Population pharmacokinetics and pharmacodynamics of bivalirudin in young healthy Chinese volunteers

Aim:

To investigate the population pharmacokinetics (PK) and pharmacodynamics (PD) ofbivalirudin, a synthetic bivalent direct thrombin inhibitor, in young healthy Chinesesubjects.

Methods:

Thirty-six young healthy volunteers were randomly assigned into 4 groups receivedbivalirudin 0.5 mg/kg, 0.75 mg/kg, and 1.05 mg/kg intravenous bolus, 0.75 mg/kgintravenous bolus followed by 1.75 mg/kg intravenous infusion per hour for 4 h. Bloodsamples were collected to measure bivalirudin plasma concentration and activatedclotting time (ACT). Population PK-PD analysis was performed using the nonlinearmixed-effects model software NONMEM. The final models were validated with bootstrap andprediction-corrected visual predictive check (pcVPC) approaches.

Results:

The final PK model was a two-compartment model without covariates. The typical PKpopulation values of clearance (CL), apparent distribution volume of thecentral-compartment (V₁), inter-compartmental clearance (Q) andapparent distribution volume of the peripheral compartment (V₂) were0.323 L·h^-1·kg^-1, 0.086 L/kg, 0.0957L·h^-1·kg^-1, and 0.0554 L/kg, respectively. Theinter-individual variabilities of these parameters were 14.8%, 24.2%, fixed to 0% and15.6%, respectively. The final PK-PD model was a sigmoid E_max modelwithout the Hill coefficient. In this model, a covariate, red blood cell count(RBC^*), had a significant effect on the EC₅₀ value. Thetypical PD population values of maximum effect (E_max),EC₅₀, baseline ACT value (E₀) and the coefficient ofRBC^* on EC₅₀ were 318 s, 2.44 mg/L, 134 s and 1.70,respectively. The inter-individual variabilities of E_max,EC₅₀, and E₀ were 6.80%, 46.4%, and 4.10%,respectively.

Conclusion:

Population PK-PD models of bivalirudin in healthy young Chinese subjects have beendeveloped, which may provide a reference for future use of bivalirudin in China.