Population pharmacokinetics and pharmaco- dynamics 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 （VI）, inter-compartmental clearance （Q） and apparent distribution volume of the peripheral compartment （V2） were 0.323 L.h^-1·kg^-1.086 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 Emax model without the Hill coefficient. In this model, a covariate, red blood cell count （RBC＊）, had a significant effect on the ECho value. The typical PD population values of maximum effect （Emax）, EC50, baseline ACT value leo） and the coefficient of RBC＊ on ECho were 318 s, 2.44 mg/L, 134 s and 1.70, respectively. The inter-individual variabilities of Emax, EC50, and Eo 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.