NDLI: Assessing the relative potency of (S)- and (R)-warfarin with a new PK-PD model, in relation to VKORC1 genotypes

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Assessing the relative potency of (S)- and (R)-warfarin with a new PK-PD model, in relation to VKORC1 genotypes

Content Provider	Springer Nature Link
Author	Ferrari, Myriam Pengo, Vittorio Barolo, Massimilia Bezzo, Fabrizio Padrini, Roberto
Copyright Year	2017
Abstract	The purpose of this study is to develop a new pharmacokinetic-pharmacodynamic (PK-PD) model to characterise the contribution of (S)- and (R)-warfarin to the anticoagulant effect on patients in treatment with rac-warfarin.Fifty-seven patients starting warfarin (W) therapy were studied, from the first dose and during chronic treatment at INR stabilization. Plasma concentrations of (S)- and (R)-W and INRs were measured 12, 36 and 60 h after the first dose and at steady state 12–14 h after dosing. Patients were also genotyped for the G>A VKORC1 polymorphism. The PK-PD model assumed a linear relationship between W enantiomer concentration and INR and included a scaling factor k to account for a different potency of (R)-W. Two parallel compartment chains with different transit times (MTT1 and MTT2) were used to model the delay in the W effect. PD parameters were estimated with the maximum likelihood approach.The model satisfactorily described the mean time-course of INR, both after the initial dose and during long-term treatment. (R)-W contributed to the rac-W anticoagulant effect with a potency of about 27% that of (S)-W. This effect was independent of VKORC1 genotype. As expected, the slope of the PK/PD linear correlation increased stepwise from GG to GA and from GA to AA VKORC1 genotype (0.71, 0.90 and 1.49, respectively).Our PK-PD linear model can quantify the partial pharmacodynamic activity of (R)-W in patients contemporaneously exposed to therapeutic (S)-W plasma levels. This concept may be useful in improving the performance of future algorithms aiming at identifying the most appropriate W maintenance dose.
Starting Page	699
Ending Page	707
Page Count	9
File Format	PDF
ISSN	00316970
Journal	European Journal of Clinical Pharmacology
Volume Number	73
Issue Number	6
e-ISSN	14321041
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2017-04-05
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Pharmacodymamics Pharmacokinetics (S)-warfarin (R)-warfarin VKORC1 Pharmacology/Toxicology
Content Type	Text
Resource Type	Article
Subject	Pharmacology Pharmacology (medical)

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