PHARMACOKINETIC-PHARMACODYNAMIC MODELING OF DP-1904, A NOVEL THROMBOXANE SYNTHETASE INHIBITOR IN RABBITS, BASED ON AN INDIRECT RESPONSE MODEL

A new imidazole derivative, DP-1904, produces a selective, potent and long-acting inhibition of thromboxane A(2) (TXA(2)) syntheses and plat elet aggregation. This study was designed to investigate the pharmacok inetics and pharmacodynamics (PK/PD) of DP-1904. DP-1904 disappeared f rom plasma with a half-life of 20 min after i.v. dosing, and the bioav ailability after oral dosing was approximately 70%. The level of serum TXB(2), which is a pharmacological marker for thromboxane synthetase inhibition, was measured to characterize the pharmacodynamics of DP-19 04. A marked reduction of serum TXB(2) was exhibited within 1 h after both i.v. and oral doses, reflecting the rapid onset of action of DP-1 904. Serum TXB(2) returned to the basal level much more slowly after o ral dosing than after i.v. dosing, due to the longer half-life after o ral 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 than used to predict a pharmacological profile after i .v. dosing; good agreement between the observed and predicted values w as achieved. Thus, the present modelling procedure may be useful for o ptimizing the therapeutic regimens of DP-1904.