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
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
Cytochrome 2C9/VKORC1 & anticoagulation The challenge. Variability in warfarin dose requirement in order to reach target INR Number of Patients 25 20 15 10 5 1 mg/day 5 mg/day 10 mg/day 10-fold variation 0 5.0 to 10 11 to 15 16 to 20 21 to 25 26 to 30 31 to 35 36 to 40 41 to 45 46 to 50 51 to 55 56 to 60 61 to 65 66 to 70 75 to 80 Weekly Dose Reynolds et al. Pers Med 2007 3
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
Regulatory bodies: the FDA. Regulatory bodies: the FDA. 5
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
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
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
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) 900 800 700 600 500 400 300 200 n=11 n=69 n=90 n=11 30% of standard dose CYP2D6 genotyping: *3, *4, *5, *6, 100 0 0 1 2 >2 CYP2D6 SGD (Schenk et al 2008 Mol Psychiatry) 9
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) 900 800 700 600 500 400 300 200 100 0 0 1 2 >2 CYP2D6 SGD (Schenk et al 2008 Mol Psychiatry) CYP2D6 and Tamoxifen Breastcancer Effectivity of therapy 10
Tamoxifen metabolism & breast cancer Most effective component CYP2D6 genotype and endoxifen levels Endoxifen (nmol/l) 100 90 80 70 60 50 40 30 20 10 0 wt/wt wt/vt Vt/Vt (Vt=*4 = deficient; Based on Jin et al 2005) (Averages + s.e.m.) 11
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 2010 167 *4, *5, *10, *21, *36, *41 RFS + Goetz et al. JCO 2005 190 *4 TTR, RFS + Schroth et al. JCO 2007 206 *4, *5, *10, *41 TTR, RFS + Lim et al. JCO 2007 21 *10 TTP + Ramon y Cajal et al. Breast Cancer Res Treat 2010 91 *4, *5, *41 DFS + Bijl et al. Breast Cancer Res Treat 2009 85 *4 OS + Schroth et al. JAMA 2009 1325 *3, *4, *5, *6, *10, *41 DFS + Kiyotani et al. JCO 2010 282 *4, *5, *10, *10-*10, *14, *21, *36, *41 RFS + Lammers et al. Br J Cancer 2010 102 *3, *4, *5, *6, *10, *41 OS, TTP + Xu et al. Ann Oncol 2008 152 *10 DFS + Newman et al. Clin Cancer Res 2008 115 *3, *4, *5, *41 OS + Stingl et al. Curr Med Res Opin 2010 496 *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 2009 173 *3, *10 RFS - Toyama et al. JCO 2009 154 *10 OS - Dezentje et al. JCO 2010 747? DFS - Nowell et al. Breast Cancer Res Treat 2005 162 *3, *4, *6 PFS - Wegman et al. Breast Cancer Res 2005 76 *4 RR invers Wegman et al. Breast Cancer Res 2007 677 *4 DFS invers Slide courtesy of M Schwab 12
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<0.000001 Current controversy.. Laboratory/Clin Pharmacology view ----------------------------------------------------- 1. CYP2D6 theoretically involved 2. Genotype proved to affect metabolism 3. Genotype proved to affect outcome Oncology view ----------------------------------------------------- 1. Not all studes confirm the effect of CYP2D6 on outcome 2. There has been no randomized controlled trial available 13