title: Population pharmacokinetics and pharmacodynamics of TS-943 for selective nonpeptide platelet glycoprotein IIb/IIIa receptor antagonist in normal healthy subjects.
abstract: The pharmacokinetics and pharmacodynamics of TS-943 were evaluated with use of NONMEM in 36 healthy male subjects after constant infusion of five different single-dose regimens. Population analysis showed the plasma concentration-time profiles of TS-943 to be best-fit characterized by a two-compartment open model with constant infusion and first-order elimination. The pharmacodynamic model that best fitted the platelet aggregation was a sigmoid Emax model. The final estimates for baseline effect, 50% inhibitory concentration (IC50), and the Hill coefficient were 79.4%, 23.4 ng/mL and 1.63, respectively. The maximum effect (Emax) was fixed at 80% (submaximal aggregation response). In addition, correlations between TS-943 plasma concentration and extension of template bleeding time were examined by fitting with an exponential model. The model estimates that the TS-943 plasma concentration necessary to double template bleeding time is approximately 63 ng/mL (ie, 2.7-fold greater than the IC50). The population approaches for pharmacokinetic-pharmacodynamic investigation can be useful for the analysis of concentration-effect relationships and concentration-adverse event relationships for a platelet glycoprotein IIb/IIIa receptor antagonist.
authors.affiliation: Research Center, Taisho Pharmaceutical Co, Ltd, Saitama, Japan. s13220@ccm.taisho.co.jp
authors.forename: A
authors.initials: A
authors.lastname: Furuya
authors.forename: N
authors.initials: N
authors.lastname: Kato
authors.forename: S
authors.initials: S
authors.lastname: Jingu
authors.forename: M
authors.initials: M
authors.lastname: Akimoto
authors.forename: S
authors.initials: S
authors.lastname: Higuchi
authors.forename: T
authors.initials: T
authors.lastname: Suwa
authors.forename: H
authors.initials: H
authors.lastname: Ogata
mesh_terms: D000328:Adult; D000578:Amidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D001760:Bleeding Time; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007262:Infusions, Intravenous; D007564:Japan; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D012016:Reference Values; D013844:Thiazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D000578:Amidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C409044:TS 943; D013844:Thiazoles