Clinical Toxicology & Pharmacology, Calvary Mater Newcastle Genetic polymorphism & drug interactions in pain management Prof Ian Whyte, FRACP, FRCPE Calvary.

Clinical Toxicology & Pharmacology, Calvary Mater Newcastle

Genetic polymorphism & drug Genetic polymorphism & drug interactions in pain managementinteractions in pain management

Prof Ian Whyte, FRACP, FRCPECalvary Mater NewcastleUniversity of Newcastle


Napoleon Bonaparte Napoleon Bonaparte (1769 – 1821)(1769 – 1821)

“Medicine is a collection of uncertain prescriptions, the results of which, taken collectively, are more fatal than useful to mankind”


Variability in drug responseVariability in drug response

Common and multifactorial– environment, genes, disease, other drugs– absorption, distribution, metabolism,

excretion Optimise dosage regimen for each

individual patient



Drug metabolismDrug metabolism

Analgesics– need to get into the brain to work– hydrophobic (fat soluble)

Elimination– hydrophilic (water soluble)

Enzymatic conversion– liver– intestinal wall


Drug metabolising enzymesDrug metabolising enzymes

Phase I (oxidating enzymes)– reductases, oxidases, hydrolases

Phase II (conjugating enzymes)– transferases

glucuronidase, sulphatase, acetylases, methylases

Transmembrane transporters– P-glycoprotein (P-gp)


Cytochrome P-450 enzymesCytochrome P-450 enzymes

Superfamily of microsomal drug-metabolising enzymes (Phase I)

Biosynthesis and degradation– steroids, lipids, vitamins

Metabolism of chemicals in our diet and the environment– medications


CYPsCYPs

Classified by amino acid similarities – family number– subfamily letter – number for each gene within the subfamily– asterisk followed by a number (and letter) for

each genetic (allelic) variant allele *1 is the normal function gene (wild allele) CYP2D6*1a gene encodes wild-type protein CYP2D6.1

http://www.imm.ki.se/CYPalleles/


Genetic polymorphismGenetic polymorphism

Greek– poly: different and morph: form

Differences in gene expression– frequency > 1% of the population

Many enzymes– drug metabolism– drug transporters– drug targets


SignificanceSignificance

Drug– eliminated > 50% by a polymorphic enzyme– narrow therapeutic window– activity depends on metabolite (pro-drug)

Drug interactions– interacting drug is inhibitor or inducer

mimic genetic variability

Phenotype– different profile of enzyme activity


Analgesic metabolismAnalgesic metabolism

Main enzymes involved are – CYP2C9, CYP2D6, CYP3A4

can be inhibited and / or induced

Amount of enzyme related to– mix of non-functional, decreased

function or fully functional alleles– co-administration of inducers or

inhibitors



CYP2C9 genotypesCYP2C9 genotypes 6 known allelic variants In Caucasians

– CYP2C9*1, *2 and *3 CYP2C9*1 (80 – 82%) encodes normal (wild type) activity CYP2C9*2 (11%) slightly reduced enzymatic activity CYP2C9*3 (7 to 9%) 5 – 10-fold decreased enzyme activity

Ethnic variability– Ethiopia

CYP2C9*2 is 4% CYP2C9*3 is 2%

– Far East CYP2C9*2 is 0% CYP2C9*3 is 2%


CYP2C9 functionCYP2C9 function

Most substrates are weak acids– NSAIDs

ibuprofen, indomethacin, flurbiprofen, naproxen, diclofenac, piroxicam, lornoxicam, mefenamic acid, meloxicam, celecoxib

Ibuprofen and celecoxib– homozygous carriers of CYP2C9*3

clearance is halved and half-life doubled

No clinical correlates demonstrated


CYP2D6 genotypesCYP2D6 genotypes CYP2D6 polymorphism autosomal recessive

– almost 80 allelic variants Non-functional alleles

– CYP2D6*4– CYP2D6*5– CYP2D6*3

Decreased function alleles– CYP2D6*10– CYP2D6*17

Normal function (wild type) allele– CYP2D6*1


CYP2D6 phenotypesCYP2D6 phenotypes

Poor metabolisers (PMs)– homozygous for a non-functional allele

CYP2D6*4 (20 – 25% Caucasians; 70 – 90% PMs) CYP2D6*5 (5%) CYP2D6*3 (2%)

– complete enzyme deficiency 5 – 10% of Caucasians

Ethnic variability– PMs rare outside Caucasians– Asians and Africans < 2% non-functional alleles


CYP2D6 phenotypesCYP2D6 phenotypes Intermediate metabolisers (IMs)

– homozygous for a decreased function allele CYP2D6*10 CYP2D6*17

– decreased enzyme activity 10 – 15% of Caucasians

Ethnic variability– 50% of Asians are carriers of CYP2D6*10

Extensive metabolisers (EMs)– homozygous for the normal function allele

CYP2D6*1 60 – 70% of Caucasians


CYP2D6 phenotypesCYP2D6 phenotypes Ultra-rapid metabolisers (UMs)

– multiple (2 – 13) copies of normal function alleles 1 to 10% of Caucasians

Ethnic variability– Middle East (20%)– Ethiopia (up to 29%)– Europe

North / South gradient– Sweden (1 – 2%)– Germany (3.6%)– Switzerland (3.9%)– Spain (7 – 10%)– Sicily (10%)


CYP2D6 clinical implicationsCYP2D6 clinical implications Metabolism

– 25% of common drugs many opioids, most antidepressants

Effect varies– activity of parent compound – activity of any metabolite

UMs have increased elimination– antidepressants

standard doses can result in ineffective treatment

PMs higher concentrations after standard doses– increased efficacy but also toxicity– dose adjustment is therefore essential


CYP2D6 and codeineCYP2D6 and codeine Bioactivation by CYP2D6

– codeine, tramadol, hydrocodone, oxycodone affects efficacy and toxicity

Codeine is converted to morphine for analgesia– EMs

10% of codeine is converted to morphine– PMs

none (0%) is converted to morphine– codeine is an ineffective analgesic

– UMs morphine production is increased

– severe intoxication with codeine at standard dosages– death in a child

• UM mother breastfeeding while on codeine


CYP2D6 and tramadolCYP2D6 and tramadol CYP2D6 activity important for

– analgesic effect– side effect profile

Tramadol– low affinity for μ-opioid receptor

O-desmethyl-tramadol > 200-fold affinity– inhibits reuptake of 5HT > NA

PMs – unlike codeine – tramadol retains activity

opioid effect decreases but monoaminergic effect increases non-responders twice as frequent (46.7%) as in EMs (21.6%) increased risk of serotonin toxicity

UMs– no issues reported


CYP2D6 and methadoneCYP2D6 and methadone

Marked interindividual differences in steady state blood concentrations– higher in PMs on maintenance

over 70% of PMs had effective treatment 28% of PMs required doses > 100 mg

– lower in UMs on maintenance 40% of UMs had effective treatment almost 50% of UMs required doses > 100 mg


CYP2D6 and opioid dependenceCYP2D6 and opioid dependence

PMs may be protected– no PMs were found in those addicted to

codeine– 4% in patients never substance addicted– 6.5% in those with other dependencies

(alcohol, cocaine, amphetamines) Pharmacogenetic protection against

oral codeine dependence– odds ratio > 7


CYP2D6 and antidepressantsCYP2D6 and antidepressants

Antidepressants used as co-analgesics– over 25% of patients do not respond

Most metabolised by CYP2D6– 30 to 40 fold variation in plasma levels

UM phenotype– risk factor for therapeutic ineffectiveness

PMs– toxic effects at recommended doses


CYP2D6 and antidepressantsCYP2D6 and antidepressants Clearance decreased in PMs

– amitriptyline, clomipramine, desipramine, imipramine, nortriptyline, trimipramine, paroxetine, citalopram, fluvoxamine, fluoxetine, venlafaxine

Increased side effects in PMs– desipramine

only PMs had adverse reactions – confusion, sedation, orthostatic hypotension

– venlafaxine cardiotoxicity

– palpitations, dyspnoea, arrhythmias

– twice as many PMs among patients reporting side effects


CYP2D6 and antidepressantsCYP2D6 and antidepressants Effective dosing in depression

– depends on PM or UM status nortriptyline 10 to 500 mg/day amitriptyline 10 to 500 mg/day clomipramine 25 to 300 mg/day Chinese patients (majority IMs) need generally lower doses

Dose recommendations– PMs

50 to 80% dose reduction for tricyclic antidepressants 30% dose reduction for SSRIs

– UMs increase dose to 260% for desipramine 300% for mianserin 230% for nortriptyline


CYP3A4 CYP3A4 CYP3A subfamily has a role in 45 to 60% of all drugs

– codeine, tramadol, buprenorphine, methadone, fentanyl, dextromethorphan

30-fold differences in expression of CYP3A exist in certain populations

CYP3A subfamily consists of four enzymes– CYP3A4, CYP3A5, CYP3A7, CYP3A43

most important is CYP3A4

Allelic variants of CYP3A4 are described– none results in a significant change of enzyme activity


CYPs and drug interactionsCYPs and drug interactions

Plasma levels of substrates may increase with co-administration of inhibitors– potentially increased side effects

Plasma levels of substrates may decrease with co-administration of inducers– potentially less therapeutic effect


CYP2C9CYP2C9

Inhibitors of CYP2C9– amiodarone, fluvastatin, fluconazole,

phenylbutazone, sulphinpyrazone, sulphonamides

– potentially increased NSAID side effects Inducers of CYP2C9

– carbamazepine, phenobarbitone, ethanol– potentially less NSAID therapeutic effect


CYP2D6CYP2D6

Inhibitors of CYP2D6– antiarrhythmics (quinidine), neuroleptics

(chlorpromazine, haloperidol, thioridazine, levopromazine), many antidepressants (paroxetine, fluoxetine)

– increase plasma concentrations– inactivate pro-drugs (codeine)

Inducers of CYP2D6– None


CYP3A4CYP3A4

Inhibitors of CYP3A4 – grapefruit juice, macrolide antibiotics

(erythromycin), some antidepressants (paroxetine), neuroleptics (olanzapine), protease inhibitors (ritonavir, indinavir, saquinavir), amiodarone

– increase methadone plasma levels toxicity (overdose)

– 4 – 5-fold reduction in metabolism fentanyl, alfentanil, sufentanil


CYP3A4CYP3A4

Inducers of CYP3A4– rifampicin, carbamazepine, phenytoin– decrease plasma levels of methadone

symptoms of opioid withdrawal– > 3-fold increase in clearance of

alfentanil– unclear clinical significance




P-glycoproteinP-glycoprotein Transmembrane transport protein

– expels drugs out of cells– decreases drug levels in the tissue– ~ 30 mutations

Substrates– loperamide, morphine, methadone, meperidine,

hydromorphone, naloxone, naltrexone, pentazocine, some endorphins and enkephalins

Decreased intestinal P-gp function– increased amount absorbed– increased plasma concentration

Minor influence on brain bioavailability of morphine, methadone and fentanyl


PhenotypingPhenotyping

Characterises enzyme activity in an individual patient

Test substrate given– parent drug, metabolite in blood / urine– metabolic ratio

amount of unchanged parent drug / amount of metabolite


PhenotypingPhenotyping

Quick, simple, inexpensive and reproducible

Must give a pharmacologically active substance for a diagnostic purpose– may raise ethical questions

Information on the phenotyping of specific groups is limited– children, elderly, renal and liver disease


Phenotyping availabilityPhenotyping availability

CYP2C9– 1 out of 507 (0.2%)

Hospital / University facility

CYP2D6– 6 out of 507 (1.2%)

Hospital (2), Hospital / University (2), University (2)

CYP3A4– None


Genotyping (PCR)Genotyping (PCR) Advantages

– direct analysis of genetic mutations– does not require a substrate drug– not influenced by drugs or environmental factors– performed once in a lifetime

Disadvantages– not commonly available– cost and sensitivity varies with the CYP– only detects currently described allelic variants

not all mutations detected– new allelic variants found on a regular basis

may need to repeat the test


Genotyping availabilityGenotyping availability CYP2C9

– 5 out of 507 (1.0%) commercial pathology laboratory (1), state government

pathology service (1), university (2), university/hospital (1)

CYP2D6– 4 out of 507 (0.6%)

commercial pathology laboratory (1), state government pathology service (1), hospital/university (1), university (1)

CYP3A4– None


GenesFX Health Pty. LtdGenesFX Health Pty. Ltd(http://www.genesfx.com)(http://www.genesfx.com)

Individual gene tests– CYP2C9 – $140– CYP2D6 – $180– CYP3A4/5 – Not available

DNADose – $270– CYP2D6, CYP2C9, CYP2C19, VKORC1– "Personalised Drug-Specific report“

Dosage guidance for all drugs that GenesFX is informed about

Suggestions of alternative drugs when appropriate Suggestions of drugs to avoid in the future


Clinical utilityClinical utility May occasionally be justified retrospectively

– few cases of treatment failure or drug toxicity poor compliance vs fast metabolism excessive intake vs poor metabolism

– suspected drug addiction vs metabolic defect high intake of codeine

Limited availability Dose recommendations are preliminary Efficacy and clinical utility remain to be validated No economic analysis

– tests needed to prevent one case of toxicity vs cost


ConclusionsConclusions Analgesics

– importance of individualisation of drug prescription– most are metabolised by CYPs subject to genetic polymorphism

may help explain some of the ineffectiveness or toxicity Detection of these polymorphisms could give us tools for

– optimising drug treatment anticipating therapeutic side effects and ineffective therapy identifying the right drug and the right dose predict the most effective and safest drug for each patient

– distinguish between rapid metabolism and drug abuse Cost / benefit analysis has not been done We are not there yet but

– there is real potential

Clinical Toxicology & Pharmacology, Calvary Mater Newcastle Genetic polymorphism & drug interactions in pain management Prof Ian Whyte, FRACP, FRCPE Calvary.

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