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Pharmacogenetics in Development, Assessment and Use of Medicines

Pharmacogenetics in Development, Assessment and Use of Medicines. Dr Rashmi Shah Pharmaceutical Consultant Former Senior Clinical Assessor, MHRA, London. N = 94. Are Drugs Effective?. Disease Efficacy Annual Rx Cost. Alzheimer’s 30% $ 1,500

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Pharmacogenetics in Development, Assessment and Use of Medicines

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  1. Pharmacogenetics in Development, Assessment and Use of Medicines Dr Rashmi Shah Pharmaceutical Consultant Former Senior Clinical Assessor, MHRA, London N = 94

  2. Are Drugs Effective? Disease Efficacy Annual Rx Cost Alzheimer’s 30% $ 1,500 Analgesics 80% $ 1,350 Cardiac arrhythmia 60% $ 650 Depression 60% $ 700 Diabetes 55% $ 1,300 Hepatitis C 45% $ 5,000 Incontinence 40% $ 1,000 Migraine 50% $ 600 Oncology 25% $ 3,500 Inter-individual and/or Inter-ethnic differences Prescribed drugs are generally effective in about 50% of patients.

  3. Incentives to Pharmacogenetics in Therapeutics –Health resources About 1-2 adverse effect per GP per day 3-5% of all hospital admissions are due to ADRs 5-8% of the hospital inpatients experience an ADR Duration of hospital stay increased by about 4 days per patient by ADRs 5-10% of all in-hospital costs are related to ADRs 0.3-0.5% of deaths are ADR-related deaths. Physician and hospital litigations Overall, annual costs vary according to the country and the UK estimate is at least £ 2 billion every year

  4. Clinical consequences of NAT2 acetylation polymorphism - some examples

  5. Drug metabolism by CYP P450 isoforms • 315 drugs profiled for their metabolism • Of these, 56% primarily metabolised by CYP P450 isoforms - 50% CYP 3A4 (about 30% of liver P450 content) - 20% CYP 2D6 * (about 2% of liver P450 content) - 15% CYP 2C9/19 *,CYP 2C8 * (about 20% of liver P450 content) - 15% CYPs 2E1, 2A6 *, 2B6 *, 1A2 * etc (about 24% of liver P450 content) CYP2D6 is the most widely studied. It metabolises a large number of CNS and CVS drugs – most with narrow therapeutic index * These CYP isoforms display genetic polymorphism

  6. Pharmacokinetic Consequences of CYP 2D6 Polymorphism Extensive metaboliser arbitrarily assigned 10 units

  7. Clinical Consequences in PMs of CYP 2D6 Polymorphism Debrisoquine : Postural hypotension and physical collapse Sparteine : Oxytocic effects Perphenazine : Extrapyramidal symptoms Flecainide : Proarrhythmic effects Perhexiline : Peripheral neuropathy and/or hepatotoxicity Phenformin : Lactic acidosis Propafenone : CNS toxicity and bronchoconstriction Metoprolol : Loss of cardioselectivity Nortriptyline : Hypotension and confusion Terikalant : QT Interval Prolongation d-fenfluramine : Nausea, vomiting and headache

  8. ClinicalConsequences in PMs of CYP 2D6 Polymorphism Codeine : Poor analgesic effect Hydrocodon : Poor analgesic effect Tramadol : Poor analgesic effect Opiates : Protection from oral opiate dependence

  9. ClinicalConsequences in EMs of CYP 2D6 Polymorphism In ultrarapid EMs: Nortriptyline:Poor antidepressant effect Require megadoses of nortriptyline for efficacy Propafenone :Poor antiarrhythmic effect Codeine: Morphine toxicity Encainide: ? Proarrhythmias Tropisetron: Poor antiemetic effect

  10. Indication and target population Dose For EM Genotyped target population Dose For IM Dose For PM Un-genotyped target population Standard dose

  11. Encainide metabolism Quinidine Encainide CYP2D6 N-desmethyl-encainide (NDE O-desmethyl-encainide (ODE) CYP2D6 3-methoxy-O-desmethyl-encainide (MODE) N,O-didesmethyl-encainide (DDE, also known as NODE)

  12. Encainide/Quinidine Interaction Chronic administration PMs of CYP2D6 Inhibition achieved with 60mg quinidine for 5 days Redrawn from data from Turgeon et al, J Pharmacol Exp Ther, 1990; 255: 642-649

  13. Encainide/Quinidine Interaction Chronic administration EMs of CYP2D6 Inhibition achieved with 60mg quinidine for 5 days Redrawn from data from Turgeon et al, J Pharmacol Exp Ther, 1990; 255: 642-649

  14. 2-adrenoreceptor polymorphisms Lima JJ et al, Clin Pharmacol Ther, 1999; 65: 519-525 Pharmacokinetics Plasma Mean of 16 patients with moderate asthma following a single oral dose of 8mg

  15. 2-adrenoreceptor polymorphisms Lima JJ et al, Clin Pharmacol Ther, 1999; 65: 519-525 Pharmacodynamics Median Mean of 16 patients with moderate asthma following a single oral dose of 8mg

  16. 2-adrenoreceptor polymorphisms Some 1-adrenoceptor or 2-adrenoceptors polymorphisms have been related to survival in patients with cardiac failure 2-adrenoceptor polymorphism also influences therapeutic response to carvedilol. Patients who are homozygous for Gln27 display a significantly lower proportion of good responders than patients who are homozygous or heterozygous for the Glu27 polymorphism(26% versus 63%)

  17. Depression is a heterogeneous disease • Genetic variation of serotonin transporter is involved in clinical • remission of major depressive episodes after twelve weeks of • citalopram treatment (Arias et al, 2003) • The short allele of the 5HTTLPR may identify patients at risk for • developing insomnia or agitation with fluoxetine treatment • (Perlis et al, 2003) • Subjects homozygous for the long allele of 5HTTLPR showed a • significantly faster response to sertraline or paroxetine • (Durham et al, 2004; Pollock et al, 2000) • Lack of LL genotype = Lack of response (in 83.3%) • (Kim et al, 2000)

  18. Clinical Therapeutics Efficacy, adverse drug reactions and drug interactions are often genotype-dependent

  19. Disease Drug and dose Genotype Drug metabolising enzymes Pharmacological targets SCG or SNP or haplotype The theory Response to drug administration Phenotype

  20. Improving risk and benefit through pharmacogenetics Managing pharmacokinetic variability and Managing pharmacodynamic variability by pharmacogenetic biomarkers

  21. Improving risk and benefit through pharmacogenetics P O L Y M O R P H I S M Pharmacodynamic Diminished efficacy Choice among drugs acting at different targets Possibly personalised medicine Choice among doses specific to different DME genotypes Pharmacokinetic Increased toxicity

  22. Improving risk and benefit through pharmacogenetics Pharmacokinetic variability Managed by dose adjustment Pharmacodynamic variability Manageable generally only by modulating a different pharmacological target

  23. Promise of Pharmacogenetics

  24. Major factors influencing efficacy and safety Genetics Co-medications Co-morbidity Physiological Environmental Pharmaco kinetics Pharmaco dynamics Dose response curve Primary pharmacology Secondary pharmacology Safety Efficacy

  25. Pharmacogenetics and Individually targeted medicines Anecdotal case reports genotype of phenotypic cases ……… No prospective studies on phenotypes of genotype

  26. Pharmacogenetics and clinical outcomes Problems with Retrospective Association Studies No clear definitions of phenotype Lack of acceptable genotype-phenotype correlation Small samples Confounding factors [co-medications, co-morbidity] Heterogeneous demography and disease

  27. Pharmacogenetics and clinical outcomes No evidence from prospective controlled studies to suggest that routine genotyping for drug metabolising enzymes prior to commencing therapy is helpful or cost-effective With emphasis on clinical outcomes and numbers needed to treat to improve the outcome in 1 case

  28. Not all clinical problems have a pharmacogenetic basis

  29. Other CYP Polymorphisms and Clinical Outcomes CYP2C9:Warfarin sensitivity  Phenytoin sensitivity  Diclofenac hepatotoxicity  NSAID-induced gastric ulcers  CYP2C19:Improved efficacy with PPIs  Lower serum B12 following PPIs  Visual disturbances following PPIs  Proguanil treatment failure ?

  30. Warfarin and CYP2C9 Polymorphism Relative contribution to variability in response: CYP2C9 genotype: 10% Age: 12% VKORC genotype: 30-37% Loebstein et al. 2001; Bodin et al. 2005

  31. Warfarin, CYP2C9 and VKORC1 206 patients Genotyped for CYP2C9*2 and *3 and VKORC1 (C1173T) Standard dosing followed an empirical protocol, whereas pharmacogenetic guided dosing followed a regression equation including the 3 genetic variants and age, sex, and weight. Anderson JL et al, 2007

  32. Warfarin, CYP2C9 and VKORC1 • “However, there is insufficient evidence, at this time, to recommend • for or against routine CYP2C9 and VKORC1 testing in • warfarin-naive patients. Prospective clinical trials are needed that • provide direct evidence of the benefits, disadvantages, and costs • associated with this testing in the setting of initial warfarin dosing. • Although the routine use of warfarin genotyping is not endorsed by • this work group at this time, in certain situations, CYP2C9 and • VKORC1 testing may be useful, and warranted, in determining the • cause of unusual therapeutic responses to warfarin therapy.” American College of Medical Genetics Working Group on Pharmacogenetic Testing of CYP2C9, VKORC1 Alleles for Warfarin Use. Genet Med. 2008 Feb;10(2):139-50.

  33. Genotype and Response to Atomoxetine Selective norepinephrine reuptake inhibitor indicated for Attention Deficit/Hyperactivity Disorder Metabolised by CYP2D6 to pharmacologically equipotent 4-hydroxy-atomoxetine EM PM Half-lives: 5.2 h 21.6 h Cmax 5-fold AUC 10-fold

  34. Genotype and Response to Atomoxetine During clinical trials: - Many neuropsychiatric adverse events were generally twice as frequent in PMs. - 5% of the EMs and 7% of the PMs discontinued treatment as a result % PMs in Caucasians: 9% What does this mean for routine genotyping? If a population of 100 patients was NOT genotyped: 0.63 (un-genotyped) PM will have discontinued 4.55 (un-genotyped) EMs will have discontinued (7.2 EMs for every 1 PM)

  35. Examples of CNS drugs metabolised by CYP 2D6

  36. Genotype and Response to Neuroleptics From 17 studies (1995-2000) which included 1379 patients Investigated CYP2D6 genotype associations with drug levels, failure to respond, frequency and severity of tardive dyskinesia, neuroleptic malignant syndrome and EPS Relationship with plasma concentrations shown for drugs with dominant CYP mediated metabolism but large intra-genotypic variability obscures clinical utility. However. no relationship tofailure to respond beneficially General modest trend observed towards a positive correlation between the genotype, especially the presence of *10 allele in the Japanese, and severity of tardive dyskinesia and EPS

  37. Genotype and Response to Antidepressants Plasma concentrations of fluoxetine or paroxetine significantly correlated with CYP2D6 genotype (Charlier C et al, 2003) CYP2D6 gene duplication is a possible factor in persistence of mood disorders (8 out of 81 patients who failed to respond) (Kawanishi C et al, 2003) CYP2D6 PM status does not necessarily lead to increased ADRs (Roberts RL et al, 2004)

  38. Genotype and Response to Antidepressants Bijl MJ et al, 2008

  39. Limitations of pharmacogenetic

  40. Improving risk and benefit through pharmacogenetics Threats to benefits from pharmacogenetics Ethnic differences in allele frequencies Promotion of high doses Drug interactions Disregard of prescribing information Gene-gene interactions Lack of or poor genotype-phenotype correlation Clinical motivation and practicalities

  41. Alleles at CYP2D6 locus 52 major alleles (86 total variants) reported as at 17 April 2005 Homozygosity for alleles *3, *4 and * 5 identify approximately 95% of all CYP2D6 poor metabolisers

  42. Alleles at CYP2D6 locus Global heterogeneity in % frequency of CYP2D6 alleles The ethnic origin of the clinical trial population may be important when extrapolating data to populations of other ethnic origins Ingelman-Sundberg M et al, TiPS, 1999; 20: 342-349

  43. “SNP Fever” There are virtually no examples where a single DNA variant site (genotype) can always be associated with a particular trait (disease phenotype or drug response) in all subjects within all human populations.

  44. Pharmacokinetics, Pharmacodynamics or Dose related regulatory actions

  45. Cisapride Reporting rates per million patient-months of exposure

  46. Cisapride: • Regulatory actions Contraindicated with a number of azole antifungals and macrolides Caution in patients with pre-existing prolongation of QT interval or in patients taking other QT prolonging drugs FDA database as at 31 December 1999: 341 reports of arrhythmias 80 had fatal outcome Drug withdrawn from the US market 14 July 2000 Available in the US only for specific clinical eligibility criteria for a limited-access protocol

  47. “QT Prolongation” risk is a moving target Wysowski D et al, 2001 341 reports of cisapride-induced QT interval prolongation and ventricular arrhythmias - CYP3A4 inhibitors 126 (37 %) - Electrolyte imbalance 17 (5 %) - Proarrhythmic drugs 17 (5 %) - Heart failure 29 (8.5 %) - Other cardiac disease 66 (19.4 %) - Cisapride overdose 9 (2.6 %) - No risk factors 38 (11 %)

  48. Chronology of cerivastatin (USA)

  49. Risk-benefit evaluation in approval of drugs Dose of a drug Change in risk/benefit Increase in plasma concentrations Ethnicity or genotype of the patient Co-medications Co-morbidity

  50. Risk-benefit of a potential blockbusterWithdrawal of cerivastatin ‘Baycol’ Dose of cerivastatin 0.3mg increased to 0.8mg Change in risk/benefit Disregard for labelling changes: Contraindications and Low starting dose Potentially fatal rhabdomyolysis Increase in plasma concentrations Genotype ? CYP2C8 PMs Co-medication with gemfibrozil

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