Implementation of CYP2C19 Genotyping for Clopidogrel

Gwen McMillin, PhD, DABCC (CC,TC)

July 27, 2010

Outline

• Demand for CYP2C19 genotyping

• Laboratory considerations

• Reporting considerations

• Other uses for CYP2C19 genotyping

CYP2C19 Orders July 2009 – June 2010

~40-fold increase in Q4 vs Q1 test volumes

CYP2C19 Patients (Q4)

• Average age: 70 yrs (median 72 yrs)

• 55% male

• 37 states

Distribution of alleles detected (Q4)

Negative*2*3*4*6*8*17

Predicts PM

Predicts UM

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

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)

MOL.3600, CAP, Molecular Pathology, 2009

Possible algorithm for clopidogrel

GenotypeCYP2C19

No PMVariantsor CYP2C19*17 only

Active drug expected Drug-drug interactions?Monitor response

One PM variant

Two PM variantsAlternate drug(e.g., prasugrel)Monitor response

Consider alternate drugConsider escalated doseMonitor response

Turnaround Time?

Clinical need

Laboratory and cost efficiency

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

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

CYP2C19*17 could “accelerate” PK or convert CYP2C19 from a minor to a major pathway

Impairment could interfere with

expected drug activation or inactivation

Impairment could interfere with

expected drug activation or inactivation