Population Pharmacokinetic Modeling and Simulation of Recombinant Single-Chain Factor VIII (r VIII-SingleChain) in Patients with Hemophilia a

Introduction: Hemophilia A is a rare but serious X-linked recessive bleeding disorder that affects males and is characterized by a deficiency in the plasma protein known as coagulation Factor VIII. rVIII-SingleChain is a proprietary, lyophilized formulation of clotting factor VIII (FVIII) produced by recombinant technology. As part of the clinical development of rVIII-SingleChain, a population pharmacokinetic (PK) analysis was undertaken, utilizing data from Study CSL627_1001 in subjects with hemophilia A, with the objectives of (a) characterizing the PK of rVIII-SingleChain at a population level, (b) assessing the ability of various patient characteristics (e.g., von Willebrand factor, VWF) to describe variability in the PK parameters, and (c) enable population-based simulations of rVIII-SingleChain dosing regimens that may provide improved prophylaxis coverage compared with octocog alfa (Advate®).

Methods: Twenty-seven male subjects (aged 19-60 years) enrolled in Study CSL627_1001 (Part 1) received a single 50 IU/kg IV infusion of Advate®, followed by a single 50 IU/kg IV infusion of rVIII-SingleChain, with a minimum 4-day washout period. Plasma PK samples (for the determination of FVIII activity) were collected over 72 hours for both Advate® and rVIII-SingleChain (at pre-specified time points) and were measured by a validated chromogenic assay. Population PK models were developed separately for rVIII-SingleChain and Advate®, using the NONMEM 7 with FOCEI method. Various covariates, including VWF, body weight, and effect of age on clearance (CL) and volume of distribution were tested. Bootstrap and visual predictive check (VPC) were used for model evaluation. Simulations of different dosing regimens were performed to evaluate the FVIII activity plasma exposure profiles that may provide improved prophylaxis coverage.

Results: A two-compartmental model with first-order elimination was developed to describe FVIII plasma activity data for both rVIII-SingleChain and Advate®. VWF was found to be a significant covariate influence on FVIII plasma activity CL, whilst body weight influenced both CL and volume of distribution in the central compartment. Population parameter estimates indicated a lower CL (2.02 vs 2.49 dL/h) and longer half-life (13.1 vs 9.3 h) for rVIII-SingleChain compared with Advate®. The results of bootstrap and VPC implied that the model was stable, and the parameters were estimated with good precision. PK simulations indicated that rVIII-SingleChain, at the same doses and frequencies, resulted in higher FVIII plasma activities throughout the dosing period, as reflected in higher area-under-the-curve (AUC). The dosing regimens for the simulations were designed based on the dosing recommendations of the Advate® label and rVIII-SingleChain phase III study. The results showed that rVIII-SingleChain provided a higher percentage of subjects with trough levels of at least 1% FVIII plasma activity, compared with Advate® at the same dosing regimen. Every 3 days dosing at 40-50 IU/kg rVIII-SingleChain was predicted to achieve similar prophylaxis protection compared with Advate® every 2 days (i.e., about 90% of subjects with trough levels of at least 1% FVIII plasma activity). In addition, 73-90% of subjects were predicted to achieve trough levels of at least 1% FVIII plasma activity with twice weekly dosing (4- and 3-day schedule) at 50 IU/kg rVIII-SingleChain, compared with 65-80% of subjects dosed with Advate® using the same regimen.

Conclusion: The population model shows that rVIII-SingleChain has a longer half-life, lower CL and higher AUC compared with Advate®. Simulations demonstrated that rVIII-SingleChain resulted in higher trough concentrations when compared with Advate®, indicating the possibility of greater prophylaxis coverage.