Pharmacokinetic and pharmacodynamic re-evaluation of a genetic-guided warfarin trial

Abstract

Purpose: A previous trial failed to demonstrate the superiority of a demographic-genetic algorithm in predicting warfarin (W) dose over a standard clinical approach. The purpose of the present study is to re-analyse the results in subgroups of patients with differing baseline sensitivity to W, integrated with additional pharmacokinetic data.

Methods: The original trial allocated 180 treatment-naïve patients with non-valvular atrial fibrillation to a control arm (CTL, n = 92) or a genetic-guided arm (GEN, n = 88). Before starting anticoagulation treatment, all patients were genotyped for CYP2C9, VKORC1 and CYP4F2 variants and classified into four quartiles (Q1, Q2, Q3, Q4) according to the algorithm-predicted W maintenance dose. International normalised ratios (INR) and plasma concentrations of S-warfarin [S-W]s and R-warfarin [R-W]s were measured at baseline and on days 5, 7, 9, 12, 15 and 19 of therapy.

Results: In the lowest dose quartile (Q1), the number of INRs > 3 and mean INR values on days 5 and 7 were significantly higher in CTL than in GEN. In Q3 and Q4, the mean INR values reached therapeutic level (> 2) 2 days later in CTL than in GEN. During follow-up, the mean time courses of INRs and [S-W]s in GEN were remarkably stable in all dose quartiles. Thus, mean changes from starting to final doses were significantly smaller in GEN than in CTL. Plasma concentrations of R-W (a partially active enantiomer) steadily increased from day 5 to day 19 in all Qs in both CTL and GEN, except in the Q1 CTL group, due to the marked dose reduction required.

Conclusions: This analysis showed that the demographic-genetic algorithm used to predict the W dose can identify patients with differing degrees of sensitivity to W and to 'normalise' their average anticoagulant responses. The progressive rise in [R-W]s throughout the 19-day follow-up indicates that the (partial) contribution of R-W to the W anticoagulant effect changes continually during the early phase of treatment.

Keywords: Algorithm; Pharmacodynamic; Pharmacogenetics; Pharmacokinetics; Warfarin.