Antiplatelet Effect of a Pulaimab [Anti-GPIIb/IIIa F(ab)2 Injection] Evaluated by a Population Pharmacokinetic-pharmacodynamic Model

Author(s): Ya-Ou Liu, Zi-Ning Wang, Chao-Yang Chen, Xian-Han Zhuang, Chang-Geng Ruan, Ying Zhou, Yi-Min Cui*

Journal Name: Current Drug Metabolism

Volume 20 , Issue 13 , 2019

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Graphical Abstract:


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.

Keywords: Chinese healthy subjects, pulaimab [anti-GPIIb/IIIa F(ab)2 injection], antiplatelet, population pharmacokinetics, population pharmacodynamics, model.

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Year: 2019
Published on: 23 January, 2020
Page: [1060 - 1072]
Pages: 13
DOI: 10.2174/1389200220666191122120238
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