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The pharmacokinetics and pharmacodynamics of single dose (R)‐ and (S)‐warfarin administered separately and together: relationship to VKORC1 genotype
Author(s) -
Maddison John,
Somogyi Andrew A.,
Jensen Berit P.,
James Heather M.,
Gentgall Melanie,
Rolan Paul E.
Publication year - 2013
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2012.04335.x
Subject(s) - pharmacokinetics , pharmacodynamics , warfarin , vkorc1 , pharmacology , medicine , genotype , cyp2c9 , biology , atrial fibrillation , genetics , metabolism , cytochrome p450 , gene
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The contribution of (S)‐warfarin to the clinical effect of rac ‐warfarin is well understood. The extent to which (R)‐warfarin contributes to the clinical effect of rac‐ warfarin is unclear. WHAT THIS STUDY ADDS • Using unequivocally pure (R)‐ and (S)‐warfarin we have demonstrated that (R)‐warfarin contributes to the hypoprothrombinaemic effect of single large doses of warfarin. • The extent of the interaction is dependent on VKORC1 genotype. AIMS 1) To determine the pharmacokinetics and pharmacodynamics of (R)‐ and (S)‐warfarin given alone and in combination and 2) to determine whether the relative potency of (R)‐ and (S)‐warfarin is dependent on VKORC1 genotype. METHODS A three way crossover study was conducted in which 17 healthy male subjects stratified by VKORC1 1173 C>T genotype and all CYP2C9 1*/1* received (R)‐warfarin 80 mg, (S)‐warfarin 12.5 mg and rac‐ warfarin sodium 25 mg. Plasma (R)‐ and (S)‐warfarin unbound and total concentrations and prothrombin time were determined at multiple time points to 168 h. RESULTS Pharmacokinetic parameters for (R)‐ and (S)‐warfarin were similar to the literature. (R)‐warfarin 80 mg alone resulted in a mean AUC PT (0,168 h) of 3550 s h (95% CI 3220, 3880). Rac‐ warfarin sodium 25 mg containing (S)‐warfarin 11.7 mg produced a greater effect on AUC PT (0,168 h) than (S)‐warfarin 12.5 mg (mean difference 250 s.h, 95% CI 110, 380, P < 0.002) given alone. In a mixed effects model the ratio of response between (R)‐ and (S)‐warfarin (AUC PT((R)‐warfarin) : AUC PT((S)‐warfarin) ) was 1.21 fold higher (95% CI 1.05, 1.41, P < 0.02) in subjects of VKORC1 TT genotype compared with the CC genotype. CONCLUSIONS (R)‐warfarin has a clear PD effect and contributes to the hypoprothrombinaemic effect of rac ‐warfarin. VKORC1 genotype is a covariate of the relative R/S potency relationship. Prediction of drug interactions with warfarin needs to consider effects on (R)‐warfarin PK and VKORC1 genotype.