rVIII-SingleChain in hemophilia A patients: A population pharmacokinetic model
Y. Zhang2, J. Roberts2, D. Bensen-Kennedy2, A. Veldman1, K. S. Ledger2, J. Sidhu3 (1Marburg, Germany, 2King of Prussia, United States, 3Parkville, Australia)
Bleeding disorders, coagulation and fibrinolytic factors
Time: 17:15 - 18:15
Objective: rVIII-SingleChain, a novel recombinant Factor VIII (FVIII), is a single-chain construct in which a truncated B-domain covalently links the heavy and light chain. A model was developed to characterize the population pharmacokinetics (PPK) of rVIII-SingleChain in adult and pediatric subjects with hemophilia A and to support clinical dosing.
Methods: A total of 130 hemophilia A patients taking part in the AFFINITY clinical trial series (≥12–65 years [n=91]; 0–<12 years [n=39]) were dosed with a 50 IU/kg dose of rVIII-SingleChain and serial blood samples were taken over a 72-hour period. Plasma FVIII activity was determined using a validated chromogenic assay. The data were analyzed using a nonlinear mixed effects modeling approach (NONMEM). The model was evaluated using a visual predictive check (VPC). The effect of various covariates in the PPK model were analyzed, including anti-drug antibody levels, body weight, baseline von Willebrand factor (VWF) and hematocrit. The final FVIII activity PPK model was used to simulate FVIII activity-time profiles for a range of dosing regimens.
Results: A two-compartmental model with first-order elimination adequately described the FVIII plasma activity data following rVIII-SingleChain dosing. For central distribution volume body weight was found to be significant covariate; for clearance body weight and levels of VWF were significant covariates. The model evaluation was deemed adequate and showed good precision by VPC. Using the final PPK model, simulations predicted that 63–93 % patients would maintain FVIII activity levels above 1% with rVIII-SingleChain dosing at 20–50 IU/kg 2- or 3-times weekly.
Conclusion: The PK of rVIII-SingleChain in adult and pediatric hemophilia B patients was well described by the PPK model. The model can be used to simulate FVIII activity-time profiles for various dosing regimens. The PPK simulation supported the dose regimens of 20–50 IU/kg rVIII-SingleChain 2- or 3-times weekly, so that the majority of patients maintain total FVIII activity levels above 1%.