Pharmacogenetics (PG): Drug Metabolism and Dosage

1. Pharmacogenetics (PG): Drug Metabolism and Dosage Lawrence J. Lesko, Ph.D.Director, Office of Clinical Pharmacology and BiopharmaceuticsCenter for Drug Evaluation And ResearchFood and Drug AdministrationFDA Science BoardRockville, MarylandApril 9, 2003

2. The Proposition of the Usual Dose “The dose makes the poison” Paracelsus (1493-1541)

3. Paradox of Modern Drug Development 1. Clinical trials provide evidence of efficacy and safety at usual doses in populations

4. The Problem of Variability “Variability is the law of life, and as no two faces are the same, so no two bodies are alike, and no two individuals react alike,and behave alike under the abnormal conditions which we know as disease.” Sir William Osler (1849-1919)

5. Paradox of Modern Drug Development 1. Clinical trials provide evidence of efficacy and safety at usual doses in populations2.Physicians treat individual patients who can vary widely in their response to drug therapy

6. How Can The Causes of Variability be Unraveled? Pharmacogenomics: systemic genomic analysis in populations of treated subjects to identify variants that predict drug response including the occurrence of adverse reactions

7. GCCCGCCTC GCCCACCTC Pharmacogenomics Strategy Applied to the Practice of Medicine From McLeod and Evans, Ann Rev of Pharmacol and Toxicol, 2001: 41,101-121

8. Pharmacogenomics Strategy Applied to Drug Development Pharmacogenomics: systemic genomic analysis in populations of treated subjects to identify variants that predict drug response including the occurrence of adverse reactions Differential Diagnosis Cause of Disease Drug Discovery Drug Therapy Drug Selection By 2010 By 2005 By 2008 Targets Dosing Class

9. Number of New Chemical Entities During Drug Development: This May Reduce Attrition 100 80 60 40 20 0 Preclinical Phase 1 Phase 2 Phase 3 NDA

10. During Drug Development: This May Increase Probability of Success

11. During Drug Development: This May Identify Failures in Advance

12. PK Basis for Differences in Drug Response • Extrinsic factors • environment (smoking, diet, alcohol) • drug interactions (Rx, OTC and herbal) • Intrinsic factors • demographic (gender, age, race) • disease (renal, hepatic) • pharmacogenetics (PGt) • polymorphisms in genes encoding metabolic enzymes

13. GCCCGCCTC GCCCACCTC PGt and Drug Metabolism Same dose but different plasma concentrations Patient A Wild type CYP450 Concentration Wild type Time Patient B Mutation CYP450 Concentration Mutation Time

14. Family: CYP 2Subfamily: CYP 2D6Gene: CYP 2D6*3 Many CYP450 Enzymes Are Polymorphic: Example CYP 2D6 • Responsible for metabolism of 40% of all Rx drugs • Over 300 million Rx’s for drugs with polymorphism per year

15. PGt: Possible Impact on PK and Dose-Response Efficacy: reduction in anxiety and symptoms of depression Example: Nortriptyline Safety: tachycardia, arrhythmias and drowsiness

16. Nortriptyline: 25-300 mg 140 120 100 80 Dose (mg) 60 40 20 0 PM IM EM Phenotype Inherited Activity of CYP 2D6 and Nortriptyline Dosing IM Doses need forequivalent exposure EM PM Nortriptyline Plasma Levels Consequences: discontinue medication (ADR, lack of efficacy), delay to relief of symptoms (suicide), premature switch to other medications

17. Pharmacogenomics in the PDR Search of the electronic 2003 version of the PDR containing 2000 entries identified 51 labels containing pharmacogenomic information. In most cases, the information could not be easily translated to clinical practice.

18. An Informative Label: Thioridazine (MellarilR) • Contraindications • thioridazine is contraindicated in patients, comprising 7% of the normal population, who are known to have a genetic defect leading to reduced levels of P450 2D6 • Warnings • certain circumstances may increase the risk of torsade de pointes…its use in patients with reduced activity of P450 2D6

19. Pharmacogenomics During Drug Development • 80% of new clinical trials include collection of samples for DNA analysis Pharmaceutical R&D Source Book and PhRMA PG WG

20. Informal Survey of PG in INDs and NDAs Wendy Chou, Ph.D. and Others OCPB, FDA (ASCPT Poster, Thursday, April 3, 2003)

21. Others 22.9% Receptors 7% Pgp 4.3% CYP 2D6 72.9% PhaseII 11.4% CYP1A2 7.1% CYP3A4/5 14.3% CYP2C19 CYP2C9 14.3% 4.3% Breakdown of Genotyping and Phenotyping in FDA Survey • Genotyping and phenotyping performed in some submissions • Phase II enzymes measured: NAT-2, UGT, GSTM1, etc • Receptors: Dopamine, 5-HT, beta-adrenergic, alpha-1 adrenergic, potassium channels, etc • Others: HMC, CETP, ACE, alpha-reductase, AAG, CYP2B6, glyceraldehyde 3 -phosphate dehydrogenase, ApoE etc.

22. A Recent Example of a More Informative Label: Atomoxetine (StraterraR)* Human PK A fraction of the population are PM’s resulting in … Drug-Drug Interactions Inhibitors of CYP2D6 in EM’s increase exposure…similar to PM’s Adverse Reactions The following ADR’s were either twice as frequent or statistically significantly more frequent in PM’s compare to EM’s... Laboratory Tests Laboratory tests are available to identify CYP 2D6 PM’s * Approved by FDA’s Neuropharmacology Division in January 2003

23. Pharmacogenomics Strategy Applied to Drug Dosing • Determine alleles of polymorphic CYP enzymes to determine dose and dosage regimens “We continue to be concerned that despite the widespread availability of simple PG tests to determine a patient’s genotype with regard to CYP 450 enzymes, there has been little use of this information to tailor drug dosing…” Lesko and Woodcock, The Pharmacogenomics Journal 2, 20-24, 2002

24. During Drug Therapy PGt May Reduce Adverse Events • 28% of hospitalized patients have drug-related ADRs…Miller et al, Am. J. Hosp. Pharm 30, 584, 1973 • 17% of hospitalized children have drug-related ADRs…Mitchell et al, Am. J. Epid. 110, 196, 1979 • overall incidence of drug-related ADRs is 7%…Lazarou et al, JAMA, 279, 1200, 1998 • cost of drug-related morbidity and mortality is $177 billion…Ernst et al, J. Am. Pharm. Assoc., 41, 192, 2001

25. Scientific Basis for Using PGt • Top 27 drugs frequently cited in ADR reports • 59% (16/27) metabolized by at least one enzyme having poor metabolizer (PM) genotype • 38% (11/27) metabolized by CYP 2D6 • mainly drugs acting on CNS and cardiovascular systems, including nortriptyline Phillips et al, JAMA, 286 (18), 2001, 2270-2279

26. How Can PGt Improve Existing Therapies? All medicines that have been approved by the FDA for prevention or treatment of any disease in humans, under patent or not.

27. 6MP: Approved for Acute Lymphocytic Leukemia • Mainstay of therapy for over 50 years • Clinical studies during last 20 years have focused on methods of refining optimal doses • incremental advances in using pharmacogenetics • Risk of myelosuppression is primary limitation • chief determinant is dose, duration and intensity of treatment • blood counts traditionally used to monitor therapy • pharmacogenetic testing can significantly reduce, although not eliminate, this risk

28. Off-Label Uses of 6MP • Inflammatory bowel disease • Autoimmune diseases • rheumatoid arthritis • ulcerative colitis • psoriatic arthritis • multiple sclerosis

29. Genetic Basis for 6MP Intolerance is Well-Known* • TPMT catalyzes inactivation of 6MP • TPMT-deficient patients accumulate excessive thioguanine nucleotides in hematopoietic tissues • Accumulation of thioguanine in RBC’s leads to increased risk of severe and possibly fatal myelosuppression * Causality well-established

30. Prevalence of TPMT Genotypes • Three major SNPs (single gene) define mutant alleles (v) • Common: TPMT *3A (85%), TPMT *3C (<5%), TPMT *2 (<5%), • Rare: TPMT *3B (1:120,000) • Remaining allele: TPMT*3D, but also contains TPMT*3A SNP

31. Clinical Utility: Incidence of Toxicity • Interrupting therapy for recovery from toxicity lessened intensity oftreatment • Reduction of 6MP dose allowed for full dosages of other chemotherapy • TPMT polymorphism is important even for heterozygous patients Relling et al, J Natl Cancer Inst 1999;91:1983-1985

32. Clinical Utility: 6-MP Tolerability Personal Communication, Dr. Atik Rahman

33. Would a TPMT Test Bring Value to Public Health: Public Health Criteria for an “At-Risk” Genetic Test • Phenotype is relatively common • Impact of phenotype is serious • Early detection alters treatment • Treatment alters outcome • Accurate, reliable test is available • Counseling is available Secretary’s Advisory Committee on Genetic Testing (SACGT), January 2000

34. FDA Pharmacogenomics Working Group Lawrence Lesko (Chair), Office of Clinical Pharmacol. and Biopharm., CDER Shiew-Mei Huang, Office of Clinical Pharmacol. and Biopharm/, CDER Jerry Collins, Laboratory of Clinical Pharmacology, CDER John Leighton, Office of New Drug, CDER Robert Meyer, Office of New Drug, CDER Richard Pazdur, Office of New Drug, CDER Frank Sistare, Office of Pharmaceutical Science, CDER Sue Jane Wang, Office of Pharmaceutical Science, CDER Grant Williams, Office of New Drug, CDER Mitchell Weitzman, ORP/DRPI, CDER Mark Kramer, OC/ALS Patricia Y. Love, OC/ALS (On Detail) David Essayan, Office of Testing and Research,, CBER Joe Hackett, Office of Testing and Research, CDRH Elizabeth Mansfield, Office of Testing and Research, CDRH Jim MacGregor, Washington Operations, NCTR

35. Goals of FDA PG WG • To serve on organizing committees for public workshops with industry • To make presentations at public meetings on regulatory perspectives • To develop a draft guidance for industry on pharmacogenomics • To discuss the scientific details of a “submission requirement” for PG data

36. Modern Rendition of Paracelsus “The dose makes the poison, but differently for genetically different individuals.” Paracelsus (1493-1541)