Pharmacogenetics: DNA analysis. to explain / predict. response to drug therapy. Maurizio Ferrari & Ron van Schaik

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1 Maurizio Ferrari & Ron van Schaik Workshop IFCC Kuala Lumpur November 19, 2012 Predictive, Preventive and Personalized Medicine Part II: Pharmacogenetics l r.vanschaik@erasmusmc.nl Pharmacogenetics: DNA analysis to explain / predict response to drug therapy 1

2 Drug metabolism Drug concentration in blood Dose Time Slow metabolism Genetics?!? Ultra-rapid metabolism Dose Toxicity 6% of total hospitalizations 5th cause of death Therapeutic window Only 25-60% of drugs is effective Insufficient effect Cytochrome P450s metabolize 80% of all drugs (liver) 2

3 Cytochrome 2C9/VKORC1 & anticoagulation The challenge. Variability in warfarin dose requirement in order to reach target INR Number of Patients mg/day 5 mg/day 10 mg/day 10-fold variation to to to to to to to to to to to to to to 80 Weekly Dose Reynolds et al. Pers Med

4 Metabolism of warfarin (acenocoumarol) 68% High activity (EM) 30% Intermediate (IM) 2% Low activity (PM) Caused by genetic polymorphisms (Reynolds et al 2007 Personalized Medicine) Genetic polymorphism at target molecule VKORC1-1639G>A: 30% GG normal dose 50% GA normal dose 20% AA low dose 90% of bleeding complications occur in the VKORC1 AA group (Reynolds et al 2007 Personalized Medicine) 4

5 Regulatory bodies: the FDA. Regulatory bodies: the FDA. 5

6 Comparative trial. (MedCo) Warfarin Genotyping and Risk of Hospitalization -25% unadjusted incident hospitalization rate [%] within 6 months control group: Intervention group: without genotyping genotyping (Epstein RS et al 2010 J Am Coll Cardiol)) Cardiology: CYP2C19 & Clopidogrel 6

7 Clopidogrel: needs activation by CYP2C19 (Caucasians: 3% PMs, 26% IMs; Asian: 30% PM, 50% IM) Clopidogrel (prodrug) CYP2C19 (CYP3A4, CYP3A5) Active metabolite Clopidogrel: needs activation by CYP2C19 (Caucasians: 3% PMs, 26% IMs; Asian: 30% PM, 50% IM) CYP2C19 (CYP3A4, CYP3A5) Active metabolite 7

8 Clopidogrel: needs activation by CYP2C19 (3% PMs, 26% IMs) Test for CYP2C19 variants: Meta-analysis Geisler et al 2011 Pharmacol & Ther: CY2C19*2 carriers are at risk Negative clopidogrel Positive prasugrel Meta-analysis Zabalza et al 2012 BMJ: Large studies fail to confirm risk (?) Big general hospital specialized in Cardiology (Antonius Hospital Nieuwegein Netherlands) Erasmus MC Psychiatry: CYP2D6 & antidepressants 8

9 CYP2D6 activity distribution in the Caucasian population 75% Extensive 15% Intermediate 3% Ultrarapid 5-10% Poor Metabolizerss Debrisoquine CYP2D6 4OH-debrisoquine Psychiatry: Imipramine (antidepressive) CYP2C19 CYP2D6 Imipramine Desipramine 2OH desipramine Fig. 2g Imipramine doses after reaching steady state 4-6 weeks TDM (TAE) IMI dose (mg/day) n=11 n=69 n=90 n=11 30% of standard dose CYP2D6 genotyping: *3, *4, *5, *6, >2 CYP2D6 SGD (Schenk et al 2008 Mol Psychiatry) 9

10 Imipramine (tricyclic antidepressant) CYP2C19 CYP2D6 Imipramine Desipramine 2OH desipramine Fig. 2g Imipramine doses after reaching steady state n=11 n=69 n=90 n=11 IMI dose (mg/day) >2 CYP2D6 SGD (Schenk et al 2008 Mol Psychiatry) CYP2D6 and Tamoxifen Breastcancer Effectivity of therapy 10

11 Tamoxifen metabolism & breast cancer Most effective component CYP2D6 genotype and endoxifen levels Endoxifen (nmol/l) wt/wt wt/vt Vt/Vt (Vt=*4 = deficient; Based on Jin et al 2005) (Averages + s.e.m.) 11

12 CYP2D6 genotype and adjuvant TAM (n=1,325) EM IM PM (Schroth et al 2009 JAMA (Oct 7)) CYP2D6*3, *4, *5 and *10, *4 Published Articles: contradictory results.. Study n Genotyping Endpoint result Kiyotani et al.pharmacogen Genom *4, *5, *10, *21, *36, *41 RFS + Goetz et al. JCO *4 TTR, RFS + Schroth et al. JCO *4, *5, *10, *41 TTR, RFS + Lim et al. JCO *10 TTP + Ramon y Cajal et al. Breast Cancer Res Treat *4, *5, *41 DFS + Bijl et al. Breast Cancer Res Treat *4 OS + Schroth et al. JAMA *3, *4, *5, *6, *10, *41 DFS + Kiyotani et al. JCO *4, *5, *10, *10-*10, *14, *21, *36, *41 RFS + Lammers et al. Br J Cancer *3, *4, *5, *6, *10, *41 OS, TTP + Xu et al. Ann Oncol *10 DFS + Newman et al. Clin Cancer Res *3, *4, *5, *41 OS + Stingl et al. Curr Med Res Opin *4 TTP, PFS - Leyland-Jones et al. San Antonio 2010 (abstract) 1243 *4 DFS - Rae et al. San Antonio 2010 (abstract) 588 *3, *4, *6, *10, *41 RR - Okishiro et al. Cancer *3, *10 RFS - Toyama et al. JCO *10 OS - Dezentje et al. JCO ? DFS - Nowell et al. Breast Cancer Res Treat *3, *4, *6 PFS - Wegman et al. Breast Cancer Res *4 RR invers Wegman et al. Breast Cancer Res *4 DFS invers Slide courtesy of M Schwab 12

13 San Antonio Breast cancer studies not valid (?) Hardy-Weinberg equilibrium Expected distribution of heterozygotes and homozygotes given an allele frequency P>0.05 is good Rae study: HWE p< Current controversy.. Laboratory/Clin Pharmacology view CYP2D6 theoretically involved 2. Genotype proved to affect metabolism 3. Genotype proved to affect outcome Oncology view Not all studes confirm the effect of CYP2D6 on outcome 2. There has been no randomized controlled trial available 13