Pharmacogenetics and Pharmacogenomics

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Biol 601 SeminarMay 10, 2012Raul SotoAdam GainfordGreg StangerThe Role of Pharmacogenetics / Pharmacogenomics in Drug Development and Regulatory Review

http://www.liv.ac.uk/pharmacogenetics/dna_and_pills.jpg

Good evening, our group members are Adam Gainford, Greg Stanger, and myself Raul Soto.

Were going to talk about the Role of Pharmacogenetics and Pharmacogenomics in Drug Development and Regulatory Review1

Different [drugs] to different patients, for the sweet ones do not benefit everyone, nor do the astringent ones, nor are all the patients able to drink the same things. Diseases IIIHippocrates, father of Western Medicine, 2500 years ago

Weve known for a long time that not all substances have the same effects on all patientsWith the development of molecular genetics, now we can begin to explore WHY

http://www.sculpturegallery.com/two/hippocrates5.jpg

I want to start with a quote (read it)

This is from Hippocrates, one of the great men of Ancient Greece, the father of Western Medicine

Weve known for a long time But just NOW, with the development

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Overall ScopeHow DNA-based differences affect PK and PD of medications

How pharmacogenomics info is applied and reviewed in IND, and NDA/BLA submissions

Critical issues in regulatory review

Labeling implications

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In very general terms, we will talk about (read)3

DefinitionsPharmacogenetics: the convergence of pharmacology and genetics, deals with genetically determined responses to drugs also concerned with the differences in the metabolism of medications among children, adults, and senior citizens; men and women; and people with various medical conditions.Source: MedicineNet, www.medterms.com/script/main/art.asp?articlekey=4858

Pharmacogenomics: biotechnological science that combines techniques from medicine, pharmacology, and genomics; and is concerned with developing drug therapies to compensate for genetic differences in patients which cause varied responses to a single therapeutic regimen. Patient-drug interactions is a complex trait influenced by many genes.Source: www.pharmainfo.net/reviews/role-pharmacogenomics-drug-development

http://www.cognigencorp.com/index.php/cognigen/our_services/

Lets start with some definitions

Pharmacogenetics deals with how an individuals genetic makeup affects the persons response to drugs differences in how drugs are metabolized based on age, gender, ethnic background, medical conditions

Pharmacogenomics deals with using knowledge from various branches of science to compensate for those differences, for example by changing doses.4

DefinitionsPharmacokinetics: The process by which a drug is Absorbed, Distributed, Metabolized, and Eliminated (ADME) by the body.Source: http://medical-dictionary.thefreedictionary.com/pharmacokinetics

Pharmacodynamics: The study of how a drug acts on a living organism, including the pharmacologic response and the duration and magnitude of response observed relative to the concentration of the drug at an active site in the organism .Source: http://medical-dictionary.thefreedictionary.com/pharmacodynamics

PK:what the organism does to the drugPD: what the drug does to the organism

Pharmacokinetics is the study of how a drug gets ABSORBED into the organism, DISTRIBUTED throughout tissues, METABOLIZED, and ultimately ELIMINATED from the organism the typical acronym for this is ADME

Pharmacodynamics is the study of how the drug acts on the body: WHAT is the EFFECT that is has, HOW INTENSE is that effect, HOW LONG does it last, any associated TOXICITY as a function of its concentration.

So in summary PK 5

Variability in Drug ResponsePeoples responses to a drug substance may vary according to various intrinsic and extrinsic factorsIntrinsic:AgeGenderEthnicityDisease State (i.e. diabetes, heart disease)Organ dysfunctions (i.e. liver or kidney diseases)Physiological states (i.e. pregnancy, lactation)GeneticsExtrinsic:SmokingDietMedications a person is taking

What do these have in common?Differences in the levels and patterns of gene expression

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The SAME dose of a drug substance can have different effects on different individuals. This can be due to a series of INTRINSIC and EXTRINSIC factorsSome of these factors are (read them)

What do they all have in common? All related to differences 6

PolymorphismsTypeEffectsChanges in a genes protein coding region in translated amino acid sequence => protein structure, conformation => protein functionChanges in a genes promoter /regulatory regions in protein expression levelsChanges in # of copies of a gene in protein expression levelsIf gene codes for a transcription factor in protein expression for multiple genesIf gene codes for an intron/exon splicing enzyme in protein structure/function for multiple proteinsDeleted / inactivated geneNo protein expression, protein is absentIf gene codes for metabolism-related proteins in way drugs are absorbed, distributed, metabolized, excreted; in duration and intensity of effect; in toxicity

Polymorphisms in enzymes, receptors, transporters, signaling proteins, etc. may affect a drugs PK/ PD profileNOT limited to a drugs target!

A bit of a review from our Genetics courses

When you have various versions of a gene, various alleles If the change is in the coding region that MAY alter the structure and function of the protein productIf its in the promoter region that may alter how and when the gene is expressedEtc

NOT limited to the drugs target So we all probably know that if we our drug targets a receptor, and theres 4 alleles coding for 4 slightly different versions of this receptor, and our drug binds better to allele 1 and not so good to allele 4 thats only ONE way genetic polymorphisms can affect how our drug works. Polymorphisms in metabolic enzymes that interact with our drug are ALSO incredibly important. 7

http://www.pharmainfo.net/reviews/role-pharmacogenomics-drug-development

For some people the SAME dose of the SAME drug will be NOT toxic AND beneficialFor some it will be NOT toxic but also NOT beneficialFor some it will be TOXIC but also beneficialAnd for some it will be TOXIC AND not beneficial

So, how BIG is this problem in real life it turns out to be VERY BIG8

http://mostgene.org/2009_conference/personalized_meds_Gettig.pdf

These are some of the most common health issues and you can see that major drugs are just NOT EFFECTIVE for a significant percentage of the population 9

Examples Women have better response to serotonin reuptake inhibitor antidepressants (SSRIs) like Prozac and Paxil, than to tricyclic antidepressants like Elavil and Tofranil; also more likely to develop depression due to low serotonin levels.Some anti-anxiety medications have better effect on men than women.Women have better response to narcotic pain relievers than to non-narcotics.Carvedilol (Coreg), a beta-adrenergic blocking agent used to lower blood pressure, is more effective in Africans than Caucasians.Enalopril (Vasotec), an angiotensin II inhibitor to lower blood pressure, is more effective in Caucasians than Africans.Heart failure combined treatment with hydralazine + isosorbine is more effective in Africans than Caucasians.Expression of high levels of alcohol dehydrogenase enzyme in Asians (85%) vs Caucasians (Swiss 20%, British 10%); alcohol is metabolized faster, causes slow heartbeat, facial flushing.

I wont go into the details, these are just examples, for those of you who are interestedof various substances that have different effects on different groups of people depending on gender or ethnicity. 10

Real life implications 1980-1999 study of 354 drugs

21 % required dose changes 79 % of those changes were safety-related dose reductionsMany changes based on new info obtained AFTER drug market releaseUsually dose recommendations for specific populations, i.e.Renal / hepatic impairmentConcomitant medicationsPregnancy

Drug manufacturers should have dosing recommendations for individuals with intrinsic /extrinsic factors BEFORE market release to AVOID risks of Adverse Drug Reactions (ADR).

Refer to study that found that ONE FIFTH of all people have required changes in the doses of their medicationAnd out of those instances, almost 80% were because of SAFETY dose reductions, people having adverse events.Now these are CORRECTIVE measures, they were finding that these drugs had these negative effects on some groups AFTER the drug was released. And that is just NOT ENOUGH

The take-home message here is that drug manufacturers should FIND OUT about these effects BEFORE drugs are released, to PREVENT putting the patiente at risk of an Adverse Drug Reactions11

Adverse Drug Reactions (ADRs)5 % hospital admissions10% hospitalized patients experience them106,000 deaths and 2.2 million serious events caused by adverse drug reactions (ADRs) in the US each year (Lazarou 1998)Jason Lazarou, MSc;Bruce H. Pomeranz, MD, PhD;Paul N. Corey, PhD. Incidence of Adverse Drug Reactions in Hospitalized Patients: A Meta-analysis of Prospective Studies. JAMA.1998;279(15):1200-12054th 6th leading cause of death in the US for hospitalized patients

May lead to drug being withdrawn from the market

http://www.scientificamerican.com/article.cfm?id=a-biochemical-way-to-reduce

And that is because Adverse Drug Reactions are a BIG problem. 5% of all hospital admissions10% of all hospitalized people have themOVER 100,000 deaths and over 2 MILLION people affected every year, in the USA alone.4th 6th leading cause of death in hospitals

The key point here is that Adverse Reactions are a BIG deal. We are in this business to HELP people, NOT to send them to the hospital, or hurt them, or kill them.

In some cases the FDA will order your drug removed from the market because of ADRs12

Drugs withdrawn from the US market

Heres a list of drugs the FDA removed from the market between 1997 and 2001 , due to adverse reactions .13

ADRs vs polymorphismsMany metabolic enzymes are polymorphic=> Evolutionary defense process

7 22 % of a sample of randomly selected drugs are substrates for polymorphic enzymes

59 % of drugs that cause ADRs are metabolized by polymorphic enzymes

http://media.rbi.com.au/AD_Media_Library/Fluvax.jpg

So , whats the relationship between Adverse Reactions and polymorphisms?

Many if you take a random sample of the most commonly prescribed drugs, from 7 22% of them are substrates for polymorphic metabolic enzymes HOWEVER if you take the drugs that tend to cause Adverse Reactions, you will find that almost 60% of them are metabolized by polymorphic enzymes

So there is a correlation there if your drug is metabolized by a polymorphic metabolic enzyme, theres a chance people with different versions of the enzyme will metabolize the drug differently, and SOME may get Adverse Reactions14

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You give the SAME dose of the SAME drug to 3 people with different versions of a metabolic enzyme.

If a person is homozygous for the wild type alleles of this metabolic enzyme, theyll take the drug, they get a therapeutic effect, stays within the safety region

NOW You get a person who is heterozygous, with a wild type allele AND a variant that works slightly different, THAT person will have a DIFFERENT response to the drug. They will still get a therapeutic effect, in fact MORE effect for the same dose than the first person, but they will ALSO get some ADVERSE drug reactions due to toxicity. So for this person a SMALLER dose of the drug would bring the desired effect and lower the risk.

THEN you get a person who is homozygous for the variant, and that person is going to have a COMPLETELY different reaction to the drug. Thats persons liver is going to metabolize the drug in a COMPLETELY different manner he or she will experience serious adverse side effects. THIS person probably needs a different drug.15

Metabolizing enzymes and transportersPhase I metabolizing enzymesCytochromes P450Phase II metabolizing enzymesUGTs, GSTs, SULTs, MTs, EHs, NATsDrug transportersInflux transporters: PGPsEfflux transporters: OATPs (organic anion transport proteins), OCTPs (organic cation transport proteins).Drug receptorsClass 1 receptors : ligand-controlled ion channelsClass 2 receptors : G-protein coupled receptorsReceptors regulating gene expressionG-proteinsi.e. GNAS1, GNB3

Genetic Variations can influence the activity of, or have an effect on the expression of, the following types of proteins

Like I mentioned before, our drug molecule interacts with various other proteins in the body, not just the target. There are metabolizing enzymes families, there are also drug transporter protein families

Polymorphisms in all these can have an effect on how the drug acts on the patients body16

Drug Metabolism : pathwaysBody uses enzymes to modify drug substancesRate of this process is relevant to duration and intensity of a drugs pharmacological action

Phase I: non-synthetic reactionsOxidation, reduction, hydrolisis, cyclization, decyclizationActivate / deactivate substances

Phase 2: conjugation reactionsTypically detoxify / deactivate substancesMethylation, sulphation, acetylation. glucuronidation, glutathione conjugation, glycine conjugation

Interference (induction, suppression, inhibition) with these processes accounts for the most common and potentially severe ADRs.

This is basically background information about how drugs are metabolized. Theres two main phases , each has different types of biochemical processes, they are mediated by different enzymes.

The key point here is that the MAJORITY of Adverse reactions happen when these processes are affected in some way.17

Drug Metabolism: sitesLIVER : principal site of drug metabolismSmooth endoplasmic reticulum of liver cells

OTHERS: most tissue has some metabolic capabilitiesEpithelial cells of gastrointestinal tract, skin, lung, kidneys

http://www.doctorfungus.org/thedrugs/images/antifung_1.jpg

This is basic anatomy; the main site in the body where drugs are metabolized is the LIVER

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CYPsCytochrome P450 superfamily of polymorphic enzymesFound all over the bodyCatalyze most Phase I oxidative reactionsMajor enzymatic activity occurs in hepatic CYPs (liver)Also expressed in the brain, lungs, kidneys, intestines, monocytes, macrophages, lymphocytesRelevant in the bioactivation and metabolism of 75% of drugs

http://www.p.chiba-u.ac.jp/lab/bukka/cyp2c9.png

Theres a very important family of metabolic enzymes called CYPThey are highly polymorphic, lot of different versionsTheyre the main enzyme responsible for Phase I of drug metabolism in the liverThey are involved in activating and metabolizing 75% of the drugs

Polymorphisms in liver enzyme CYP2D6 : people with low levels of CYP2D6 will require smaller doses of many drugs, and are more at risk of adverse drug reactions.

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CYP NomenclatureFamilies:17 families in humansSubfamilies:42 sub-families in humansEnzyme/gene:55 genes and 29 pseudogenes in humans

http://www.doctorfungus.org/thedrugs/images/antifung_2.gif

This is the naming convention for these enzymes, I bring this so you can see there are 17 families, 42 subfamilies, and there are over 50 genes coding for them.

Run the permutations in your head This should give you an idea of how many different CYPs there are, of the immense complexity of human metabolism

However, theres good news20

Approximately 95% of all drug oxidation in humans is the actionof SIX CYP enzymes

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Crestor Member of a class of molecules called statins

Used to treat high cholesterol and related conditions caused by dyslipidemia (abnormal elevation of lipids in blood

Approved by FDA in August 2003 in 10mg, 20mg, and 40mg presentations

5 mg presentation was later developed for Japan

Now after seeing how pharmacogenetics may affect a persons response to a drug, lets take a look at a real-world case

CRESTOR, from AstraZeneca, a statin, lowers bad cholesterol and increases the good one.

It was originally approved by the FDA in August 2003. I was part of that launch, I worked at the AZ manufacturing site that makes Crestor, was responsible for the startup and validation of the packaging building, packaging lines.

AZ initially came out with 3 presentations for Crestor, 10, 20, and 40.

But LATER it was necessary to develop an additional presentation, a 5mg dose for the Japanese market. WHY?22

X-fold changes in AUC for various population groupsAUC : area under the plasma concentration curveAUC for Crestor varies depending on several factors :Ethnicity (esp. Japanese, Singapore ethnic Chinese)Hepatic impairmentRenal impairmentPerson taking cyclosporine, gemfibrozil, itraconazole

One important parameter in Pharmacokinetics, the area under the plasma concentration curve

This figure shows the X-fold increase in AUC for various groups when compared to the control group.

And you can see that some people were metabolizing Crestor differently from most people people with kidney and liver problems, people taking some specific medicines, and people from an East Asian ethnic background.

And this was discovered AFTER Crestor was released to the market. 23

Because Asians appear to process the drug differently, half the standard dose can have the same cholesterol-lowering benefit in those patients, though a full dose could increase the risk of side-effectshttp://articles.latimes.com/2005/mar/03/nation/na-crestor3

Pharmacogenetics information was reflected in the CRESTOR product label

So AstraZeneca CHANGED the labeling information for Crestor, taking into account these groups that metabolize the drug differently25

Variability in Drug ResponseVariability in drug response and factors that contribute to it must be investigated during the drug development process

Companies should submit to regulatory agencies data for key PK/PD parameters as part of the drug IND, and NDA/BLA reviews.AUC: Area under the plasma concentration curveCmax:maximum plasma concentration

Phase III clinical trials should include how these parameters vary in various population groups

This information should be included in the drugs label

So, KEY TAKEAWAYS

(read)26

Changes in PK/PD parametersEfficacy / safetyLabeling of other drugs in the same pharmacological classIntrinsic factorsExtrinsic factorsDrug R & DPatientsDrug labeling recommendations

Your drug labeling info should include all of these 27

Applications in Drug Development CYP2D6 is commonly used polymorphic enzyme to test drug metabolizing.

It is becoming increasingly more common for submissions to use genotyping vs. phenotyping Distribution of submissions from 1992-2001 evaluating polymorphic enzymes

What do the Applications of Pharmacogenomics/PG have as goals?PK differences in different phenotypes and genotypesUse genotypes as a covariant for PK/PD in clinical trial analysisExplain outliers in PK/PD in clinical trialsSort subjects into genotypic categories by clinical effectivenessDetermine if ADR is relative to certain genotypes

What is to come for future applications?More genotypic analysis and evaluationsInvestigation of multiple enzyme and transporters and receptors

Genomic Analysis examples

http://universe-review.ca/I11-50-PCR.jpghttp://www.biosci.ohio-state.edu/~plantbio/osu_pcmb/pcmb_lab_resources/images/pcmb102/biotech/restriction_digest1.jpghttp://upload.wikimedia.org/wikipedia/en/thumb/d/d9/DotBlotDemo.jpg/350px-DotBlotDemo.jpg

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Type of genomic data for drug developmentAlleles in different races and ethnic groups for dose-response must be considered

https://encrypted-tbn0.google.com/images?q=tbn:ANd9GcR_MoE0AXc6jdEMSCwSnMBbAAKIP5dLBsCYNHjqWJ05lfg7uJGu8Qhttp://www.nature.com/clpt/journal/v84/n3/images/clpt2008114f1.gif31

New FDA guidelines based on purpose of evaluations and the validity of biomarkers used.

Need to submit new drug applications when using metabolizing enzyme biomarkers.

Table 2.5

Altered Drug Responses and Interactions Can be caused by dietary supplements or other drugs. These interactions may be impacted by genotypes Has begun to appear in product labels

Voluntary vs. RequiredSubmission of Genomic Data Regulations and guidelinesDictate what data needs to be shared with the regulating agencies and in what formHeavily regulated clinical trial environment

VGDS VXDSVoluntary Genomic Data SubmissionIPRG review

Why The Data Regulations? At any given time, there are thousands of clinical trials underway. A standard must be set to ensure consistency in the analysis of:EfficacyVariabilityDrug use and administrationPatient screeningData qualityAdverse Effectsand any other characteristic of the drug development process

Access to pharmacogenomic data (VGDS)May lead to a large database of genomic data for research and optimization purposes

How to Present the Data The possible outcomes for data submission:Full Study ReportsContains all clinical and pharmacological data that may contribute to the evaluation of effectiveness for the proposed indication along with any information stated in the labelAbbreviated ReportDoes not involve the effectiveness or pharmacology. Contains all of the safety information that would be found in the full study reportSynopsisFormat allowing the reviewer to successfully evaluate the safety data

Submission Guidelinesfor IND Data

Is the data used for clinical or preclinical decisions?

Used to support the drug description?

Was the data collected through the detection of a known valid biomarker?* Known valid biomarker one that is accepted by the scientific community at-large to predict a clinical outcome

Submission Guidelinesfor NDA/BLA data

Will the data be used towards approval or labeling justification?

Was the data collected through the detection of a known or probable biomarker?* Probable valid biomarker Appears to have predictive value but not yet replicated or widely accepted

Examples(Book gives four) 2

3 4Stage: IND

Situation: The NME is metabolized by CYP2C19. The patients genotypes are screened for CYP2C19 to determine drug dosing.

Data submission format: Full Report

Reasoning: Data used to support scientific arguments based on drug dosing selectionStage: Phase III

Situation: The NME is metabolized by CYP2D6. After the testing occurred, a subset of patients were screened genotypically for CYP2D6 to analyze any genotype and dosing association.

Data submission format: Full Report

Reasoning: This data will be used for proposed labeling.Stage: Phase III

Situation: The NME is metabolized by CYP2D6. After trial completion, a subset of patients were screened genotypically for CYP2D6 to find an association between plasma clearance values and genotype. Not used for labeling.

Data submission format: Abbreviated Report

Reasoning: Not used for label or drug description

Stage: Drug Interaction Study

Situation: The NME is metabolized by CYP3A. The patients genotypes are screened for CYP3A5, a polymorphism to determine its effect on inter-individual variability.

Data submission format: Synopsis only required for NDA/BLA. A VGDS is recommended for NDA/BLA/IND.

Reasoning: Data used to support scientific arguments based on drug dosing selection

Voluntary Genomic Data Submission* Regardless of data influence on drug efficacy, safety or labeling, a VGDS is recommended for all pharmacogenomic data Goal:

Better collaboration between sponsors and FDA for PG data

The education of physicians, healthcare management and the patient* IPRG Agency wide review group that reviews VGDS and works on providing public and industry knowledge

Pharmacogenetic Labeling

* Regulated by 21 CFR 201.56 PG data can be included in the following label sections:

Indications and Usage Dosage and Administration Contraindications Warnings and Precautions Adverse Reactions Drug Interactions Use in Specific Populations

DrugLabel SectionDescriptionHerceptinIndications and UsageShould be used in patients whose tumors were evaluated with a HER2 predicting assay.PurinetholWarnings / Dosage and AdministrationThose homozygous for TPMT defect gene may be sensitive to myelosuppressive effects and rapid bone marrow suppression.MellarilContraindications7% of the normal population have a genetic defect leading to reduced activity of P450 2D6. This leads to contraindication.

Examples of PG LabelingDepending on the risk/benefit, the information can be placed in multiple label sections.

A few IF THEN statementsIF:

Genomic testing must occur prior to dosing

Dose is dependent on the genotype

Serious Adverse Events due to PG profileTHEN:

The information goes to the Indications and Usage sections

The information goes to the Dosage and Administration / Warnings sections

The information goes to the Contraindications section

Conclusion Pharmacogenomic data can greatly help us to understand the variability in drug response from person to personThis will in turn lead to improved safety and efficacy during the drug development process

The FDA is taking an active role for the integration of pharmacogenomic data in the drug development process.

The VGDS (now VXDS) allows for an industry wide compilation for the association between genomics and drug response.Drug Response Variation- Genetic differences

There has been a consistent rise in the amount of pharmacogenomic data labeling and the trend will increase as we further understand our genome and the many factors that effect PK and PD of drug substances

The continuous creation of assays allowing for biomarker detection presents a greater possibility for personalized medicine based on genome

Conclusion