title: Pharmacokinetic and pharmacodynamic analysis of TS-943, a selective non-peptide platelet glycoprotein-IIb/IIIa (GPIIb/IIIa) receptor antagonist, using a nonlinear mixed effect model in dogs.
abstract: A simultaneous analysis of the pharmacokinetics and pharmacodynamics of TS-943, a selective nonpeptide platelet glycoprotein-IIb/IIIa (GPIIb/IIIa) receptor antagonist, was made in dogs using a nonlinear mixed effect model. Plasma concentrations of TS-943 were determined after bolus intravenous injection, constant infusion and bolus plus constant infusion. Pharmacokinetic/pharmacodynamic data were fitted using NONMEM software. The pharmacokinetics of TS-943 fitted a two-compartment open model with first-order elimination. The pharmacodynamic model that best fitted platelet aggregation was an inhibitory sigmoid Emax model. The final estimates for E0 (baseline effect), Emax (maximum effect), IC50 (50% inhibitory concentration) and gamma (Hill coefficient) were 66.3%, 64.3%, 104 ng mL(-1) and 1.37, respectively. Correlations between TS-943 plasma concentration and extension of template bleeding time were examined by fitting with an exponential model. The TS-943 plasma concentration necessary to double bleeding time (C2-BTE) was approximately 209 ng mL(-1). The model estimated that the C2-BTE/IC50 (inhibition of platelet aggregation) ratio was approximately 2.0-fold in dogs. Our results suggest that the ratio values for dogs and man are comparable. A nonlinear mixed effect model was a useful tool for exploring the concentration-effect relationship for both efficacy and safety of TS-943 in dogs and man. In this study, the dog was found to be a useful model for screening of efficacy and safety of TS-943 in man.
authors.affiliation: Research Center, Taisho Pharmaceutical Co, Ltd, Saitama, Japan. atsushi.furuya@po.rd.taisho.co.jp
authors.forename: A
authors.initials: A
authors.lastname: Furuya
authors.forename: M
authors.initials: M
authors.lastname: Nozawa
authors.forename: J
authors.initials: J
authors.lastname: Gotoh
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: D000578:Amidines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000818:Animals; D004285:Dogs; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D000578:Amidines; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C409044:TS 943; D013844:Thiazoles