Pharmacokinetic and Pharmacodynamic Modeling of a Novel Thromboxane Synthetase Inhibitor, DP-1904, in Human

Abstract

Pharmacokinetic and pharmacodynamic (PK/PD) analyses for a novel thromboxane synthetase inhibitor, DP-1904, were performed to predict its PK/PD profiles in human after single and repeated oral administration. The pharmacodynamics of DP-1904 was characterized by serum levels of thromboxane B₂(TXB₂), a pharmacological marker for thromboxane synthetase inhibition. Based on a quantitative relationship between the plasma DP-1904 and serum TXB₂ concentrations after single oral dosage, IC₅₀ and E_max values were estimated to be 0.54 ng/ml and 94%, respectively. An integrated, simple PK/PD model was developed to simulate the changes in serum TXB₂ levels after single oral administration of DP-1904 at various doses, and the simulation curves corresponded well with the observed data. The PK/PD model was then used to predict a pharmacological profile of DP-1904 after repeated oral doses in human; the predicted curves were in relatively good agreement with the observed data. Thus, it is suggested that our PK/PD model is feasible and practical for developing optimum dosing regimens of DP-1904 in clinical situations.