wirkmechanismus von 6-Mercaptopurin?6-Mercaptopurin ist ein zytotoxischer, immunsuppressiver Wirkstoff, der vorrangig zur Behandlung von akuten und chronischen myeloischen Leukämien eingesetzt wird. 6-Mercaptopurin ist ein Purinanalogon und hemmt als Antimetabolit sowohl die Purinsynthese als auch die DNA- und RNA-Synthese.

Gene

Welche Gene beeinflussen die Wirkung von 6-Mercaptopurin?Das Enzym Thiopurin-Methyltransferase (TPMT) inaktiviert 6-Mercaptopurin durch Methylierung der Sulfhydrylgruppe. Bei einem Mangel an TPMT entstehen im Abbauprozess toxische Metabolite, die im hämatopoetischen Gewebe eine Myelosuppression mit lebensbedrohenden Nebenwirkungen auslösen können. Für das TPMT-Gen sind in der Bevölkerung aktivitätsmindernde Genvarianten bekannt, die eine Dosierungsanpassung erforderlich machen, um die Verträglichkeit des Wirkstoffs zu erhöhen.

Test


Indikation

Wann sollte getestet werden?Der Gentest sollte vor Beginn einer geplanten Therapie mit 6-Mercaptopurin durchgeführt werden, um gegebenenfalls durch eine Anpassung der Startdosis oder die Verordnung eines alternativen Wirkstoffs das Risiko einer Myelosuppression (Störung der Hämatopoese) zu senken.



Tabelle 1: Empfehlungen für die 6-Mercaptopurin-Therapie in Abhängigkeit vom TPMT-Genotyp


Wildtyp Anwendung gemäß der Fachinformationen

Risikovariante, heterozygot Startdosis sollte 30-70 Prozent der normalen Dosierung entsprechen

Risikovariante, compound heterozygot oder homozygotWirkstoffwechsel oder drastisch reduzierte Startdosis zur Behandlung maligner Erkrankungen (10-fach reduziert und nur an 3 Tagen/Woche)

Kosten

Die Kosten für die genetische Analyse des TPMT-Gens werden für gesetzlich und privat versicherte Patienten erstattet, wenn die Testung durch einen Arzt angeordnet wird. Das Budget des behandelnden Arztes wird dadurch nicht belastet.

1 Clinical Pharmacogenetics ImplementationConsortium Guidelines for ThiopurineMethyltransferase Genotype and Thiopurine Dosing: 2013 Update, Relling MV, Gardner EE, Sandborn WJ, Schmiegelow K, Pui CH, Yee SW, Stein CM, Carrillo M, Evans WE, Hicks JK, Schwab M, Klein TE. Clin Pharmacol Ther 2013 93(4):324-325 (PMID:23422873)


Genski test za smanjenje rizika kod primjene 6-merkaptopurina

Lijek

Koje su indikacije i mehanizmi djelovanja lijeka 6-merkaptopurina?6-merkaptopurin je imunosupresiv koji se primarno koristi u lije�enju akutne mijeloi�ne leukemije. 6-merkaptopurin je neaktivni prolijek koji djeluje kao antagonist purina te inhibira de novo sintezu purina te time posljedi�no i sintezu DNA i RNA.

Geni

Koji geni utje�u na djelovanje 6-merkaptopurina?Enzim tiopurin S-metiltransferaza (TPMT) je odgovoran za inaktivaciju 6-merkaptopurina putem metilacije sulfhidrilne grupe. Kod nedostatka TPMT u procesu razgradnje nastaju toksi�ni metaboliti koji mogu izazvati supresiju koštane srži (primarno leukopeniju i trombocitopeniju) s nuspojavama koje mogu biti opasne po život. Za gen TPMT su me�u stanovništvom poznate varijante koje snizuju aktivnost enzima što zahtijeva podešavanje doze lijeka s ciljem pove�anja podnošljivost lijeka.

Analiza

Što se analizira?Analizira se genotip pacijenta na naju�estalije klini�ki relevantne varijante gena TPMT (*2, *3A, *3B, *3C i *4) gena koje u slu�aju kombiniranih (združenih) heterozigota (compound heterozygous) ili homozigota dovode do potpunog gubitka aktivnosti enzima TPMT.

Indikacije

U kojim je slu�ajevima potrebno napraviti analizu?Gensko testiranje potrebno je napraviti prije po�etka planirane terapije 6-merkaptopurinom da bi se u slu�aju potrebe reducirao rizik supresije koštane srži i to putem podešavanja po�etne doze ili ordiniranjem alternativnog lijeka.

Preporuke

Na koji na�in se terapija mora prilagoditi rezultatima genske analize?Preporuke su temeljene na smjernicama Clinical Pharmacogenetics Implementation Consortium (CPIC)1 i imaju najvišu klini�ku razinu dokaza 1A.

Tabela1: Preporuke za lije�enje 6-merkaptopurinom, ovisno o genotipu TPMT


Divlji tip (wt/wt) Terapija sukladno uputama o lijeku (Informacijama za korisnika)

Rizicna varijanta, heterozigot Pocetnu dozu smanjiti na razinu 30-70 posto prosjecne doze

Rizicna varijanta, kombinirani (združeni) heterozigot («compound heterozygous»), homozigot

Promjena lijeka ili drasticno smanjena pocetna doza kod lijecenja malignih bolesti (10-struko reducirana i samo 3 dana/tjedno)

Troškovi

Priznavanje i povrat troškova za navedenu analizu varira od države do države. Ukoliko je testiranje ordinirano od strane lije�nika, troškovi analize gen TPMT biti �e priznati i refundirani za bolesnike koji imaju obvezno i privatno osiguranje, pa budžet nadležnog lije�nika ili institucije u kojoj nadležni lije�nik radi zbog toga ne�e biti optere�en.



Phenprocoumon Phenprocoumon

Fenprokumonom (U Hrvatskoj se u iste svrhe koristi Varfarin)


Gene test to minimise the risks related to therapy with phenprocoumon

Drug

What are the indications and the mechanism of action of phenprocoumon?Phenprocoumon is an anticoagulant drug used among other things for prevention of thromboembolic events in atrial fibrillation and after the implantation of artificial heart valves and vascular bypass procedures. As a vitamin K antagonist, phenprocoumon suppresses the activation of the coagulation factors II, VII and X as well as the synthesis of the anticoagulant proteins C and S.

Genes

Which genes influence the effect of phenprocoumon?Phenprocoumon inhibits the enzyme vitamin K epoxide reductase complex, subunit 1 (VKORC1) that is responsible for the regeneration of vitamin K. The gene variant c.-1173C>T in the VKORC1 gene alters a transcription factor binding site and leads to a reduced VKORC1 protein synthesis.

In addition to the activity of the VKORC1 protein, the effectiveness of the decomposition of the active ingredient through the liver enzyme CYP2C9) is also important for the high phenprocoumon dose variability (approx. 36%) in our population. Two common gene variants in the CYP2C9 gene (*2,*3) influence the metabolism rate of phenprocoumon.

Test

What will be tested?The patient’s genotype is tested in the VKORC1 gene for the risk gene variant c.-1173C>T and the CYP2C9 gene for the risk alleles *2 and *3.

Indication

When should a test be performed?The genetic test should be performed before the start of planned therapy with phenprocoumon in order to quickly achieve constant INR values through dose adjustment if necessary and to avoid adverse effects.


How does the therapy have to be adapted to the test results?The following procedure takes place in accordance with the Clinical Pharmacogenetics Implementation Consortium (CPIC)1 guidelines for warfarin and has been adapted for phenprocoumon2.

Table 1: Recommendations for phenprocoumon therapy subject to the genotype combination for VKORC1 and CYP2C9

VKORC1/CYP2C9 genotype Therapy recommendation

VKORC1, wild type / CYP2C9, wild type Therapy in accordance with Summary of Product Characteristics

VKORC1, wild type or risk variant heterozygous / CYP2C9, risk variant heterozygous or homozygous

Reduction of starting dose by 27-34 percent, frequent INR controls necessary

VKORC1, risk variant homozygous / CYP2C9, wild type Reduction of starting dose by 50 percent, frequent INR controls necessary

VKORC1, risk variant homozygous / CYP2C9, risk variant heterozygous or homozygous

Reduction of starting dose by 55-61 percent, frequent INR controls necessary

Costs

Costs for the VKORC1 and CYP2C9 genetic analyses will be reimbursed for statutory and privately insured patients if the testing is prescribed by a physician. The attending physician’s budget is not burdened as a result.

1 Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1Genotypes and Warfarin Dosing. Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM, Anderson JL, Kimmel SE. Clin Pharmacol Ther. 2011 Oct;90(4):625-9. (PMID: 21900891)2 2 VKORC1 and CYP2C9 genotypes and phenprocoumon anticoagulation status: interaction between both genotypes affects dose requirement.Schalekamp T, Brassé BP, Roijers JF, van Meegen E, van der Meer FJ, van Wijk EM, Egberts AC, de Boer A. Clin Pharmacol Ther. 2007;81: 185-93. (PMID: 17192772)


Gentest zur Optimierung der Arzneimitteltherapie mit Phenprocoumon

Arzneimittel

Wie sind die Indikationen und der Wirkmechanismus von Phenprocoumon?Phenprocoumon ist ein gerinnungshemmender Wirkstoff, der u.a. zur Vorbeugung thromboembolischer Ereignisse bei Vorhofflimmern und nach der Implantation von künstlichen Herzklappen und Gefäß-Bypässen eingesetzt wird. Phenprocoumon unterdrückt als Vitamin-K-Antagonist sowohl die Aktivierung der Gerinnungsfaktoren II, VII und X als auch die Synthese der antikoagulativen Proteine C und S.

Gene

Welche Gene beeinflussen die Wirkung von Phenprocoumon?Phenprocoumon hemmt das Enzym Vitamin-K-Epoxid-Reduktase (VKOC1), das für die Regeneration von Vitamin-K verantwortlich ist. Die Genvariante c.-1173C>T im VKORC1-Gen verändert eine Transkriptionsfaktor-Bindungsstelle und führt zu einer verringerten VKORC1-Proteinsynthese.Für die hohe Phenprocoumon-Dosis-Variabilität von ca. 36 Prozent in unserer Bevölkerung ist neben der Aktivität des VKORC1-Proteins auch die Effektivität des Wirkstoffabbaus durch das Leberenzym CYP2C9 von Bedeutung. Zwei häufige Genvarianten im CYP2C9-Gen (*2,*3) beeinflussen die Metabolisierungsrate von Phenprocoumon.

Test

Was wird getestet?Das Erbgut der Patienten wird im VKORC1-Gen auf die Risiko-Genvariante c.-1173C>T und das CYP2C9-Gen auf die Risiko-Allele *2 und *3 untersucht.

Indikation

Wann sollte getestet werden?Der Gentest sollte vor Beginn einer geplanten Therapie mit Phenprocoumon durchgeführt werden, um gegebenenfalls durch Dosisanpassung schnell konstante INR-Werte zu erreichen und Nebenwirkungen zu vermeiden.


Wie muss die Therapie an die Testergebnisse angepasst werden?Folgendes Vorgehen erfolgt in Anlehnung an die Leitlinie des Clinical Pharmacogenetics Implementation Consortium (CPIC)1 für Warfarin und wurde für Phenprocoumon2 adaptiert.

Tabelle 1: Empfehlungen für die Phenprocoumon-Therapie in Abhängigkeit von der Genotypkombination für VKORC1 und CYP2C9

VKORC1/CYP2C9-Genotyp Therapieempfehlung

VKORC1,Wildtyp / CYP2C9, Wildtyp Therapie gemäß Fachinformation

VKORC1, Wildtyp oder Risikovariante heterozygot/ CYP2C9, Risikovariante hetero- oder homozygot

Reduzierung der Startdosis um 27-34 Prozent, Häu³ge INR-Kontrollen notwendig

VKORC1, Risikovariante homozygot/ CYP2C9, Wildtyp Reduzierung der Startdosis um 50 Prozent, Häu³ge INR-Kontrollen notwendig

VKORC1, Risikovariante homozygot/ CYP2C9, Risikovariante hetero- oder homozygot

Reduzierung der Startdosis um 55-61 Prozent, Häu³ge INR-Kontrollen notwendig

Kosten

Die Kosten für die VKORC1- und CYP2C9-Genanalysen werden für gesetzlich und privat versicherte Patienten erstattet, wenn die Testung durch einen Arzt angeordnet wird. Das Budget des behandelnden Arztes ist dadurch nicht belastet.



Genski test za smanjenje rizika kod primjene terapije fenprokumonomNapomena: u Hrvatskoj se u iste svrhe primjenjuje drugi kumarinski antikoagulans: varfarin, a smjernice Clinical Pharmacogenetics Implementation Consortium se prvenstveno odnose na varfarin i adaptirane su za fenprokumon jer se on više propisuje u Zapadnoj Europi uklju�uju�i i Njema�ku

LijekKoje su indikacije i mehanizmi djelovanja lijeka fenprokumona?Fenprokumon je antikoagulans koji se primjenjuje u prevenciji tromboembolijskih bolesti poput onih povezanih s atrijskom fibrilacijom te nakon implantacije umjetnog sr�anog zaliska i kirurškog premoš�ivanja krvnih žila. Kao antagonist vitamina K suprimira aktivaciju faktora zgrušavanja II, VII i X ali i sintezu antikoagulantnih proteina C i S.

GeniKoji geni utje�u na djelovanje fenprokumona?Fenprokumon inhibira enzim vitamin K-epoksid reduktaza-kompleks, podjedinicu 1 (VKORC1), koji je odgovoran za regeneraciju vitamina K. Genska varijanta VKORC1 1173C>T mijenja mjesto vezivanja transkripcijskog faktora te dovodi do smanjene sinteze proteina VKORC1. Osim aktivnosti enzima VKORC1, za veliku varijabilnost u doziranju lijeka (36%) je važna i u�inkovitost razgradnje aktivnog lijeka putem jetrenog enzima CYP2C9. Na metabolizam fenprokumona utje�u dvije u�estale varijante gena CYP2C9 (*2,*3).

AnalizaŠto se analizira?Analizira se gen VKORC1 kako bi se utvrdila rizi�na varijanta 1173C>T, te gen CYP2C9 na rizi�ne alele *2 i *3.

IndikacijeU kojim je slu�ajevima potrebno napraviti analizu?Genski test bi trebalo provesti prije po�etka planirane terapije fenprokumonom da bi se putem prilago�ene doze brzo postigle uobi�ajene vrijednosti INR-a (me�unarodni normalizirani omjer) te izbjegle nuspojave.

Posljedice rezultata testovaNa koji na�in se terapija mora prilagoditi rezultatima testa?Preporuke su temeljene na smjernicama Clinical Pharmacogenetics Implementation Consortium (CPIC)1 za varfarin, a adaptirane su za fenprokumon 2.

Tabela 1: Preporuke za lije�enje fenprokumonom ovisno o kombinaciji genotipova VKORC1 i CYP2C9

VKORC1/CYP2C9-genotip Preporu�ena terapija

VKORC1,wt/wt / CYP2C9, wt/wtTerapija sukladno uputama o lijeku (Informacijama za korisnika)

VKORC1, wt/wt ili rizicna varijanta heterozigot / CYP2C9, rizicna varijanta hetero ili homozigot

Smanjenje pocetne doze za 27-34 posto, potrebne su ucestale kontrole INR

VKORC1, rizicna varijanta homozigot / CYP2C9, wt/wt Smanjenje pocetne doze za 50 posto, potrebne su ucestale kontrole INR

VKORC1, rizicna varijanta homozigot / CYP2C9, rizicna varijanta hetero ili homozigot

Smanjenje pocetne doze za 55-61 posto, potrebne su ucestale kontrole INR

Troškovi

Priznavanje i povrat troškova za navedenu analizu varira od države do države. Ukoliko je testiranje ordinirano od strane lije�nika, troškovi analize VKORC1 i CYP2C9 gena biti �e priznati i refundirani za bolesnike koji imaju obvezno i privatno osiguranje, pa budžet nadležnog lije�nika ili institucije u kojoj nadležni lije�nik radi zbog toga ne�e biti optere�en



Phenytoin Phenitoin

Fenitoin


Gene test to minimise the risks related to therapy with phenytoin

Drug

What are the indications and the mechanism of action of phenytoin?Phenytoin is an antiepileptic and antiarrhythmic agent for treatment of epilepsies and cardiac arrhythmias. The anticonvulsant effect of phenytoin is based on its function as a sodium channel blocker, whereby the membrane potential of central and peripheral nerve cells is stabilized.

Genes

Which genes influence the effect of phenytoin?The tolerance to phenytoin is significantly influenced by variations in the HLA-B and CYP2C9 gene. In addition to a variety of adverse drug effects, the most severe cutaneous hypersensitivity reactions can arise among carriers of the HLA-B*15:02 genotype under phenytoin therapy. The HLA-B*15:02 allele is more commonly found in the Asian population (1-10%) than among Europeans (<0.1%). However, activity-reducing variants which can lead to partial or complete loss of CYP2C9 function and thereby to various adverse effects are known in all ethnic groups with regard to the CYP2C9 gene that catalyses the decomposition of phenytoin in the liver.

Test

What will be tested?The patient’s genotype (especially among Asians) is tested for the HLA-B*15:02 allele (HLA-B gene). However, the testing of activity-reducing CYP2C9 gene variants (*2,*3) is recommended for all ethnic groups.

Indication

When should a test be performed?The genetic test should be performed before the start of planned therapy with phenytoin in order to possibly reduce the risk of serious adverse effects through an adjustment of the starting dose or the prescription of an alternative active ingredient.



Table 1: Recommendations for phenytoin therapy subject to HLA-B genotype

HLA-B genotype Therapy recommendation

HLA-B*15:02, negative Use in accordance with Summary of Product Characteristics

HLA-B*15:02, heterozygous or homozygous Change of active ingredient recommended

1 Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C9 and HLA-B genotypes and phenytoin dosing. Caudle KE, Rettie AE, Whirl-Carrillo M, Smith LH, Mintzer S, Lee MT, Klein TE, Callaghan JT Clin Pharmacol Ther. 2014 96(5): 542-548 (PMID: 25099164)


Table 2: Recommendations for phenytoin therapy subject to CYP2C9 metabolism type


Extensive metabolizer (91%) Use in accordance with Summary of Product Characteristics

Intermediate metabolizer (8%) Reduction of starting dose by 25 percent

Poor metabolizer (1%) Reduction of starting dose by 50 percent

Costs

Costs for the HLA-B genotyping and the CYP2C9 genetic analysis will be reimbursed for statutory and privately insured patients if the testing is prescribed by a physician. The attending physician’s budget is not burdened as a result.


Gentest zur Risikominimierung der Therapie mit Phenytoin

Arzneimittel

Wie sind die Indikationen und der Wirkmechanismus von Phenytoin?Phenytoin wird als Antiepileptikum und Antiarrhythmikum zur Behandlung von Epilepsien und Herzrhythmusstörungen eingesetzt. Die krampflösende Wirkung von Phenytoin beruht auf seiner Funktion als Natriumkanalblocker, wodurch das Membranpotential zentraler und peripherer Nervenzellen stabilisiert wird.

Gene

Welche Gene beeinflussen die Wirkung von Phenytoin?Die Verträglichkeit von Phenytoin wird maßgeblich durch die Genotypen im HLA-B- und CYP2C9-Gen beeinflusst. Neben einer Vielzahl von Arzneimittelnebenwirkungen kann es bei Trägern des HLA-B*15:02-Genotyps unter Phenytoin-Therapie zu schwersten kutanen Überempfindlichkeitsreaktionen kommen. Das HLA-B*15:02-Allel kommt häufiger in der asiatischen Bevölkerung (110%) als bei Europäern (<0,1%) vor. Für das CYP2C9-Gen, das den Abbau von Phenytoin in der Leber katalysiert, sind allerdings aktivitätsmindernde Varianten in allen ethnischen Gruppen bekannt, die zum partiellen oder kompletten CYP2C9-Funktionsverlust und damit zu verschiedenen Nebenwirkungen führen können.

Test

Was wird getestet?Das Erbgut Patienten (vor allem bei Asiaten) wird auf das HLA-B*15:02-Allel (HLA-B-Gen) untersucht. Die Überprüfung der aktivitätsmindernden CYP2C9-Genvarianten (*2,*3) ist jedoch für alle ethnischen Gruppen empfohlen.

Indikation

Wann sollte getestet werden?Der Gentest sollte vor Beginn einer geplanten Therapie mit Phenytoin durchgeführt werden, um gegebenenfalls durch eine Anpassung der Startdosis oder die Verordnung eines alternativen Wirkstoffs das Risiko für schwere Nebenwirklungen zu senken.



Tabelle 1: Empfehlungen für die Phenytoin-Therapie in Abhängigkeit vom HLA-B-Genotyp

HLA-B-Genotyp Therapieempfehlung

HLA-B*15:02, negativ Anwendung gemäß Fachinformation

HLA-B*15:02, heterozygot oder homozygot Wirkstoffwechsel empfohlen

1 Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and HLA-B genotypes and phenytoin dosing. Caudle KE, Rettie AE, Whirl-Carrillo M, Smith LH, Mintzer S, Lee MT, Klein TE, Callaghan JT Clin Pharmacol Ther. 2014 96(5): S. 542-548 (PMID: 25099164)


Tabelle 2: Empfehlungen für die Phenytoin-Therapie in Abhängigkeit vom CYP2C9-Metabolisierungstyp


Schnelle Metabolisierer (91%) Anwendung gemäß der Fachinformation

Intermediäre Metabolisierer (8%) Reduzierung der Startdosis um 25 percent

Langsame Metabolisierer (1%) Reduzierung der Startdosis um 50 percent

Kosten

Die Kosten für die HLA-B-Gentypisierung und die CYP2C9-Genanalyse werden für gesetzlich und privat versicherte Patienten erstattet, wenn die Testung durch einen Arzt angeordnet wird. Das Budget des behandelnden Arztes wird dadurch nicht belastet.


Genski test za smanjenje rizika pri primjeni fenitoina

Lijek

Koje su indikacije i mehanizam djelovanja fenitoina?Fenitoin je antiepileptik i antiaritmik. Primjenjuje se u lije�enju epilepsije. Antikonvulzivni u�inak fenitoina temeljen je na blokiranju Na+ kanala pri �emu se stabilizira membranski potencijal centralnih i perifernih živ�anih stanica.

Geni

Koji geni utje�u na djelovanje fenitoina?Podnošljivost fenitoina je pod zna�ajnim utjecajem gena HLA-B- i CYP2C9. Uz razli�ite nuspojave, nositelji alela HLA-B*15:02 mogu prilikom primjene fenitoina razviti kožne reakcije preosjetljivosti. Alel HLA-B*15:02 je �eš�e prisutan me�u Azijatima (1-10%) nego u Europljana (<0,1%). Me�utim, varijante gena koje smanjuju ili dokidaju aktivnost enzima, što može dovesti do razvoja razli�itih nuspojava, prisutne su u svim etni�kim skupinama.

Analiza

Što se analizira?Analizira se genotip (prije svega Azijata), na prisustvo alela HLA-B*15:02 (gen HLA-B). Me�utim analiza genskih varijanti (*2,*3) koje smanjuju aktivnost enzima CYP2C9 preporu�uje se za sve etni�ke skupine.

Indikacije

U kojim slu�ajevima je potrebno napraviti analizu?Genski test bi trebalo provesti prije samoga po�etka planirane terapije sa fenitoinom da bi se u slu�aju potrebe putem prilago�avanja po�etne doze ili ordinirane alternativne aktivne tvari smanjio rizik ozbiljnih nuspojava.


Na koji na�in se terapija mora prilagoditi rezultatima testa ?Preporuke su temeljene na smjernicama Clinical Pharmacogenetics Implementation Consortium (CPIC)1 i imaju najvišu klini�ku razinu dokaza 1A.

Tabela 1: Preporuke za lije�enje fenitoinom ovisno o genotipu HLA-B

HLA-B-genotip Preporu�ena terapija


HLA-B*15:02, heterozigot ili homozigot Preporucuje se promjena lijeka

1 Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and HLA-B genotypes and phenytoin dosing. Caudle KE, Rettie AE, Whirl-Carrillo M, Smith LH, Mintzer S, Lee MT, Klein TE, Callaghan JT Clin Pharmacol Ther. 2014 96(5): S. 542-548 (PMID: 25099164)


Tabela 2: Preporuke za lije�enje fenitoinom- ovisno o sposobnosti metaboliziranja lijeka putem enzima CYP2C9

CYP2C9-fenotip metabolizatora Preporu�ena terapija

Brzi metabolizator (UEM) (91%)Terapija sukladno uputama o lijeku (Informacijama za korisnika)

Intermedijarni metabolizator (IM) (8%) Smanjiti pocetnu dozu za 25 posto

Spori metabolizator (PM) (1%) Smanjiti pocetnu dozu za 50 posto

Troškovi

Priznavanje i povrat troškova za navedenu analizu varira od države do države.Ukoliko je testiranje ordinirano od strane lije�nika, troškovi analize genotipa HLA-B i CYP2C9 biti �e priznati i refundirani za bolesnike koji imaju obvezno i privatno osiguranjepa budžet nadležnog lije�nika ili institucije u kojoj nadležni lije�nik radi zbog toga ne�e biti optere�en.


Ribavirin and PEG-interferon-α Ribavirin und PEG-interferon-α Ribavirin i Peginterferon alfa


Gene test to minimise the risks related to therapy with ribavirin and PEG-interferon-α

Drug

What are the indications and the mechanism of action of ribavirin and PEG-interferon-α?Ribavirin is a virostatic agent is used in combination therapy with PEG-interferon alpha 2a and 2b for treatment of chronic hepatitis C (type 1). Ribavirin belongs to the group of nucleoside analogues and blocks viral RNA and DNA synthesis as an antimetabolite. Ribavirin is only excreted at a slow rate and accumulates intracellularly.

The PEG-interferons alpha 2a and 2b are agents from the group of interferons which are used for treatment of viral chronic hepatitis. Both alpha interferons have antiviral and anti-proliferative properties. Their effect is based on the tissue-specific binding to specific interferon receptors on the cell surface. Intracellular signal pathways which inhibit the cell growth and thereby also virus replication are regulated as a result. The exact mechanism of action is not known. Through the binding of the agent to polyethylene glycol (pegylation), a significantly slower release of interferons is achieved and the effect is prolonged by 5 hours in comparison with native interferon alpha-2a.

Genes

Which genes influence the effect of ribavirin and PEG-interferon-α?Therapeutic success of ribavirin and PEG-interferon-α is significantly associated with the genotype of the variant c.151-152C>T (rs12979860) in the interferon lambda-3 (IFNL3) gene. The IFNL3 protein is primarily formed in the liver and in the epithelial cells. Therapeutic success is prognosticated on the basis of the sustained virological response (SVR) rate, which is defined by the lack of viral RNA in the blood serum after 12-24 weeks of treatment.

Test

What will be tested?The patient’s genotype is tested in the IFNL3 gene for the risk gene variant c.151-152C>T.

Indication

When should a test be performed?The genetic test should be performed before the start of planned combination therapy with ribavirin and PEG-interferon-α in order to assess the benefit of therapy.


How does the therapy have to be adapted to the test results?The following recommendation is based on the Clinical Pharmacogenetics Implementation Consortium (CPIC)1 guidelines and has the highest clinical level of evidence 1A.

Table 1: Recommendations for ribavirin/PEG-interferon therapy subject to IFNL3 genotype

IFNL3 genotype Prognosis of therapeutic success under ribavirin / PEG-interferon-α

Wild type Therapeutic success of 70 percent prognosticated, higher SVR rates expected

Risk variant, heterozygous or homozygous Therapeutic success of 30 percent prognosticated, lower SVR rates expected, benefit of therapy is questionable.

Costs

Costs for the IFNL3 genotyping will be reimbursed for statutory and privately insured patients if the testing is prescribed by a physician. The attending physician’s budget is not burdened as a result.

1 Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for IFNL3 (IL28B) Genotype and PEG Interferon-α–Based Regimens. AJ Muir et al. Guidelines Clinical Pharmacology & Therapeutics 95 (2) 2014: 141-146


Gentest zur Risikominimierung der Therapie mit Ribavirin und PEG-Interferon-α

Arzneimittel

Wie sind die Indikationen und der Wirkmechanismus von Ribavarin und PEG-Interferon-αRibavirin ist ein virostatischer Wirkstoff, der in der Kombinationstherapie mit PEG-Interferon alpha 2a und 2b zur Behandlung der chronischen Hepatitis C vom Typ1 eingesetzt wird. Ribavirin gehört zur Gruppe der Nukleosid-Analoga und blockiert als Antimetabolit die virale RNA- und DNA-Synthese. Ribavirin wird nur langsam ausgeschieden und kumuliert intrazellulär.Die PEG-Interferone alpha 2a und 2b sind Wirkstoffe aus der Gruppe der Interferone, die zur Behandlung der viral bedingten chronischen Hepatitis eingesetzt werden. Beide alpha-Interferone haben antivirale und antiproliferative Eigenschaften. Ihre Wirkung beruht auf der gewebespezifischen Bindung an spezifische Interferon-Rezeptoren auf der Zelloberfläche. Dadurch werden intrazelluläre Signalwege reguliert, die das Zellwachstum und damit auch die Virusreplikation hemmen. Der genaue Wirkmechanismus ist nicht bekannt. Durch die Bindung des Wirkstoffs an Polyethylenglycol (Pegylierung) wird eine deutlich langsamere Freisetzung der Interferone erreicht und die Wirkung im Vergleich zu nativem Interferon alfa-2a um 5 Stunden verlängert.

Gene

Welche Gene beeinflussen die Wirkung von Ribavirin und PEG-Interferon-αDer Therapieerfolg unter Ribavirin und PEG-Interferon-α ist signifikant mit dem Genotyp der Variante c.151-152C>T (rs12979860) im Interferon lambda 3 Gen (IFNL3) assoziiert. Das IFNL3-Protein wird vor allem in der Leber und in Epithelzellen gebildet. Anhand der virologischen Ansprechrate (SVR = Sustained virological response), die durch das Fehlen viraler RNA im Blutserum nach 12-24 Wochen Behandlung definiert ist, wird der Therapieerfolg prognostiziert.

Test

Was wird getestet?Das Erbgut der Patienten wird im IFNL3 Gen auf die Risiko-Genvariante c.151-152C>T untersucht.

Indikation

Wann sollte getestet werden?Der Gentest sollte vor Beginn einer geplanten Kombinationstherapie mit Ribavirin und PEG-Interferon-α durchgeführt werden, um den Nutzen der Therapie abzuschätzen.


Wie muss die Therapie an die Testergebnisse angepasst werden?Folgende Empfehlung basiert auf den Leitlinien des Clinical Pharmacogenetics Implementation Consortium (CPIC)1 und hat den höchsten klinischen Evidenzlevel 1a.

Tabelle 1: Empfehlungen für die Ribavirin-PEG-Interferon-Therapie in Abhängigkeit vom IFNL3-Genotyp

IFNL3-Genotyp Therapieerfolgsprognose unter Ribavirin / PEG-Interferon-α

Wildtyp Therapieerfolg von 70 Prozent prognostiziert, höhere SVR-Raten erwartet

Risikovariante, heterozygot oder homozygot Therapieerfolg von 30 Prozent prognostiziert, niedrigere SVR-Raten erwartet, Nutzen der Therapie fraglich.

Kosten

Die Kosten für die IFNL3-Genotypisierung werden für gesetzlich und privat versicherte Patienten erstattet, wenn die Testung durch einen Arzt angeordnet wird. Das Budget des behandelnden Arztes ist dadurch nicht belastet.

1 Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for IFNL3 (IL28B) Genotype and PEG Interferon-α–Based Regimens. AJ Muir et al. Guidelines Clinical pharmacology & Therapeutics 95 (2) 2014: 141-146


Genski test za smanjenje rizika pri primjeni ribavirina i peginterferona alfa

Lijek

Koje su indikacije i mehanizmi djelovanja ribavirina i peginterferona alfaRibavirin je antivirusni lijek koji se primjenjuje pri lije�enju kroni�nog hepatitisa C (tip 1) u kombinaciji s peginterferonom alfa 2a i 2b. Ribavirin je sintetski analog nukleozida i blokira sintezu virusne RNA i DNA. Ribavirin se nakuplja u stanicama i izlu�uje se vrlo sporo. Peginterferoni alfa 2a i 2b su supstance iz grupe interferona koji se primjenjuju u lije�enju kroni�nog virusnog hepatitisa. Oba alfa-interferona imaju antivirusni i antiproliferativni u�inak. Njihovo djelovanje temelji se na vezivanju za specifi�ne interferonske receptore na površini stanice. Putem toga se reguliraju unutarstani�ni signalni putevi koji zaustavljaju rast stanice i samim time i replikaciju virusa. To�an mehanizam djelovanja još nije poznat. Vezivanjem ribavirina na polietilen-glikol (pegilacija) postiže se sporije osloba�anje interferona, a djelovanje se u odnosu na prirodni interferon alfa-2a produžuje za 5 sati.

Geni

Koji geni utje�u na djelovanje ribavirina i peginterferona alfa?Terapijski u�inci ribavirina i peginterferona alfa zna�ajno su povezani s genotipom varijante c.151-152C>T (rs12979860) gena interferon lambda 3 (IFNL3). Protein IFNL3 se prije svega stvara u jetri kao i u epitelnim stanicama. Uspjeh lije�enja se može prognozirati na temelju održivog virološkog odgovora («Sustained virological response» (SVR)), koji je definiran nepostojanjem virusne RNA u serumu nakon 12-24 tjedana lije�enja.

Analiza

Što se analizira?Analizira se genotip pacijenata, posebice gen IFNL3 na varijantu c.151-152C>T.

Indikacije

U kojim slu�ajevima je potrebno napraviti analizu?Analizu bi trebalo provesti prije po�etka planirane kombinirane terapije ribavarinom i peginterferonom alfa u svrhu procijene koristi same terapije.


Na koji na�in se terapija mora prilagoditi rezultatima testa?Preporuke se temelje na smjernicama Clinical Pharmacogenetics Implementation Consortium (CPIC)1 i imaju najvišu klini�ku razinu dokaza 1A.

Tabela 1: Preporuke za lije�enje ribavirinom i peginterferon alfa ovisno o genotipu IFNL3

Genotip IFNL3 Prognoza uspješnosti terapije ribavirinom / PEG-Interferonom-α

wt/wt Prognoza uspješnosti terapije 70 posto ocekivana viša stopa SVR-a

Rizicna varijanta, heterozigot ili homozigot Prognoza uspješnosti terapije 30 posto ocekivana niža stopa SVR-a, Upitna korist terapije.

Troškovi

Priznavanje i povrat troškova za navedenu analizu varira od države do države. Ukoliko je testiranje ordinirano od strane lije�nika, troškovi analize genotipa IFNL3 biti �e priznati i refundirani za bolesnike koji imaju obvezno i privatno osiguranje. Budžet nadležnog lije�nika ili institucije u kojoj nadležni lije�nik radi zbog toga ne�e biti optere�en.

1 Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for IFNL3 (IL28B) Genotype and PEG Interferon-α–Based Regimens. AJ Muir et al. Guidelines Clinical pharmacology & Therapeutics 95 (2) 2014: 141-146


Simvastatin Simvastatin Simvastatin


Gene test to minimise the risks related to therapy with simvastatin

Drug

What are the indications and the mechanisms of action of simvastatin?Simvastatin is a lipid lowering medication and is used to treat hypercholesteraemia of different origins and is used for prevention of cardiovascular diseases. Like all statins, simvastatin inhibits the HMG-CoA reductase, the rate-limiting enzyme for the synthesis of cholesterol. This leads to an increased synthesis of LDL receptors and to an elevated uptake of LDL in the hepatic cells. The levels of LDL and triglyceride in the blood decrease and the level of HDL increases.

Genes

What genes influence the effect of simvastatin?Toxic myopathy, a structural and functional change of the skeletal muscles, which may lead to rhabdomyolysis is considered a severe side effect of statins (especially simvastatin). The muscular damage is caused by a genetic variant in the SLCO1B1 gene leading to a deficiency of the SLCO1B1 transport protein and thus to an elevated level of simvastatin in the blood and to a delayed breakdown of statins in the liver. Approx. 15 percent of the European population carry this genetic variant.

Test

What is tested?The genotype of patients is tested with regard to the genetic variant c.521T>C (p.Val174Ala) in the SLCO1B1 gene which leads to a SLCO1B1 protein deficiency.

Indication

When should a test be carried out?Genetic testing should be carried out before the initiation of the scheduled therapy with simvastatin in order to reduce the risk of myopathy, as required, by means of an adjustment of the dose or by prescribing an alternative statin preparation (e.g. atorvastatin, rosuvastatin or pitavastatin).


How does the therapy need to be adjusted to the test results?The following procedure is based on the recommendations of the guidelines of the Clinical Pharmacogenetics Implementation Consortium (CPIC)1 and has the highest clinical level of evidence, 1A.

Table 1: Recommendations for simvastatin therapy depending on the SLCO1B1 genotype

SLCO1B1 genotype Recommended therapy


Risk variant, heterozygous < 40 mg/day with regular CK tests or change of the active agent

Risk variant, homozygous < 20 mg/day with regular CK tests or change of the active agent

Costs

Costs for the SLCO1B1 gene analysis are reimbursed for patients with a statutory or private health insurance if the testing is requested by a doctor. The budget of the doctor responsible for treatment is not affected.

1 The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1 and Simvastatin-Induced Myopathy: 2014 Update, Ramsey LB, Johnson SG, Caudle KE, Haidar CE, Voora D, Wilke RA, Maxwell WD, McLeod HL, Krauss RM, Roden DM, Feng Q, Cooper-DeHoff RM, Gong L, Klein TE, Wadelius M, Niemi M Clinical pharmacology & Therapeutics 2014, 96(4): 423-8 PMID: 24918167


Gentest zur Risikominimierung der Therapie mit Simvastatin

Arzneimittel

Wie sind die Indikationen und der Wirkmechanismus von Simvastatin?Simvastatin ist ein Lipidsenker und wird zur Behandlung der Hypercholesterolämie verschiedener Genese und zur kardiovaskulären Prävention verordnet. Wie alle Statine hemmt Simvastatin die HMG-CoA-Reduktase, das Schrittmacherenzym der Cholesterolsynthese, und bewirkt durch eine vermehrte Aufnahme von LDL in die Leberzellen sowohl die Senkung der LDL- und der Triglycerid-Werte als auch einen Anstieg des HDL-Spiegels im Blut.

Gene

Welche Gene beeinflussen die Wirkung von Simvastatin?Die toxische Myopathie, eine strukturelle und funktionelle Veränderung der Skelettmuskulatur, die zur Rhabdomyolyse führen kann, gilt als eine schwere Nebenwirkung von Statinen (insbesondere von Simvastatin). Ursächlich für die Muskelschädigung ist eine genetische Variante im SLCO1B1-Gen, die zu einem Mangel des SLCO1B1-Transportproteins und damit zu einem erhöhten Simvastatin-Blutspiegel und einem verzögerten Statinabbau in der Leber führt. In der europäischen Bevölkerung sind ca. 15 Prozent Träger dieser Genvariante.

Test

Was wird getestet?Das Erbgut der Patienten wird auf die Genvariante c.521T>C (p.Val174Ala) im SLCO1B1-Gens getestet, die zum SLCO1B1-Proteinmangel führt.

Indikation

Wann sollte getestet werden?Der Gentest sollte vor Beginn einer geplanten Therapie mit Simvastatin durchgeführt werden, um gegebenenfalls durch eine Dosisanpassung oder die Verordnung eines alternativen Statin-Präparates (z.B. Atorvastatin, Rosuvastatin oder Pitavastatin) das Myopathie-Risiko zu minimieren.


Wie muss die Therapie an die Testergebnisse angepasst werden?Folgendes Vorgehen basiert auf Empfehlungen des Clinical Pharmacogenetics Implementation Consortium (CPIC)1 und hat den höchsten klinischen Evidenzlevel 1A.

Tabelle 1: Empfehlungen für die Simvastatin-Therapie in Abhängigkeit vom SLCO1B1-Genotyp

SLCO1B1-Genotyp Therapieempfehlung

Wildtyp Anwendung gemäß Fachinformation

Risikovariante, heterozygot <40 mg/Tag bei regelmäßigen CK-Kontrollen oder Wirkstoffwechsel

Risikovariante, homozygot <20 mg/Tag bei regelmäßigen CK-Kontrollen oder Wirkstoffwechsel

Kosten

Die Kosten für die Analyse des SLCO1B1-Gens werden für gesetzlich und privat versicherte Patienten erstattet, wenn die Testung durch einen Arzt angeordnet wird. Das Budget des behandelnden Arztes ist dadurch nicht belastet.

1 The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1 and Simvastatin-Induced Myopathy: 2014 Update, Ramsey LB, Johnson SG, Caudle KE, Haidar CE, Voora D, Wilke RA, Maxwell WD, McLeod HL, Krauss RM, Roden DM, Feng Q, Cooper-DeHoff RM, Gong L, Klein TE, Wadelius M, Niemi M Clinical pharmacology & Therapeutics 2014, 96(4): 423-8 (PMID: 24918167)


Genski test za smanjenje rizika pri primjeni simvastatina

Lijek

Koje su indikacije i mehanizmi djelovanja lijeka simvastatina?Simvastatin je lijek koji snizuje koncentraciju lipida te se ordinira kod lije�enja hiperkolesterolemije razli�ite geneze kao i kod prevencije nastanka kardiovaskularnih bolesti. Poput svih statina, inhibira HMG-CoA reduktazu, enzim važan za sintezu kolesterola, što dovodi do pove�ane sinteze LDL receptora te pove�anog prihvata LDL u stanicama jetre. Posljedi�no nivo LDL i triglicerida u krvi se snižava, te dolazi do porasta razine HDL u krvi.

Geni

Koji geni utje�u na djelovanje simvastatina?Toksi�na miopatija, koja dovodi do strukturnih i funkcionalnih promjena skeletnih miši�a, može dovesti do rabdomiolize i smatra se težom nuspojavom statina, posebice simvastatina. Uzrok ošte�enja muskulature je jedna varijanta u genu SLCO1B1, koja dovodi do smanjene aktivnosti transportnog polipeptida OATP1B1 (kodiran genom SLCO1B1) i time do pove�ane razine simvastatina u krvi kao i do odgo�ene razgradnje statina u jetri. Približno 15 posto populacije Europe su nositelji ove varijante gena.

Analiza

Što se analizira?Analizira se genotip pacijenta, posebice varijanta gena SLCO1B1 c.521T>C (p.Val174Ala), što dovodi do smanjene aktivnosti OATP1B1.

Indikacije

U kojem slu�aju je potrebno napraviti analizu?Genski test potrebno je provesti prije po�etka planirane terapije simvastatinom da bi se prilago�avanjem doze ili ordiniranjem alternativnog statina (npr. atorvastatin, rosuvastatin ili pitavastatin) smanjio rizik nastajanja gore opisanih miopatija.

Preporuke

Na koji na�in se terapija mora prilagoditi rezultatima testa?Sljede�i postupak temelji se preporukama Clinical Pharmacogenetics Implementation Consortium (CPIC)1 i ima najvišu klini�ku evidencijsku razinu 1A.

Tabela 1: Preporuke za lije�enje simvastatinom ovisno o genotipu SLCO1B1

Genotip SLCO1B1 Preporu�ena terapija

wt/wt Terapija sukladno uputama o lijeku (Informacijama za korisnika)

Rizicna varijanta, heterozigot <40 mg/dnevno (ukljuciti i redovitu kontrolu kreatin kinaze) ili promjeniti lijek

Rizicna varijanta, homozigot <20 mg/ dnevno (ukljuciti i redovitu kontrolu kreatin kinaze) ili promjeniti lijek

Troškovi

Priznavanje i povrat troškova za navedenu analizu varira od države do države. Ukoliko je testiranje ordinirano od strane lije�nika, troškovi analize gena SLCO1B1 biti �e priznati i refundirani za pacijente koji imaju obvezno i privatno osiguranje, pa budžet nadležnog lije�nika ili institucije u kojoj nadležni lije�nik radi zbog toga ne�e biti optere�en.

1 The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1 and Simvastatin-Induced Myopathy: 2014 Update, Ramsey LB, Johnson SG, Caudle KE, Haidar CE, Voora D, Wilke RA, Maxwell WD, McLeod HL, Krauss RM, Roden DM, Feng Q, Cooper-DeHoff RM, Gong L, Klein TE, Wadelius M, Niemi M Clinical pharmacology & Therapeutics 2014, 96(4): 423-8 (PMID: 24918167)


Tamoxifen Tamoxifen Tamoksifen


Gene test to minimise the risks related to therapy with tamoxifen

Drug

What are the indications and the mechanisms of action of tamoxifen?Tamoxifen is a prodrug which is used as an anti-oestrogen for adjuvant and palliative therapy to treat breast cancer. Tamoxifen has furthermore proven successful as preventative treatment in high risk patients. The medication is converted into its active metabolite endoxifen in the liver. While endoxifen acts as an antagonist in breast tissue, the agent has an oestrogen-like effect in the uterine mucosa, in the bones and with regard to the blood lipid metabolism. Tamoxifen is thus also referred to as SERM (Selective Estrogen Receptor Modulator). Tamoxifen’s mechanism of action is based on blocking intracellular oestrogen-receptors in cancer cells by competitive inhibition. Thus, oestrogen-mediated growth signals are suppressed which results in a decreased cell propagation.

Genes

What genes influence the effect of tamoxifen?The conversion of tamoxifen into its active metabolite endoxifen is essentially catalysed by the CYP2D6 enzyme. Whether the intended concentration of endoxifen at the target site is achieved is decisively dependent on the activity of the CYP2D6 enzyme. There are many known activity-reducing gene variants that cause a broad fluctuation range of the enzyme activity. Slow CYP2D6 metabolisers produce hardly any endoxifen.

Test

What is tested?In order to determine the CYP2D6 metabolisation type, the genotype of patients is examined with regard to the most common CYP2D6 activity reducing gene variants and also with regard to the number of active genocopies.

Indication

When should a test be carried out?Genetic testing should be carried out before the initiation of the scheduled therapy with tamoxifen in order to reduce the risk of relapse, as required, by means of an adjustment of the dose or by prescribing an alternative active agent.

Consequences of the test results

How does the therapy need to be adjusted to the test results?The following recommendations are based on the Dutch Pharmacogenetics Working Group Guideline (DPWG)1 and have the highest clinical level of evidence, 1A.

Table 1: Recommendations for tamoxifen therapy depending on the CYP2D6 metabolisation type

CYP2D6 metabolisation type Recommended therapy

Ultra-rapid metabolisers (1-2%) Use according to the summary of product characteristics

Rapid metabolisers (77-92%) Use according to the summary of product characteristics

Intermediate metabolisers (2-11%)Avoid co-treatment with an CYP2D6-inhibitor, take into consideration changing the active agent for post-menopausal women

Poor metabolisers (5-10%) Change of active agent recommended for post-menopausal women

Costs

Costs for the CYP2D6 gene analysis are reimbursed for patients with a statutory or private health insurance if the testing is requested by a doctor. The budget of the doctor responsible for treatment is not affected.

1 Swen JJ, Nijenhuis M, de Boer A, Grandia L, Maitland-van der Zee AH, Mulder H, Rongen GA, van Schaik RH, Schalekamp T, Touw DJ, van der Weide J, Wilffert B, Deneer VH, Guchelaar HJ.: Pharmacogenetics: from bench to byte--an update of guidelines. In: Clin Pharmacol Ther. 89 (5) (2011), pp. 662-673 (PMID: 21412232)


Gentest zur Risikominimierung der Therapie mit Tamoxifen

Arzneimittel

Wie sind die Indikationen und der Wirkmechanismus von Tamoxifen?Tamoxifen ist ein Prodrug und wird als Antiöstrogen zur adjuvanten und palliativen Therapie bei Brustkrebs eingesetzt. Außerdem hat sich Tamoxifen in der Prävention bei Hochrisikopatientinnen bewährt. Das Medikament wird erst in der Leber in den aktiven Wirkstoff Endoxifen umgebaut. Während Endoxifen im Brustgewebe als Antagonist wirkt, entwickelt der Wirkstoff in der Gebärmutterschleimhaut, im Knochen und im Stoffwechsel der Blutfette eine östrogenähnliche Wirkung. Tamoxifen wird deshalb auch als SERM (Selective Estrogen Receptor Modulator) bezeichnet. Das Wirkprinzip von Tamoxifen beruht auf einer Blockade der intrazellulären Östrogen-Rezeptoren in Krebszellen durch kompetitive Hemmung. Dadurch werden östrogenvermittelte Wachstumssignale unterdrückt, wodurch die Zellvermehrung im Tumor abnimmt.

Gene

Welche Gene beeinflussen die Wirkung von Tamoxifen?Die Umwandlung von Tamoxifen in den aktiven Wirkstoff Endoxifen wird maßgeblich durch das Enzym CYP2D6 katalysiert. Für das CYP2D6-Gen sind eine Vielzahl sowohl aktivitätsmindernder Genvarianten als auch aktivitätssteigernde Genduplikationen bekannt, die eine große Schwankungsbreite der Enzymaktivität bedingen. Bei langsamen CYP2D6-Metabolisierern wird nur wenig Endoxifen gebildet.

Test

Was wird getestet?Um den CYP2D6-Metabolisierungstyp zu ermitteln, wird das Erbgut der Patienten sowohl auf die häufigsten aktivitätsmindernden Varianten im CYP2D6-Gen (*2, 3*, *4, *5, *6, 9*, *10, *41) als auch auf die Anzahl der aktiven Genkopien (1XN, *2XN) untersucht.

Indikation

Wann sollte getestet werden?Der Gentest sollte vor Beginn einer geplanten Therapie mit Tamoxifen durchgeführt werden, um gegebenenfalls durch eine Dosisanpassung oder die Verordnung eines alternativen Wirkstoffs das Rezidivrisiko zu senken.


Wie muss die Therapie an die Testergebnisse angepasst werden?Die folgenden Empfehlungen basieren auf der Leitlinie der Dutch Pharmacogenetics Working Group Guideline (DPWG)1 und haben den höchsten klinischen Evidenzlevel 1A.

Tabelle 1: Empfehlungen für die Tamoxifen-Therapie in Abhängigkeit vom CYP2D6-Metabolisierungstyp


Ultraschnelle Metabolisierer (1-2%) Anwendung gemäß Fachinformation


Intermediäre Metabolisierer (2-11%)Komedikation mit einem CYP2D6-Inhibitor vermeiden, Wirkstoffwechsel bei postmenopausalen Frauen in Erwägung ziehen

Langsame Metabolisierer (5-10%) Wirkstoffwechsel bei postmenopausalen Frauen empfohlen

Kosten

Die Kosten für die Analyse des CYP2D6-Gens werden für gesetzlich und privat versicherte Patienten erstattet, wenn die Testung durch einen Arzt angeordnet wird. Das Budget des behandelnden Arztes ist dadurch nicht belastet.

1 Pharmacogenetics: from bench to byte--an update of guidelines. Swen JJ, Nijenhuis M, de Boer A, Grandia L, Maitland-van der Zee AH, Mulder H, Rongen GA, van Schaik RH, Schalekamp T, Touw DJ, van der Weide J, Wilffert B, Deneer VH, Guchelaar HJ.: In: Clin Pharmacol Ther. 89 (5) (2011), S. 662-673 (PMID: 21412232)


Genski test za smanjenje rizika pri primjeni tamoksifena

Lijek

Koje su indikacije i mehanizmi djelovanja tamoksifena?Tamoksifen je prolijek i koristi se kao anti-estrogen u adjuvantnoj i palijativnoj terapiji pri lije�enju karcinoma dojke. Pokazao se uspješnim kod prevencije visokorizi�nih pacijenata. Lijek se unutar jetre konvertira u aktivni metabolit endoksifen. Dok endoksifen djeluje kao antagonst estrogena u tkivu dojke, u sluznici maternice, u kostima te tijekom metabolizma masti u krvi djeluje kao agonist estrogena. Tamoksifen se stoga svrstava u skupinu selektivnih modulatora estrogenskih receptora (SERM). Princip djelovanja tamoksifena bazira se na blokadi intracelularnih receptora estrogena unutar stanica karcinoma putem mehanizma kompetativne inhibicije. Na taj na�in se potiskuju signali rasta vezani uz estrogen i samim time se smanjuje razmnožavanje tumorskih stanica.

Geni

Koji geni utje�u na djelotvornost tamoksifena?Pretvorba tamoksifena u aktivni metabolit endoksifen odvija se prvenstveno putem enzima CYP2D6. Da li �e se predvi�ena koncentracija endoksifena u tkivu posti�i, zna�ajno ovisi o aktivnosti enzima CYP2D6. Niz je varijanti gena CYP2D6 koje dovode do reduciranja aktivnosti enzima CYP2D6. Osobe s fenotipom slabog metabolizma - spori metabolizatori (PM) stvaraju zna�ajno manje endoksifena.

Analiza

Što se analizira?Da bi se istražilo u koju skupinu CYP2D6 metabolizatora, pacijent pripada, analiziraju se naju�estalije varijante koje dovode do smanjene aktivnosti CYP2D6 kao i broj aktivnih kopija gena.

Indikacije

U kojim slu�ajevima je potrebno napraviti analizu?Genski test bi se trebao napraviti prije samoga po�etka planirane terapije s tamoksifenom da bi se eventualno smanjio rizik recidiva putem prilago�avanja doze ili ordiniranjem alternativne terapije.

Preporuke

Na koji na�in se terapija mora prilagoditi rezultatima testa?Preporuke se temelje na smjernicama Dutch Pharmacogenetics Working Group Guideline (DPWG)1 i imaju visoku klini�ku razinu dokaza1A.

Tabela 1: Preporuke za lije�enje tamoksifenom ovisno o CYP2D6 fenotipu metabolizma

CYP2D6 fenotip metaboliziranja Preporu�ena terapija

Ultra-brzi metabolizator (UEM) (1-2%) Terapija sukladno uputama o lijeku (Informacijama za korisnika)

Brzi metabolizator (EM) (77-92%) Terapija sukladno uputama o lijeku (Informacijama za korisnika)

Intermedijarni metabolizator (IM) (2-11%)Zbog farmakokineticke interakcije izbjegavati lijecenje inhibitorima CYP2D6, razmotriti promjenu lijeka kod žena u postmenopauzi

Spori metabolizator (PM) (5-10%) Preporucuje se promjena lijeka kod žena u postmenopauzi

Troškovi

Priznavanje i povrat troškova za navedenu analizu varira od države do države. Ukoliko je testiranje ordinirano od strane lije�nika, troškovi analize gena CYP2D6 biti �e priznati i refundirani za bolesnike koji imaju obvezno i privatno osiguranje, pa budžet nadležnog lije�nika ili institucije u kojoj nadležni lije�nik radi zbog toga ne�e biti optere�en.

1 Pharmacogenetics: from bench to byte--an update of guidelines. Swen JJ, Nijenhuis M, de Boer A, Grandia L, Maitland-van der Zee AH, Mulder H, Rongen GA, van Schaik RH, Schalekamp T, Touw DJ, van der Weide J, Wilffert B, Deneer VH, Guchelaar HJ.: In: Clin Pharmacol Ther. 89 (5) (2011), S. 662-673 (PMID: 21412232)


6-Thioguanine 6-Thioguanin 6-Tiogvanin


Gene test to minimise the risks related to therapy with 6-thioguanine

Drug

What are the indications and the mechanisms of action of 6-thioguanine?6-thioguanine is a cytotoxic active agent which, as a cytostatic agent, is mainly used to treat acute and chronic lymphatic neoplasias and Hodgkin’s lymphomas. 6-thioguanine is an analogue of the naturally occurring purine base guanine and, as an anti-metabolite, inhibits purine synthesis as well as DNA and RNA synthesis.

Genes

What genes influence the effect of 6-thioguanine?The enzyme thiopurine methyltransferase (TPMT) is responsible for the inactivation of thioguanine through methylation of the sulfhydryl group. A TPMT deficiency leads to a delayed breakdown of the active agent which can cause severe, life-threatening myelosuppression as a side effect. In virtually all population, there are known activity-reducing gene variants for the TPMT gene which require an adjustment of the dose in order to increase the tolerability with regard to 6-thioguanine.

Test

What is tested?The genotype of patients is examined with regard to the most common clinically relevant TPMT gene variants (*2, *3A, *3B, *3C and *4) which in compound heterozygous or homozygous state lead to a complete loss of the TPMT enzyme activity.

Indication

When should a test be carried out?Genetic testing should be carried out before the initiation of the scheduled therapy with 6-thioguanine in order to reduce the risk of myelosuppression (disturbance of haematopoiesis), as required, by means of an adjustment of the initial dose or by prescribing an alternative active agent.


How does the therapy need to be adjusted to the test results?The following procedure is based on the recommendations of the guidelines of the Clinical Pharmacogenetics Implementation Consortium (CPIC)1 and have the highest clinical level of evidence, 1A.

Table 1: Recommendations for thioguanine therapy depending on the TPMT genotype




Risk variant, compound heterozygous or homozygous

Change of the active agent or drastic reduction of the initial dose for treatment of malignant diseases (10-fold reduction and only on 3 days / week)

Costs




Gentest zur Risikominimierung der Therapie mit 6-Thioguanin

Arzneimittel

Wie sind die Indikationen und der Wirkmechanismus von 6-Thioguanin?6-Thioguanin ist ein zytotoxischer Wirkstoff, der als Zytostatikum vorrangig zur Behandlung akuter und chronischer lymphatischer Neoplasien und zur Behandlung des Hodgkin Lymphoms eingesetzt wird. 6-Thioguanin ist ein Analogon der natürlich vorkommenden Purinbase Guanin und hemmt als Antimetabolit sowohl die Purinsynthese als auch die DNA- und RNA-Synthese.

Gene

Welche Gene beeinflussen die Wirkung von 6-Thioguanin?Das Enzym Thiopurin-Methyltransferase (TPMT) inaktiviert Thiopurine durch Methylierung der Sulfhydrylgruppe. Ein Mangel an TPMT führt zu einem verzögerten Wirkstoffabbau, wodurch es zu einer schweren, lebensbedrohenden Myelosuppression als Nebenwirkung kommen kann. Für das TPMT-Gen sind in der Bevölkerung aktivitätsmindernde Genvarianten bekannt, die eine Dosierungsanpassung erforderlich machen, um die Verträglichkeit von 6-Thioguanin zu erhöhen.

Test


Indikation

Wann sollte getestet werden?Der Gentest sollte vor Beginn einer geplanten Therapie mit 6-Thioguanin durchgeführt werden, um gegebenenfalls durch eine Anpassung der Startdosis oder die Verordnung eines alternativen Wirkstoffs das Risiko einer Myelosuppression (Störung der Hämatopoese) zu senken.


Wie muss die Therapie an die Testergebnisse angepasst werden?Folgendes Vorgehen basiert auf Empfehlungen der Leitlinien des Clinical Pharmacogenetics Implementation Consortium (CPIC)1 und haben den höchsten klinischen Evidenzlevel 1A.

Tabelle1: Empfehlungen für die Thioguanin-Therapie in Abhängigkeit vom TPMT-Genotyp


Wildtyp Anwendung gemäß Fachinformation

Risikovariante, heterozygot Startdosis sollte 30-70 Prozent der normalen Dosierung entsprechen

Risikovariante, compound heterozygot oder homozygotWirkstoffwechsel oder drastisch reduzierte Startdosis zur Behandlung maligner Erkrankungen (10-fach reduziert und nur an 3 Tagen/Woche)

Kosten

Die Kosten für die genetische Analyse des TPMT-Gens werden erstattet für gesetzlich und privat versicherte Patienten, wenn die Testung durch einen Arzt angeordnet wird. Das Budget des behandelnden Arztes wird dadurch nicht belastet.



Genski test za smanjenje rizika kod primjene terapije sa 6-tiogvaninom

Lijek

Koje su indikacije i mehanizmi djelovanja 6-tiogvanina?6-tiogvanin je citostatski lijek koji se koristi u lije�enju akutne limfoblasti�ne i akutne mijeloi�ne leukemije. 6-tiogvanin je analog purinske baze gvanina te kao anti-metabolit zaustavlja sintezu purina te posljedi�no i sintezu DNA i RNA.

Geni

Koji geni utje�u na djelovanje 6-tiogvanina?Enzim tiopurin metiltransferaza (TPMT) inaktivira tiogvanin putem metilacije sulfhidrilne skupine. Nedostak TPMT dovodi do odgo�ene razgradnje aktivne tvari, pri �emu može do�i do teške, po život opasne supresije koštane srži. U gotovo svim populacijama, poznate su varijante gena TPMT koje dovode do smanjene aktivnosti enzima i stoga je potrebno prilagoditi doziranje da bi se pove�ala podnošljivost 6-tiogvanina.

Test

Što se analizira?Analizira se genotip pacijenta na naju�estalije klini�ki relevantne varijante gena TPMT (*2, *3A, *3B, *3C i *4) jer kombinirani (združeni) heterozigot «compound heterozygous» ili homozigoti imaju potpuni gubitak aktivnosti enzimaTPMT.

Indikacije

U kojim je slu�ajevima potrebno napraviti analizu?Genski test bi se trebalo napraviti prije planirane terapije sa 6-tiogvaninom da bi se smanjio rizik supresije koštane srži (poreme�aj hematopoeze) putem prilago�avanja po�etne doze ili ordiniranjem alternativne aktivne tvari.

Preporuke

Na koji na�in se terapija mora prilagoditi rezultatima testa?Postupak je temeljen na preporukama smjernica the Clinical Pharmacogenetics Implementation Consortium (CPIC)1 uz najvišu klini�ku razinu dokaza 1A.

Tabela 1: Preporuke za lije�enjem 6-tiogvaninom ovisno o genotipu TPMT


wt/wt tip Terapija sukladno uputama o lijeku (Informacijama za korisnika)

Rizicna varijanta, heterozigot Pocetna doza trebala bi iznositi 30-70 posto prosjecne doze lijeka.


Promjena lijeka ili drasticno reducirana pocetna doza u svrhu lijecenja od malignih bolesti (10-terostruko reducirana i samo 3 dana/tjedno)

Troškovi

Ukoliko je testiranje ordinirano od strane lije�nika, troškovi analize gena TPMT biti �e priznati i refundirani za pacijente koji imaju obvezno i privatno osiguranje. Budžet nadležnog lije�nika ili institucije u kojoj nadležni lije�nik radi ne�e zbog toga biti optere�eni. Priznavanje i povrat troškova za navedenu analizu varira od države do države. Ukoliko je testiranje ordinirano od strane lije�nika, troškovi analize TPMT gena biti �e priznati i refundirani za bolesnike koji imaju obvezno i privatno osiguranje, pa budžet nadležnog lije�nika ili institucije u kojoj nadležni lije�nik radi ne�e zbog toga biti optere�eni.



Glossary

Glossar

Riječnik


Allele: Different versions of the same gene.

Allel: Alternative Versionen des gleichen Gens.

Alel: Različita varijanta (modalitet) istog gena.

Chromosome: The biological packaging system for storing and regulating DNA. Each chromosome is made up of DNA tightly coiled many times around proteins called histones that support its structure.

Chromosom: Die biologische Verpackungsform zur Speicherung und Regulation der DNA. Jedes Chromosom besteht aus einem DNA Molekül, das kompakt um Proteinpartikel, sogenannte His-tone, gewickelt ist.

Kromosom: Biološka struktura za pohranu i regulaciju DNA mo-lekule. Svaki kromosom je građen od DNA molekule koja obavija bjelančevine zvane histoni, koji daju potporu cijeloj strukturi.

Compound heterozygote: The presence of two different mutant alleles at a particular gene locus, one on each chromosome of a pair (trans).

Compound heterozygot: Die Anwesenheit von zwei verschiede-nen mutierten Allelen an einem bestimmten Genort (trans).

Kombinirani (združeni) heterozigot: Prisustvo dva različita alela na određenom genskom lokusu od kojih se svaki nalazi na razli-čitom kromosomu (trans).

Cytochromes P450 (CYPs): The superfamily of proteins. Cyto-chrome P450 enzymes account for 70 percent to 80 percent of enzymes involved in drug metabolism. Each cytochrome P450 gene is named with CYP, indicating that it is part of the cyto-chrome P450 gene family.

Cytochrom P450 (CYPs): Eine Protein Superfamilie, deren Mit-glieder Enzyme sind. Cytochrom P450 Enzyme sind für 70% bis 80% des Stoffwechsels von Medikamenten verantwortlich. Die Bezeichnung der Gene für diese Enzyme beginnt mit „CYP“, wo-durch sie als Mitglied der Cytochrom P450 Genfamilie erkennbar sind.

Citokrom P450 (CYP): Superporodica bjelančevina. Enzimi su-perporodice citokroma P450 predstavljaju 70-80% svih enzima uključenih u metabolizam lijekova. Svaki gen koji kodira enzime iz superporodice P450 označen je kao CYP, što istodobno upuću-je da je dio obitelji gena citokroma P450.

DNA: (Deoxyribonucleic acid) is organized into structures called chromosomes and housed within the nucleus of our cells. DNA is also found in cell mitochondria. It is the carrier of genetic in-formation.

DNA: Deosxyribonukleinsäure ist Träger der genetischen Infor-mation. Sie ist in Strukturen organisiert, die als Chromosomen bezeichnet werden und in den Kernen unserer Zellen unterge-bracht sind. Ein Teil der DNA ist auch in den Mitochondrien zu finden.

DNA (DNK-deoksiribonukleinska kiselina): smještena je u kro-mosomima koji se nalaze u jezgri naših stanica. DNA se isto tako nalazi i u mitohondrijima. Prenosi genetske informacije.

Drug: A medicine or other substance which has a physiological effect when ingested or otherwise introduced into the body.

Medikament, Arzneiwirkstoff: Eine künstliche oder natürliche Substanz, die aus therapeutischem Anlass geschluckt oder auf andere Weise in den Körper gebracht wird.

Lijek: Medicinsko sredstvo ili određena supstanca koja pri kon-zumaciji ili unosu u organizam na neki način ima učinak na od-vijanje bioloških funkcija.

Enzymes: Proteins that act as catalysts within living cells.

Enzyme: Katalytisch wirksame Proteine, die Stoffwechselreaktio-nen in lebenden Zellen ermöglichen.

Enzimi: Stanične bjelančevine s katalitičkim svojstvima.

Gene: A working subunit of DNA and a unit of heredity which is transferred from a parent to offspring and is held to determine some characteristic of the offspring. National Human Genome Research Institute estimates there are anywhere from 20,000 to 25,000 genes in the average human genome.

Gen: Eine funktionelle Einheit der DNA, die genetische Informa-tion von Eltern auf die Nachkommen übertragen. Das amerika-nische National Human Genome Research Institute schätzt das menschliche Genom auf 20.000 bis 25.000 Gene.

Gen: Funkcionalna podjedinica DNA molekule i jedinica naslije-đivanja koja se prenosi s roditelja na potomstvo te time određuje neke značajke potomstva. National Human Genome Research Institute procjenjuje da unutar genoma čovjeka postoji 20,000 – 25,000 gena.

Genome: The complete set of genes and genetic material present in a cell or organism.

Genom: Die Gesamtheit der Gene und des genetischen Materials in den Zellen eines Organismus.

Genom: Svi geni i genski materijal prisutan u stanici ili organiz-mu.

Genotyping: is the process of determining differences in the genetic make-up (genotype) of an individual by examining the individual’s DNA sequence using biological assays and compar-ing it to another individual’s sequence or a reference sequence.

Genotypisierung: Die Methoden zum Nachweis von Unterschie-den im genetischen Aufbau (Genotyp) eines Individuums im Vergleich zu anderen Personen durch DNA-Sequenzierung und Vergleich mit einer Referenzsequenz.

Genotipizacija: process određivanja raznolikosti genotipa (DNA sekvencije pojedinca) u odnosu na DNA sekvenciju drugog poje-dinca ili referentnu sekvencije.


HLA: The HLA gene family provides instructions for making a group of related proteins known as the human leukocyte antigen (HLA) complex. These cell-surface proteins are responsible for the regulation of the immune system in humans.

HLA: Die HLA Genfamilie enthält die Informationen zum Aufbau einer Gruppe von Proteinen, die als Human Leukozyten Antigen (HLA) Komplex bezeichnet werden. Diese Zelloberflächenprotei-ne spielen eine Schlüsselrolle bei der Regulation des Immunsys-tems.

HLA: Genski sustav ljudskih leukocitnih antigena ili genski su-stav tkivne podudarnosti, u čovjeka osigurava informacije za proizvodnju bjelančevina zvanih ljudski leukocitni antigenski kompleks (HLA). Ovi protein smješteni na površini stanice odgo-vorni su za funkcioniranje imunološkog sustava čovjeka.

Homozygous: Describes a genotype consisting of two identical alleles at a given locus

Homozygot: Bezeichnet den Genotyp mit zwei identischen Alle-len am gleichen Genort.

Homozigot: Opisuje genotip sastavljen od dva identična alela na određenom lokusu.

Heterozygous: Describes a genotype consisting of two different alleles at a locus

Heterozygot: Bezeichnet den Genotyp mit zwei unterschiedli-chen Allelen am gleichen Genort.

Heterozigot: Opisuje genotip sastavljen od dva različita alela na određenom lokusu.

Individualized medicine: Also known as personalized medicine or precision medicine is the medicine with personalization and customization of health care, with decisions and treatments tai-lored to each individual patient in every way possible.

Individuelle Medizin: Auch als personalisierte Medizin oder Prä-zisionsmedizin bezeichnet. Hierbei richten sich medizinische Behandlungen soweit irgend möglich maßgeschneidert nach den individuellen Gegebenheiten eines Patienten.

Individualizirana medicina: Poznata još kao personalizirana ili precizna medicina kojoj je temeljni cilj omogućiti specifičnu te-rapiju “skrojenu” prema potrebama pojedinca.

Mitochondria: Are often referred to as the powerhouses of the cells converting oxygen and nutrients into adenosine triphos-phate.

Mitochondrium: Häufig als Kraftwerke der Zellen bezeichnet. Diese R-förmigen Zellorganellen können als Generatoren der Zelle angesehen werden. In ihnen wird aus Nährstoffen unter Beteiligung von Sauerstoff der Energieträger Adenosin Tripsphat (ATP) gebildet.

Mitohondrij: Često zvan energetskom centralom stanice u kojem se tijekom postupka oksidacijske fosforilacije stvara adenozin trifosfat (ATP).

Mitochondrial DNA: DNA located in mitochondria.

Mitochondriale DNA: DNA die in den Mitochondrien gespeichert ist.

Mitohondrijska DNA: DNA smještena u mitohondrijima.

Mutation: Is genetic change, resulting in a variant form which may be transmitted to subsequent generations, caused by the alteration of single base units in DNA, or the deletion, insertion, or rearrangement of larger sections of genes or chromosomes.

Mutation: Eine genetische Veränderung, die die an die nach-folgende Generation weitergegeben werden kann. Sie beruht entweder auf dem Austausch eines einzelnen genetischen Bau-steins (Base) oder auf Deletionen, Insertionen oder Umlagerun-gen von Genen- oder Chromosomenabschnitten.

Mutacija: Genetska promjena koja rezultira različitim promjena-ma DNA molekule, koja može biti prenesena na sljedeću genera-ciju. Najčešće su promjene jedne baze unutar DNA molekule, ali mogu biti i promjene poput delecije, insercije ili preraspodjela većeg segmenta gena ili čak kromosoma.

Pharmacogenomics: Is the study of how genes affect a person’s response to drugs

Pharmakogenomik: Befasst sich damit, wie bei einer bestimm-ten Person Gene die Wirkung von Medikamenten beeinflussen.

Farmakogenomika: Proučava vezu između genske predispozici-je pojedinca i njegove sposobnosti da metabolizira neki lijek ili tvar.

Single nucleotide polymorphism (SNP): Are the most common type of genetic variation among people and represent a varia-tion in a single nucleotide that occurs at a specific position in the genome.

Single nucleotide polymorphism (SNP): Der häufigste Typ der genetischen Variationen von Mensch zu Mensch. SNPs basieren auf dem Austausch einer einzelnen Base in einem Gen.

Polimorfizam jednog nukleotida (SNP): Najčešći oblik genske varijacije u populaciji i predstavlja varijaciju jednog nukleotida koja se događa na specifičnoj poziciji unutar genoma.

BioGlobe GmbH - The Home of Life Sciencewww.bioglobe.net

and

St. Catherine Hospital – Member of The Leading Hospitals of The Wordwww.svkatarina.com and www.svkatarina.hr

Pharmacogenetics in clinical practice - ISABSisabs.hr/doc/Literature/Pharmacogenetics_in_clinical_practice.pdf · Pharmacogenetics in clinical practice Experience with 16 commonly

Documents