1. PGx Logical Overview

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

3. 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

4. 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

5. 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: A 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)