PGx - Clopidogrel, Warfarin, Statins

Clopidogrel Metabolizing Enzyme

CYP 2C19

CYP 2C19 Phenotypes

• UM

• RM

• NM

• IM

• PM

CPIC Clopidogrel guidelines

• IM or PM → Switch to Prasugrel or Ticagrelor

• URM/RM/NM → standard clopidogrel dosing

FDA Package insert Clopidogrel PGx

Switch agents if PM

Warfarin Metabolizing Enzyme

CYP 2C9

metabolizes S-warfarin (more potent)

Warfarin Direct Target (PD)

VKORC1

controls warfarin sensitivity

Warfarin indirect target (PD)

CYP4F2

removes excess vitamin K

Patients with reduced CYP 2C9 fx

• lower metabolism

• lower dose of warfarin

CYP 2C9 alleles more common in African Americans

5, 6, 8, 11

CYP 2C9 alleles more common in Caucasian patients

2,3

VKORC1 A/A genotype

• decreased VKORC1 expression

• greater warfarin sensitivity

• lower dose requirement

• most common in east asians and caucasian

CYP 4F2 PGx

• does NOT alter warfarin clearance

• variant of interest: *3 → decreased enzyme activity → more vitamin K available → need HIGHER warfarin doses

• higher relevance in European, Asian

Warfarin dosing for African ancestry

if CYP 2C9 *5,6,8,11 aren’t tested, default to standard clinical dosing

Current PGx dosing algorithm perform better in what populations?

European, Asian

Warfarin PGx info should be integrated with

• clinical judgement

• ancestry considerations

• INR monitoring

Statin transporter enzymes (PK)

• SLCO1B1 (all statins)

• ABCG2 (rosuvastatin)

SLCO1B1

• aka OATP1B1

• facilitates hepatic update of statins

• common variants: *5, *15 → decreased transporter function → lower dose required (increased risk of SAMS)

• highest statin risk: simvastatin

Clinically actionable SLCO1B1 phenotypes

• decreased function

• poor function

SLCO1B1 Decreased Fx Statin dosing

• atorvastatin: 40 mg max

• Pravastatin: prescribe as desired, possible increased risk over 40 mg

• Rosuvastatin: prescribe as desired, possible increased risk over 20 mg

• Simvastatin: choose alternative

SLCO1B1 poor function

• Atorvastatin: 20 mg

• Pravasatin: 40 mg

• Rosuvastatin: 20 mg

• Simvastatin: choose alt

ABCG2

• facilitates efflux of rosuvastatin into extracellular space

• no star allele nomebclature

• A allele reduces expression → higher plasma conc of rosuvastatin → uncertain myopathy risk, greater cholesterol lowering

ABCG2 poor function

20 mg max Rosuvastatin starting dose