PGx Logical Overview

PGx Alert & Guideline Development PGx Committee Clinical Geneticist Pharmacists Physicians and Specialists Lab Director Quality Director

Simvastatin Pharmacogenetic Summary Gene: SLCO1B1 Alternative names: OATP1B1 and OATP-C Function: Protein transporter facilitating hepatic uptake of drugs and endogenous substances Genetic variation: “C” allele = reduced function; “T” = normal function Risk: Increased exposure to simvastatin leading to increased risk for myalgia, myopathy, rhadbomyolysis Genotype Phenotype Percentage of Patients Myopathy Risk Max Simvastatin Dose* TT Normal function 55-88% Normal 40 mg TC Intermediate function 11-36% Intermediate 10 mg – 20 mg or alternative statin† CC Low function 0-6% High Note: Additional testing recommended for TC and CC *not including dose limiting drug interactions and contraindications †High potency: atorvastatin and rosuvastatin †Low potency: fluvastatin, pravastatin, lovastatin

Clopidogrel Pharmacogenetic Summary Gene: CYP2C19 Function: Metabolism of antidepressants, benzodiazepines, PPIs, and more Metabolism of clopidogrel converts pro-drug to active form Risk: reduced activation leading to reduced effectiveness for prevention of cardiovascular events Phenotype* Activation of clopidogrel Platelet Inhibition Percentage of Patients Recommended Action Ultrarapid metabolizer (UM) Increased Possibly increased 5-30% 75 mg/day Extensive Metabolizer (EM) Normal 35-50% Intermediate Metabolizer (IM) Intermediate Reduced 18-45% Alternative therapy† Poor Metabolizer (PM) Low or deficient Significantly reduced 2-15% *Various genotypes are associated with each phenotype †prasugrel or ticagrelor

Warfarin Pharmacogenetic Summary Gene: CYP2C9 Function: hepatic drug metabolism; primary enzyme metabolizing S-warfarin Genetic Variation: *2 and *3 alleles = reduced function (30-40% and 80-90%) Risk: reduced metabolism and elevated INR Gene: VKORC1 Function: vitamin K-epoxide reductase protein catalyzes conversion of vitamin-K epoxide to vitamin K (recycling to create functional clotting factors) Genetic Variation: -1639A variant = warfarin sensitivity and reduced dose requirements Risk: increased effects and elevated INR Recommended daily warfarin doses (mg/day) to achieve a therapeutic INR based on CYP2C9 and VKORC1 genotype using the warfarin product insert approved by the US Food and Drug Administration VKORC1: -1639G>A CYP2C9*1/*1 CYP2C9*1/*2 CYP2C9*1/*3 CYP2C9*2/*2 CYP2C9*2/*3 CYP2C9*3/*3 GG 5 – 7 mg 3 – 4 mg 0.5 – 2 mg GA AA Note: this dosing table does not consider other clinical factors (e.g., age, interactions, diet)