Population pharmacokinetics and pharmacodynamics of TS-943 for selective nonpeptide platelet glycoprotein IIb/IIIa receptor antagonist in normal healthy subjects

The pharmacokinetics and pharmacodynamics of TS-943 were evaluated with use of NONMEM in 36 healthy male subjects after constant infusion of five diff erent single-dose regimens. Population analysis showed the plasma concentra tion-time profiles of TS-943 to be best-fit characterized by a two-compartm ent open model with constant infusion and first-order elimination. The phar macodynamic model that best fitted the platelet aggregation was a sigmoid E -max model. The final estimates for baseline effect, 50% inhibitory concent ration (IC50), and the Hill coefficient were 79.4$, 23.4 ng/mL and 1.63, re spectively. The maximum effect (E-max) was fixed at 80% (submaximal aggrega tion response). In addition, correlations between TS-943 plasma concentrati on and extension of template bleeding time were examined by fitting with an exponential model, The model estimates that the TS-943 plasma concentratio n necessary to double template bleeding time is approximately 63 ng/mL (ie, 2.7-fold greater than the IC50). The population approaches for pharmacokin etic-pharmaco dynamic investigation can be useful for the analysis of conce ntration-effect relationships and concentration-adverse event relationships for a platelet glycoprotein IIb/IIIa receptor antagonist.