An expanded pharmacogenomics warfarin dosing table with utility in generalised dosing guidance.
Pharmacogenomics (PGx) guided warfarin dosing, using a comprehensive dosing algorithm, is expected to improve dose optimisation and lower the risk of adverse drug reactions. As a complementary tool, a simple genotype-dosing table, such as in the US Food and Drug Administration (FDA) Coumadin drug label, may be utilised for general risk assessment of likely over- or under-anticoagulation on a standard dose of warfarin. This tool may be used as part of the clinical decision support for the interpretation of genetic data, serving as a first step in the anticoagulation therapy decision making process. Here we used a publicly available warfarin dosing calculator (www.warfarindosing.org) to create an expanded gene-based warfarin dosing table, the CPMC-WD table that includes nine genetic variants in CYP2C9, VKORC1, and CYP4F2. Using two datasets, a European American cohort (EUA, n=73) and the Quebec Warfarin Cohort (QWC, n=769), we show that the CPMC-WD table more accurately predicts therapeutic dose than the FDA table (51 % vs 33 %, respectively, in the EUA, McNemar's two-sided p=0.02; 52 % vs 37 % in the QWC, p<1×10(-6)). It also outperforms both the standard of care 5 mg/day dosing (51 % vs 34 % in the EUA, p=0.04; 52 % vs 31 % in the QWC, p<1×10(-6)) as well as a clinical-only algorithm (51 % vs 38 % in the EUA, trend p=0.11; 52 % vs 45 % in the QWC, p=0.003). This table offers a valuable update to the PGx dosing guideline in the drug label.
Payman
P
Shahabi
Laura B
LB
Scheinfeldt
Daniel E
DE
Lynch
Tara J
TJ
Schmidlen
Sylvie
S
Perreault
Margaret A
MA
Keller
Rachel
R
Kasper
Lisa
L
Wawak
Joseph P
JP
Jarvis
Norman P
NP
Gerry
Erynn S
ES
Gordon
Michael F
MF
Christman
Marie-Pierre
MP
Dubé
Neda Gharani, PhD, 1 Templemere, Weybridge, Surrey KT13 9PA, UK, Tel.: +44 7984005796, Fax:+44 1932976519, E-mail: gharani.consulting@gmail.com.
Neda
N
Gharani
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D001281:Atrial Fibrillation / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D000072470:Cytochrome P450 Family 4 / Q000235:genetics; D016208:Databases, Factual; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics / Q000706:statistics & numerical data*; D000071184:Pharmacogenomic Variants; D011237:Predictive Value of Tests; D064417:Vitamin K Epoxide Reductases / Q000235:genetics; D014859:Warfarin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D055815:Young Adult
D000925:Anticoagulants; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases
CYP2C9; CYP4F2; Pharmacogenomics; VKORC1; warfarin