Stereochemical aspects of warfarin drug interactions: Use of a combined pharmacokinetic-pharmacodynamic model

OBJECTIVE: To apply a combined pharmacokinetic-pharmacodynamic model to data from warfarin drug interaction studies. METHODS: The pharmacokinetic model for warfarin enantiomers combined a common first-order absorption process with individual clearance and volume of distribution values and is based on unbound drug. The complete pharmacodynamic model comprised two components: that involving inhibition of prothrombin complex activity (PCA) synthesis described by a sigmoid maximum effect (Emax) model and that relating temporal changes in PCA to synthesis and degradation. The combined model was applied to prothrombin time and plasma concentration-time data obtained after oral administration of single doses of racemic warfarin to healthy subjects either alone or during multiple dosing with the metabolic enzyme inhibitor phenylbutazone or the inducer secobarbital. RESULTS: The five parameters associated with the complete pharmacodynamic model were kd (0.054 +/- 0.014 hr-1), the degradation rate constant of PCA; Cu50,S (0.0026 +/- 0.0015 mg.L-1) and Cu50,R (3.45 +/- 4.20 mg.L-1), the unbound concentrations of (S)- and (R)-warfarin required to produce a 50% reduction in PCA synthesis if administered individually; gamma (0.90 +/- 0.23), the slope parameter in the sigmoid Emax model; and td (8.2 +/- 0.3 hours), the observed delay in the onset of warfarin anticoagulant response. CONCLUSIONS: These findings qualitatively confirm the known potency difference between warfarin enantiomers. Furthermore, although phenylbutazone and secobarbital altered the pharmacokinetics of warfarin, these compounds do not appear to influence its pharmacodynamics. Simulation studies indicate that, after racemate administration, the continual presence of the more potent (S)-enantiomer precludes accurate assessment of Cu50,R. Analysis indicates that use of racemic (rather than enantiomer) warfarin concentration data in drug interaction studies may lead to misinterpretation of pharmacodynamic data.