Imipramine therapy (CYP2D6)

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1 Imipramine therapy (CYP2D6) Intake Start therapy 1st conc 08:00 2nd conc 3e spiegel 4e spiegel 1 week 1 week 1 week 1 week 1 week 22:00 ~ 50% patients need dose adjustment

2 Imipramine therapy (CYP2D6) Intake Start therapy 1st conc 2 nd conc 3rd conc 4rd conc 08:00 1 week 1 week 1 week 1 week 1 week 22:00 ~ 50% patients need dose adjustment => steady-state and discharge Total time in academic hospital: 4-6 weeks

3 Imipramine (tricyclic antidepressant) CYP2C19 CYP2D6 Imipramine Desipramine 2OH desipramine (Schenk et al 2008 Mol Psychiatry)

4 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) % of standard dose >2 CYP2D6 SGD (Schenk et al 2008 Mol Psychiatry)

5 Oncology (CYP2D6)

6 Tamoxifen metabolism & breast cancer Most effective component

7 CYP2D6 genotype and endoxifen levels Endoxifen (nmol/l) wt/wt wt/vt Vt/Vt (Vt=*4 = deficient; Based on Jin et al 2005)

8 CYP2D6 genotype and adjuvant TAM (n=1,325) Alternatief: Aromatase remmers 3% hogere survival over 15 jaar EM IM PM Ruwe inschatting: Nederland zou 15 miljoen euro per jaar kunnen besparen door invoering CYP2D6 screening (Schroth et al 2009 JAMA (Oct 7)) CYP2D6*3, *4, *5 and *10, *4

9 Current controversy.. Laboratory /Clinical pharmacology-view Theoretical involvement of CYP2D6 2. Effect genotype on metabolism proven 3. Effect genotype on outcome is proven Ready for clinical implementation Oncologists -view Not all studies show effect CYP2D6 2. No RCT was performed Not ready for clinical implementation

10 Anti-coagulation (clopidogrel/plavix) CYP2C19

11 Clopidogrel: needs activation by CYP2C19 (3% PMs, 26% IMs) Alternative: Prasugrel Succesful implementation PM (3% in Cauc, 30% Asian) Anthonius Hospital Nieuwegein P=0.003 Cardiologists in Erasmus MC: have decided to use Prasugrel as standard therapy instead of clopidogrel

12 Anti-coagulation with warfarin, acenocoumarol (Sintrom) or phenprocoumon (Marcomar) (CYP2C9/VKORC1)

13 The challenge. Variability in warfarin dose requirement in order to reach target INR 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 Number of Patients Weekly Dose Reynolds et al. Pers Med 2007

14 Metabolism 68% High activity (EM) 30% Intermediate (IM) 2% Low activity (PM) Caused by genetic polymorphisms (Reynolds et al 2007 Personalized Medicine)

15 Target molecule coumarines: VKORC1 VKORC1-1639G>A SNP: 30% GG 50% GA 20% AA Sensitive to coumarins 90% of bleeding complications occurred in the VKORC1 AA group (Reynolds et al 2007 Personalized Medicine)

16 FDA: genotype-based dose recommendations in drug label

17 Comparative trial 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))

18 Hurdles to take.. Proof of Principle (Pharmacokinetics) Proof of Efficacy (PD: do patients benefit?) Cost effectiveness

19 Cost-effectiveness. Cost of testing: $400 (!) ( 300) At Erasmus MC: 160 cost effective if available within 24 hours and costs < $200 ( 160) genotyping is unlikely to be cost effective

20 The laboratory Pharmacogenetic diagnostics service since 2006

21 care at Dept Clin Chemistry (n=1,800) CYP2B6 CYP3A5 UGT1A1 DPYD CYP2C8 BChE MDR1 NAT2 CYP1A2 VKORC1 CYP3A4 TPMT CYP2C9 CYP2C19 CYP2D6

22 The future of pharmacogenetics.(?!?) Action: YES Here is my sequence The genetic polymorphism leads to a lower metabolic capacity of CYP2D6, causing plasma concentrations of imipramine to rise (The New Yorker, 2000) Advice: Consult prescriber about lowering dose to 50% and monitor plasma concentrations to reach steady state Mechanism: Imipramine and the active metabolite desipramine are metabolized by CYP2D6. A genetic polymorphism in CYP2D6 results in higher plasmaconcentrations of both imipramine and desipramine. For additional info on PM phenotype: consult CYP2D6 background info on this site. Clinical consequences: In theory, side effects could be more comon with higher concentrations of imipramine Pharmacokinetic consequences: Imipramine: decrease in oral clearance of 47% compared to EM; increase of Css with 124%. Increase in half life with 44%. Sum-Css of imipramine and desipramine increases with376%, ratio AUC desipramine/imipramine with 664%, ratio Css desipramine/imipramine with 86%. Formation of hydroxymetabolites is low. Literature

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25 When to test?!? A B

26 How long can we do WITHOUT pharmacogenetics?!?

27 Advies Gezondheidraad 2011: Nieuw en Nodig

28 Farmacogenetica: onvervulde Kennis is aanwezig Associaties zijn Vervulde beloften: aangetoond TPMT Logistiek is er 6-Mercaptopurine Azathioprine HLA-B*5701 Abacavir Kosten zijn relatief beperkt belofte? Pending: CYP2C19 CYP2D6 Clopidogrel Tamoxifen Anti-depressiva Anti-psychotica CYP2C9/VKORC1 Coumarines Niet gehaald: Interesting: UGT1A1 irinotecan CYP2D6 codeïne, tramadol oxycodon