1. Implementation of CYP2C19 Genotyping for Clopidogrel Gwen McMillin, PhD, DABCC (CC,TC) July 27, 2010

2. Outline Demand for CYP2C19 genotyping Laboratory considerations Reporting considerations Other uses for CYP2C19 genotyping

3. CYP2C19 Orders July 2009 – June 2010 ~40-fold increase in Q4 vs Q1 test volumes

4. CYP2C19 Patients (Q4) Average age: 70 yrs (median 72 yrs) 55% male 37 states

5. Distribution of alleles detected (Q4) Predicts PM Predicts UM

6. Laboratory Considerations Specimen: blood, saliva, buccal swab Guidelines and standards: CAP, NYDOH, ACMG Quality control: no template, and previously characterized samples or commercial sources Proficiency testing: CAP Pharmacogenetics

7. Report Content Collection, specimen, and patient details Results (genotype), evidence of review Analytical –Method –List of all variants detected, using standard nomenclature –Limitations of testing –ASR status (if applicable) Clinical –Interpretation –Suggestions for additional or alternative testing –References (if applicable) –Access to consultation (genetic counselor, director)

8. MOL.3600, CAP, Molecular Pathology, 2009 “Laboratory reports should be designed to convey patient results effectively to a non- expert physician. This includes documentation of the analytical procedure used or the commercial kit version accompanied by an interpretation of findings”

9. Possible algorithm for clopidogrel Genotype CYP2C19 No PM Variants or CYP2C19*17 only Active drug expected Drug-drug interactions? Monitor response One PM variant Two PM variants Alternate drug (e.g., prasugrel) Monitor response Consider alternate drug Consider escalated dose Monitor response

10. Turnaround Time? Clinical need Laboratory and cost efficiency

11. Other uses for CYP2C19 Genotyping Drug substrate examples –Antidepressants: amitriptyline, imipramine, trimipramine, citalopram, sertraline –Anxiolytic: diazepam –Anticonvulsant: phenytoin –Muscle relaxant: carisoprodol –Gastrointestinal: omeprazole, lansoprazole –Infection: voriconazole, nelfinavir, proguanil –Oncology: tamoxifen, cyclophosphamide –Cardiology: r-warfarin, propranolol Define role of CYP2C19 in metabolism Content of CYP2C19 testing

12. Possible Scenarios for Utility CYP2C19 is a major pathway –Inactivates drug –Activates drug CYP2C19 is a minor pathway –Inactivates drug –Activates drug Must consider potential for drug-gene interactions and drug-drug interactions CYP2C19*17 could “accelerate” PK or convert CYP2C19 from a minor to a major pathway Impairment could interfere with expected drug activation or inactivation