Population pharmacokinetics of recombinant coagulation factor VIII‐SingleChain in patients with severe hemophilia A

Abstract

Background Single-chain recombinant coagulation factorVIII (rVIII-SingleChain) is a unique recombinant coagulation factorVIII molecule. Objectives To: (i) characterize the population pharmacokinetics (PK) of rVIII-SingleChain in patients with severe hemophiliaA; (ii) identify correlates of variability in rVIII-SingleChain PK; and (iii) simulate various dosing scenarios of rVIII-SingleChain. Patients/Methods A population PK model was developed, based on FVIII activity levels of 130 patients with severe hemophiliaA (n=91 for ≥12-65years; n=39 for <12years) who had participated in a single-dose PK investigation with rVIII-SingleChain 50IUkg-1 . PK sampling was performed for up to 96h. Results A two-compartment population PK model with first-order elimination adequately described FVIII activity. Body weight and predose level of von Willebrand factor were significant covariates on clearance, and body weight was a significant covariate on the central distribution volume. Simulations using the model with various dosing scenarios estimated that >85% and >93% of patients were predicted to maintain FVIII activity level above 1 IU dL-1 , at all times with three-times-weekly dosing (given on days0, 2, and 4.5) at the lowest (20IUkg-1 ) and highest (50IUkg-1 ) doses, respectively. For twice weekly dosing (days0 and 3.5) of 50IUkg-1 rVIII-SingleChain, 62-80% of patients across all ages were predicted to maintain a FVIII activity level above 1 IU dL-1 at day7. Conclusions The population PK model adequately characterized rVIII-SingleChain PK, and the model can be utilized to simulate FVIII activity-time profiles for various dosing scenarios.