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Pharmacogenetics and the Promise of Individualized Medical Care

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  1. Pharmacogenetics and the Promise of Individualized Medical Care John Deeken, M.D. May 18, 2009

  2. Pharmacogenomics

  3. All patients with same diagnosis Responders and Patients not Experiencing Severe Toxicity Non-Responders and Patients Experiencing Severe Toxicity

  4. Variability Sources of Pharmacokinetic and Pharmacodynamic Variability Drug Specific: Dose & Schedule Dosage form Morphometric: Body Size Body Composition Genetics: Demographic: Age Race/Ethnicity Sex Environment: Drug-drug interactions Drug-CAM interactions Drug-formulation interactions Drug-food constituent interactions Physiologic: Disease Hepatic Function Renal Function

  5. Pharmacogenetics Implications of polymorphisms on Pharmacokinetics • Drug Absorption • Drug Distribution • Drug Elimination • Drug Metabolism • Drug Activation Implications of polymorphisms on Drug Effect • Receptors • Target Proteins

  6. Genetic Polymorphisms • Single Nucleotide Polymorphisms (SNPs) • Non-synonymous and synonymous • Upstream/downstream regulatory regions • Copy number

  7. Pharmacogenetics Implications of polymorphisms on Pharmacokinetics • Drug Absorption • Drug Distribution • Drug Elimination • Drug Metabolism • Drug Activation Implications of polymorphisms on Drug Effect • Receptors • Target Proteins

  8. Transporters Mediate Absorption www.solvo.com

  9. Transporters Mediate Bile Elimination www.solvo.com

  10. Transporters Mediate Renal Elimination www.solvo.com

  11. ABCG2 (BCRP, ATP-binding cassette) • Involved in intrinsic or acquired multidrug resistance (MDR) phenotype of tumor cells • ABCG2 encodes a half transporter • Located on chromosome 4q-22 • 66 kb; 16 exons; 15 introns • 69 Known genetic polymorphisms including 65 SNPs; 13 SNPs in exons; 7 SNPs cause amino acid substitutions

  12. Location of ABCG2 C421A and its functional consequences Non-synonymous ABCG2 Q141K SNP: substituted amino acid residue - The 421C to A transition at exon 5 leads to a Lys to Gln amino acid substitution at codon 141 (Q141K) - Functional studies suggest that the C421A polymorphism has: 1. Reduced topotecan transport 2. Reduced protein expression in vitro 3. A 3-fold higher diflomotecan AUC after i.v. administration

  13. ABCG2 pharmacogenetics: influence on imatinib (STI-571; Gleevec) pharmacokinetics Parameter WT* Het** P Cmax 11.2 36.5 0.0064 AUC 140 536 0.0063 * N = 32 ** N = 4 Patients with GIST treated with imatinib at dose ranging, 100 – 1000 mg p.o. Lepper E, et al (Figg), Pro ASCO 2005

  14. Pharmacogenetics Implications of polymorphisms on Pharmacokinetics • Drug Absorption • Drug Distribution • Drug Elimination • Drug Metabolism • Drug Activation Implications of polymorphisms on Drug Effect • Receptors • Target Proteins

  15. Drug Metabolizing Enzymes Evans and Relling, Science 286: 487-91, 1999

  16. PGx of Drugs Used in Medical Oncology Example of anticancer drug metabolism by polymorphic enzymes Drug Pathway Variability in CL Amonafide N-acetyl transferase (NAT) >3-fold Busulfan Glutathione S-transferase (GST) 10-fold Docetaxel Cytochrome P-450 (CYP) 3A4/3A5 4 to 9-fold 5-Fluorouracil Dihydropyrimidine dehydrogenase 10-fold 6-Mercaptopurine Thiopurine methyltransferase >30-fold Evans and Relling, Science 286: 487-91, 1999

  17. Warfarin (Coumadin) • Name Your Poison

  18. Warfarin (Coumadin) • Used for chronic anticoagulation • INR and lab testing • Two enantiomers (R- and S-)

  19. Warfarin • Name Your Poison • Used for chronic anticoagulation • INR and lab testing • Two enantiomers, R and S

  20. Warfarin Metabolism Importance of CYP2C9

  21. Warfarin Pharmacodynamics Importance of VORC1

  22. Warfarin -PGx • PGx: CYP2C9 and VORC1 • Expert Committee Recommendation to FDA • Consider PGx testing, but needs further study • Multiple studies currently ongoing, main U.S. study funded by NIH • Medicare announced May 4 that it will not pay for genetic testing at this time • Will pay for genetic testing in clinical trials

  23. PGx and Clopidogrel (Plavix) • Thienopyridine inhibitor of platelet P2Y12 ADP • Prodrug, requires activitation by CYP450 enzyme(s) and also inactivated by CYP450 enzyme(s) and other esterases • Much variability between patients in terms of pK and PD (platelet aggregation)

  24. PGx and Clopidogrel (Plavix) • Mega et al (NEJM Jan 22, 2009): • healthy volunteers pK (n=162) • Cardiac patients on TRITON-TIMI study (n=1477) • Pts with at least one reduced function variant in CYP2C19: • 32% reduction in active drug plasma levels • 53% increase risk of death from CV causes, MI, or stroke (12.1% vs 8.0%, HR 1.53) • Three-fold increased risk of stent thrombosis (2.6% v. 0.8%) • Caveat: research paid for by Eli Lilly and Daiichi Sankyo since study was of prasugrel vs clopidogrel • FDA currently evaluating evidence to consider requiring PGx testing before starting clopidogrel

  25. Irinotecan (CPT-11) • Topoisomerase I inhibitor • Metabolized to active compound SN-38 • Used in colon cancer • DLT – diarrhea • SN-38 inactivated by UGT1A1 glucoronidation • Polymorphism in UGT1A1 (UGT1A1*28) leads to diminished inactivation, higher drug levels, and higher toxicity

  26. Mathijessen RHJ et al. Clin Cancer Res 2001:2168

  27. Pharmacogenomics and Oncology: New label for Irinotecan, July 2005: FDA approved test in December, 2005 We still do not know what to do with dose

  28. Pharmacogenetics Implications of polymorphisms on Pharmacokinetics • Drug Absorption • Drug Distribution • Drug Elimination • Drug Metabolism • Drug Activation Implications of polymorphisms on Drug Effect • Receptors • Target Proteins

  29. Tamoxifen • SERM • Used for adjuvant therapy in ER/PR+ breast CA • Metabolite Endoxifen is 100x more effective than parent compound • CYP2D6 mediates activation of Tamoxifen to Endoxifen

  30. TamoxifenImportance of CYP2D6

  31. Pharmacogenetics Implications of polymorphisms on Pharmacokinetics • Drug Absorption • Drug Metabolism • Drug Elimination • Drug Distribution • Drug Activation Implications of polymorphisms on Drug Effect • Receptors • Target Proteins

  32. Beta Receptor and HTN/CHF • Beta blockers – well named • ADRB1 and ADRB2 • In ADRB1, 2 common functional polymorphisms (Ser49Gly and Gly389Arg). • In HTN, pts treated with Metoprolol, Gly389: • WT/WT: 10.4% drop in SBP • WT/Variant: 2.8% • Variant/Variant: 1.1% • Similar differences found in HR and SBP at rest and with exercise • In CHF, WT patients need more medications/dosages Liu J et al. Clin Pharmacol Ther 2003, 2006 Terra SJ, et al. Clin Pharmacol Ther 2006

  33. Beta Receptor and ACS

  34. Pharmacogenetics Implications of polymorphisms on Pharmacokinetics • Drug Absorption • Drug Metabolism • Drug Elimination • Drug Distribution • Drug Activation Implications of polymorphisms on Drug Effect • Receptors • Target Proteins

  35. Pharmacogenomics and FDA “Pharmacogenomics holds great promise to shed scientific light on the often risky and costly process of drug development, and to provide greater confidence about the risks and benefits of drugs in specific populations. Pharmacogenomics is a new field, but we intend to do all we can to use it to promote the development of medicines.” -Mark McClennan, M.D. FDA Commissioner Nov, 2003

  36. Pharmacogenomics and FDA • 2002: ‘Safe Harbor’ concept for data submissions • 2003: Draft guidance for industry to submit genomic data • 2004: • PG identified as ‘Key opportunity’ in FDA’s ‘Critical Path’ for the future • Interdisciplinary PG Review Group Formed. • First Voluntary Genomic Drug Submission (VGDS) received by FDA • 2005 • Genomics Website: www.fda.gov/cder/genomics • Final rules published on guidance for industry

  37. Pharmacogenomics - Industry • Biomarker/Genetic targets: Abbott Johnson & Johnson Roche (Swiss) • Pharmacogenomics for individualized Rx: Pfizer Bristol-Myers-Squibb Genentech • Molecular diagnostic kits/devices: Roche expected sales this year: $6.5 billion expected sales by 2010: $12 billion

  38. Pharmacogenomics:Industry • First clinically available, FDA-approved genotype test in 2005 (Roche - Amplichip) • Chip for SNPs in all CYP450 genes, 2005 (GE) • Chip for p53 mutations expected mid-2006 (Roche) • Affymetrix/ParAllele DMET Chip - 1,300 SNPs covering 185 genes (enzymes and transporters) involved in drug metabolism Spring, 2006

  39. Pharmacogenomics and NIH • Pharmacogenomics Research Network (PGRN) • Initiated based on NIH Scientific Advisory Panel recommendation in 1999 • Launched in year 2000 • $140 million for first 5 years (UO1 mechanism) • 12 centers funded from 2000 to 2005 • Second 5-year period from 2005-2010, $150 million, again with 12 centers funded (not same as original) • NIGMS (General Medical Science) is lead NIH institute, with other institutes participating, including NHLBI, NIDA, NCI, NIEHS, NHGRI, NIMH, NLM, and ORWH

  40. PGx – The Future of Individualized Medicine? All patients with same diagnosis Responders and Patients not Experiencing Severe Toxicity Non-Responders and Patients Experiencing Severe Toxicity