Population pharmacokinetics and pharmacodynamics of bivalirudin in young healthy Chinese volunteers

Aim: To investigate the population pharmacokinetics (PK) and pharmacodynamics (PD) of bivalirudin, a synthetic bivalent direct thrombin inhibitor, in young healthy Chinese subjects. Methods: Thirty-six young healthy volunteers were randomly assigned into 4 groups received bivalirudin 0.5 mg/kg, 0.75 mg/kg, and 1.05 mg/kg intravenous bolus, 0.75 mg/kg intravenous bolus followed by 1.75 mg/kg intravenous infusion per hour for 4 h. Blood samples were collected to measure bivalirudin plasma concentration and activated clotting time (ACT). Population PK-PD analysis was performed using the nonlinear mixed-effects model software NONMEM. The final models were validated with bootstrap and prediction-corrected visual predictive check (pcVPC) approaches. Results: The final PK model was a two-compartment model without covariates. The typical PK population values of clearance (CL), apparent distribution volume of the central-compartment (V_1), inter-compartmental clearance (Q) and apparent distribution volume of the peripheral compartment (V_2) were 0.323 L·h~(-1)·kg~(-1), 0.086 L/kg, 0.0957 L·h~(-1)·kg~(-1), and 0.0554 L/kg, respectively. The inter-individual variabilities of these parameters were 14.8%, 24.2%, fixed to 0% and 15.6%, respectively. The final PK-PD model was a sigmoid E_(max) model without the Hill coefficient. In this model, a covariate, red blood cell count (RBC~*), had a significant effect on the EC_(50) value. The typical PD population values of maximum effect (E_(max)), EC_(50), baseline ACT value (E_0) and the coefficient of RBC~* on EC_(50) were 318 s, 2.44 mg/L, 134 s and 1.70, respectively. The inter-individual variabilities of E_(max), EC_(50), and E_0 were 6.80%, 46.4%, and 4.10%, respectively.Conclusion: Population PK-PD models of bivalirudin in healthy young Chinese subjects have been developed, which may provide a reference for future use of bivalirudin in China.supported by Shenzhen Main Luck Pharmaceuticals, Inc.中国科技核心期刊(ISTIC)中国科学引文数据库(CSCD)111387-13943