Genetic polymorphism & drug interactions in pain management

1. Genetic polymorphism & drug interactions in painmanagement Prof Ian Whyte, FRACP, FRCPE Calvary Mater Newcastle University of Newcastle

2. Napoleon Bonaparte (1769 – 1821) • “Medicine is a collection of uncertain prescriptions, the results of which, taken collectively, are more fatal than useful to mankind”

3. Variability in drug response • Common and multifactorial • environment, genes, disease, other drugs • absorption, distribution, metabolism, excretion • Optimise dosage regimen for each individual patient

5. Drug metabolism • Analgesics • need to get into the brain to work • hydrophobic (fat soluble) • Elimination • hydrophilic (water soluble) • Enzymatic conversion • liver • intestinal wall

6. Drug metabolising enzymes • Phase I (oxidating enzymes) • reductases, oxidases, hydrolases • Phase II (conjugating enzymes) • transferases • glucuronidase, sulphatase, acetylases, methylases • Transmembrane transporters • P-glycoprotein (P-gp)

7. Cytochrome 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

8. CYPs • 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/

9. Genetic polymorphism • Greek • poly: different and morph: form • Differences in gene expression • frequency > 1% of the population • Many enzymes • drug metabolism • drug transporters • drug targets

10. Significance • 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

11. Analgesic 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

13. CYP2C9 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%

14. CYP2C9 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

15. CYP2D6 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

16. CYP2D6 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

17. CYP2D6 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

18. CYP2D6 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%)

19. CYP2D6 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

20. CYP2D6 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

21. CYP2D6 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

22. CYP2D6 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

23. CYP2D6 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

24. CYP2D6 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

25. CYP2D6 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

26. CYP2D6 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

27. 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

28. CYPs 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

29. CYP2C9 • 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

30. CYP2D6 • 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

31. CYP3A4 • 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

32. CYP3A4 • 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

35. P-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

36. Phenotyping • 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

37. Phenotyping • 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

38. Phenotyping 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

39. 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

40. Genotyping 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

41. GenesFX Health Pty. Ltd(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

42. Clinical 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

43. Conclusions • 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