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

Autor: Hiroyasu Ogata, Shohei Higuchi, Atsushi Furuya, Masayuki Akimoto, J Gotoh, M Nozawa, Toshio Suwa, Shigeji Jingu
Rok vydání: 2002
Předmět:
Zdroj: Journal of Pharmacy and Pharmacology. 54:921-927
ISSN: 2042-7158
0022-3573
DOI: 10.1211/002235702760089036
Popis: A simultaneous analysis of the pharmacokinetics and pharmacodynamics of TS-943, a selective non-peptide 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 γ (Hill coefficient) were 66.3%, 64.3%, 104 ng mL−1 and 1.37, respectively. Correlations betweenTS-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.
Databáze: OpenAIRE
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