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Interindividual Variability in Drug Response

Interindividual Variability in Drug Response. How do we prescribe drugs?. How do we individualize therapy?. Oops!. Toxicity. No Effect. Too Much. Too Little. ¯ Dose. ­ Dose. No effect. Toxicity. ­ Dose. ¯ Dose. In the age of the Genome Why do people respond differently to drugs?.

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Interindividual Variability in Drug Response

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  1. Interindividual Variability in Drug Response How do we prescribe drugs? How do we individualize therapy?

  2. Oops! Toxicity No Effect Too Much Too Little ¯ Dose ­ Dose No effect Toxicity ­ Dose ¯ Dose

  3. In the age of the GenomeWhy do people respond differently to drugs? • Variability in:- • Drug metabolism genotype • Drug transporter genotype • Drug receptor genotype • Drug/drug/environment /genotype interactions

  4. Drug Oxidation - Major Route of Drug Metabolism Family of enzymes (CYPs) in liver Proportion of Pharmaceuticals Metabolized by Individual Cytochrome P450’s Major P450 Content of Human Liver Shimada et al, 1994

  5. Polymorphism of Drug Oxidation • CYP2D6 Debrisoquin/Sparteine • CYP2C19 Mephenytoin • CYP2C9 S-warfarin

  6. debrisoquine/sparteine amphetamine dexfenfluramine quanoxan ondansetron Antipsychotics perphenazine thioridazine haloperidol risperidone (9OH) minaprine venlafaxine fluvoxamine CYP2D6 Substrates Antiarrhythmics encainide flecainide S-mexillitene lidocaine Beta Blockers propafenone S-metoprolol propranolol (4OH) timolol alprenolol bufuralol carvedilol Antidepressants fluoxetine amitriptylline desipramine clomipramine imipramine Analgesics dextromethorphan codeine tramadol

  7. Frequency of Poor Metabolizersin Different Populations CYP2D6 Caucasians 8.0% Japanese 0.5% Chinese 0.7% U.S. Blacks 6.1% (1.9%)

  8. CYP2D6 Allele Frequencies Enzyme Activity Chinese CYP2D6 Caucasian Ghanaian *1 *3 *4 *5 *9 *10 *17 Normal None None None Decreased Decreased Decreased 84.2 0 10.6 2.6 0 2.6 0 57.5 0 10 5 0 12.5 15 52.4 0 0 0 0 47.6 0 Droll; Pharmacogenetics 8: 325-333, 1998

  9. Genetic Polymorphism Prediction of drug toxicity

  10. Genetic Polymorphism Prediction of drug toxicity • Phenformin • Withdrawn because of lactic acidosis • Metabolized by CYP2D6 • Lactic acidosis in PMs

  11. Phenformin and Debrisoquine Woolhouse, Clin Pharmacol Ther, 37: 512-521; 1985.

  12. Metabolism Within a Phenotype • Abnormal alleles • Gene duplication

  13. CYP2D6 - Effects of Gene Duplication Dalen et al., 1998.

  14. CYP2D6 - Gene Duplication* 10.4% 16.0% 3.5% 2.0% 1.8% 1.3% Saudi Arabians Ethiopians Spaniards Zimbabweans Germans Chinese * Includes individuals with more than one extra CYP2D6 gene McLellan et al., 1997

  15. Genetic PolymorphismCYP2C19 • S-hydroxylation of mephenytoin deficient in PM’s Index drug: Mephenytoin (R and S)

  16. Frequency of CYP2C19 Poor Metabolizers Phenotype Genotype Africans African-Americans Caucasians Chinese Japanese Koreans Amerindians 4.1 1.4 2.8 13.6 20.3 13.7 3.8 3.3 2.1 13.8 17.0 16.8 5.7

  17. S-mephenytoin hexobarbital R-mephobarbital phenytoin diazepam citalopram omperazole lansoprazole pantoprazole R-warfarin (8-OH) propranolol (in part) imipramine clomipramine amitryptylline proguanil teniposide nilutamide indomethacin moclobemide CYP2C19 Substrates

  18. Time after Omeprazole (hour) CYP2C19 l PMs ¡ EMs Sohn, JPET 262: 1195-1202; 1992

  19. CYP2C19 Activity and Fasting Gastrin Concentrations

  20. CYP2C19 Genotype + Intragastric pH Placebo Omeprazole Furuta et al., Clin Pharmacol Ther 65: 552-561, 1999.

  21. H. pylori Cure Rate Based on CYP2C19 Genotype Total cure rate = 52% (n=62) (n=9) (n=25) Percent cure rate (n=28) wt/m1 wt/m2 m1/m2 m1/m1 wt/wt Omeprazole 20 mg/day for 6-8 weeks Amoxicillin 2000 mg/day for 2 weeks T. Furuta et al., Ann. Int. Med., 129: 1027-1030, 1998

  22. CYP2C9 2C9 *3 2C9 *2 Chinese Japanese Korean African-American Caucasian 2.1% 2.2% 1.1% 0.8% 8.5% 0% 0% 0% 2.9% 10.7%

  23. tolbutamide phenytoin S-warfarin tamoxifen diclofenac ibuprofen piroxicam suprofen S-naproxen sulfamethoxazole torsemide losartan busipirone CYP2C9 Substrates

  24. CYP2C9 and Glipizide Kidd et al., Pharmacogenetics, 9: 71-80, 1999.

  25. Warfarin • Racemic mixture of (R) and (S) isomers • (S)warfarin à 7-hydroxywarfarin by CYP2C9 • (R)warfarin à 8-hydroxywarfarin by CYP2C19 • (S) 7-10 X potency of (R) as anticoagulant

  26. CYP2C9 - Allelic Variants WT CYP2C9 *1 CYP2C9 *2 CYP2C9 *3 Impaired hydroxylation in in vitro expression system Single AA substitution

  27. CYP2C9Reduced (S)-Warfarin Clearance in Heterozygotes Takahashi, CPT, 1998

  28. Warfarin Response in AC Clinic • Low dose < 1.5 mg/day • Random AC Clinic > 1.5 mg/day Lancet 353: 717; 1999

  29. Warfarin Dose and Genotype Genotype (%) < 1.5 mg/day > 1.5 mg/day Community CYP2C9 *1/*1 *1/*2 *1/*3 *2/*3 *2/*2 *3/*3 19% 33% 28% 14% 6% 0% 62% 17% 19% 0% 2% 0% 60% 20% 17% 2% 0% 1% Lancet 353: 717; 1999

  30. < 1.5 mg/day > 1.5 mg/day INR > 4 at Induction Minor bleeds (per person years) Major bleeds (per person years) 56% 5.3% 8.3% 17% 1.9% 2.3% Lancet 353: 717; 1999

  31. Adverse effects and Drug Transporters • Polymorphism of MDR-1 • Potential source of altered • Absorption • Tissue concentrations

  32. Effect of MDR-1 Genotype on Digoxin Cmax Hoffmeyer, PNAS 97:3473-3478, 2000

  33. Variable Drug Response and Pharmacogenetics Alleles coding for enzymes and transporters with no or diminished activity contribute concentration related adverse events

  34. Adverse Events Due to Altered Receptors Genotypic variability in receptor response

  35. Survival in Heart Failure S.B. Liggett et al., J. Clin. Invest., 102: 1534-1539, 1998

  36. Pharmacogenetics • Assists prediction of response • Explains variability in response • Role of genotyping/prescribing?

  37. Pharmacogenetics and variability in response • Where are we-Can we? • Predict responses • Prevent adverse responses • Improve therapy

  38. The Wall Street Journal, Friday, April 16, 1999

  39. Personalized Medication in the Future GeneChip Analysis S M A R T C A R D Alastair J.J. Wood Xenobio GeneChip GENOME (Confidential) In the future (? years), your doctor will be able to select the best drug to treat your disease and the appropriate dose based on knowledge of your specific genetic makeup!

  40. Pre-Prescription GenotypingGoal is improved patient safety • Metabolism • Prevention of toxicity • Avoiding under treatment • Response • Responders/Non responders • Drug choice • Drug interactions

  41. Genotyping in Clinical Trials - If you know (or think you know) the genotype that responds 1. Prescreen 2. Treat only that genotype 3. Or (if toxicity) do NOT treat that genotype

  42. Better prediction Dose Responders Toxicity Permit use of “toxic drugs” Smaller sample size Faster drug development Orphan drug status (<200,000) Less financial risk What is the indication? Who are the patients (limited population)? May transfer drug development costs to patient/provider Genotyping in Clinical Trials Opportunities Unresolved Issues

  43. Prescribing by GenotypeOther Issues • Single polymorphism vs. Multiple polymorphisms • Non polymorphic (CYP3A) • All targets not yet identified • Informatics Technology is non trivial • Need prospective clinical trials to define benefits

  44. Genotyping for Drug ResponseSimplistic view Drug Metabolizing Genotypes Dose

  45. Genotyping for Drug Response Drug Response Genotypes Epilepsy Genotype Auto-convulsive Sensitivity Genotype Drug Metabolizing Genotypes Toxicity Response Genotypes Dose

  46. PDR à PCR ?

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