Ya-Ou Liu, Zi-Ning Wang, Chao-Yang Chen, Xian-Han Zhuang, Chang-Geng Ruan, Ying Zhou and Yi-Min Cui* Pages 1060 - 1072 ( 13 )
Background: Cardiovascular disease has one of the highest mortality rates among all the diseases. Platelets play an important role in the pathogenesis of cardiovascular diseases. Platelet membrane glycoprotein GPIIb/IIIa antagonists are the most effective antiplatelet drugs, and pulaimab is one of these. The study aims to promote individual medication of pulaimab [anti-GPIIb/IIIa F(ab)2 injection] by discovering the pharmacological relationship among the dose, concentration, and effects. The goal of this study is to establish a population pharmacokineticpharmacodynamic model to evaluate the antiplatelet effect of intravenous pulaimab injection.
Methods: Data were collected from 59 healthy subjects who participated in a Phase-I clinical trial. Plasma concentration was used as the pharmacokinetic index, and platelet aggregation inhibition rate was used as the pharmacodynamic index. The basic pharmacokinetics model was a two-compartment model, whereas the basic pharmacodynamics model was a sigmoid-EMAX model with a direct effect. The covariable model was established by a stepwise method. The final model was verified by a goodness-of-fit method, and predictive performance was assessed by a Bootstrap (BS) method.
Results: In the final model, typical population values of the parameters were as follows: central distribution Volume (V1), 183 L; peripheral distribution Volume (V2), 349 L; Central Clearance (CL), 31 L/h; peripheral clearance(Q), 204 L/h; effect compartment concentration reaching half of the maximum effect (EC50), 0.252 mg/L; maximum effect value (EMAX), 54.0%; and shape factor (γ), 0.42. In the covariable model, thrombin time had significant effects on CL and EMAX. Verification by the goodness-of-fit and BS methods showed that the final model was stable and reliable.
Conclusion: A model was successfully established to evaluate the antiplatelet effect of intravenous pulaimab injection that could provide support for the clinical therapeutic regimen.
Chinese healthy subjects, pulaimab [anti-GPIIb/IIIa F(ab)2 injection], antiplatelet, population pharmacokinetics, population pharmacodynamics, model.
Department of Pharmacy, Peking University First Hospital, Beijing, Department of Pharmacy, Peking University First Hospital, Beijing, Department of Pharmacy, Peking University First Hospital, Beijing, Shanghai Asia United Antibody Medicine Limited Company, Shanghai, Jiangsu Institute of Hematology, The First Affiliated Hospital of Suzhou University, Suzhou, Jiangsu, Department of Pharmacy, Peking University First Hospital, Beijing, Department of Pharmacy, Peking University First Hospital, Beijing