Pharmacokinetic-pharmacodynamic modelling of DP-1904, a novel thromboxane synthetase inhibitor in rabbits, based on an indirect response model

Abstract

A new imidazole derivative, DP-1904, produces a selective, potent and long-acting inhibition of thromboxane A2 (TXA2) syntheses and platelet aggregation. This study was designed to investigate the pharmacokinetics and pharmacodynamics (PK/PD) of DP-1904. DP-1904 disappeared from plasma with a half-life of 20 min after i.v. dosing, and the bioavailability after oral dosing was approximately 70%. The level of serum TXB2, which is a pharmacological marker for thromboxane synthetase inhibition, was measured to characterize the pharmacodynamics of DP-1904. A marked reduction of serum TXB2 was exhibited within 1 h after both i.v. and oral doses, reflecting the rapid onset of action of DP-1904. Serum TXB2 returned to the basal level much more slowly after oral dosing than after i.v. dosing, due to the longer half-life after oral dosing. An Emax model was employed to fit the pharmacological data after oral dosing, and IC50 and Emax values were estimated to be 5.0 ng/ml and 81%, respectively. In order to test its predictability, the PK/PD model was then used to predict a pharmacological profile after i.v. dosing; good agreement between the observed and predicted values was achieved. Thus, the present modelling procedure may be useful for optimizing the therapeutic regimens of DP-1904.