Abstract Number: PB1162
Meeting: ISTH 2020 Congress
Background: Marzeptacog alfa (activated) (MarzAA), is a variant human rFVIIa in clinical development for subcutaneous (SQ) administration to treat episodic bleeding or prophylaxis for haemophilia A (HA) or B (HB) with or without inhibitors, and other inherited bleeding disorders.
Aims: To characterize the population pharmacokinetics (PopPK) of intravenous (IV) and SQ MarzAA to support dose selection for Phase 3 trials using simulations of varying dose regimens.
Methods: MarzAA exposure data (FVIIa activity) was evaluated after single IV doses (4.5, 9, 18 and 30 ug/kg) (NCT01439971) and single IV (18 ug/kg) and SQ doses (30 and 60 ug/kg) (NCT03407651). Using nonlinear mixed-effects modeling, data was sequentially modeled describing both IV and SQ data, including nonlinearities and allometric scaling. Model discrimination was based on parameter uncertainty, plausibility and changes in the objective function value (ΔOFV=-3.84, p< 0.05, one degree of freedom). Simulations were conducted for a 70 kg adult subject.
Results: The final PopPK model described the clinical data well (Figure 1). Subcutaneous bioavailability was estimated at 33%, with inter-individual variability of 76%. The terminal elimination half-life for IV dosing was estimated at 3.3 hours, and the absorption and elimination SQ half-lives were both estimated to be 11.8 hours, indicating flip-flop kinetics. Simulations indicated that daily SQ dosing, as well as twice and thrice in 24 hours (0, 3 and 6 hours) at 60, 90 and 120 ug/kg achieved exposures within or above the target range. Using a 60 ug/kg dose, MarzAA may be administered SQ thrice in 24 hours without significantly exceeding the defined target range (Figure 2).
Conclusions: A PopPK model was developed for clinical trial simulations for SC MarzAA to guide dosing in Phase 3 trials and suggests target levels for haemostasis may be achieved with the 60 ug/kg SC dose with 1 to 3 doses in 24 hours.
To cite this abstract in AMA style:Faraj A, Neuman L, Del Greco F, Levy H, Blouse G, Simonsson U, Knudsen T. Marzeptacog Alfa (Activated) Population PK: Simulations for Dose Selection in Phase 3 Trials [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/marzeptacog-alfa-activated-population-pk-simulations-for-dose-selection-in-phase-3-trials/. Accessed November 30, 2021.
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