Abstract Number: PB0458
Meeting: ISTH 2021 Congress
Background: Marzeptacog alfa (activated) (MarzAA), a novel human variant recombinant Factor VIIa is in clinical development for subcutaneous (SQ) administration for on-demand or prophylactic use in hemophilia A (HA) or B (HB) with inhibitors and other inherited bleeding disorders.
Aims: To support the pediatric trial dose selection for SQ MarzAA in children with HA/HB with inhibitors through simulations.
Methods: A previously developed population pharmacokinetic (popPK) model in adults including allometric scaling was used to inform the dose for the pediatric Phase 3 trial design. The relationship between clearance (CL) and bodyweight (BW) was studied. Concentration-time profiles were simulated for 1000 virtual pediatric subjects in several age categories assessing different doses. Median and 95% prediction intervals (PI) of the area-under-the-curve over 24 hours (AUC0-24) and maximum concentrations (Cmax) were derived to identify the dosing regimen that would best match the adult exposure of 60 μg/kg given on-demand at 3-hourly intervals.
Results: The relationship between MarzAA CL and BW was found to be non-linear with higher CL/kg at lower BW (Figure 1), with most of the non-linear trend below 14 kg, corresponding to the median BW in children of 2 years of age as described in The National Health and Nutrition Examination Survey (NHANES) database.
Across all age groups using a single 60 μg/kg dose, the lower bound of the 95% PI of AUC0-24h in pediatrics was only slightly lower compared to that of adults, and a similar pattern was observed for Cmax (Figure 2), indicating comparable exposure across pediatric age groups compared to adults.
Conclusions: The simulations support selecting a SQ dose of 60 μg/kg MarzAA in a clinical trial with pediatric subjects with HA/HB with inhibitors.
To cite this abstract in AMA style:Faraj A, van Wijk R, Neuman L, Desai S, E Blouse G, Knudsen T, Simonsson US. Dose Selection of Marzeptacog Alfa (Activated) in Children with Hemophilia: A Population Pharmacokinetic Exposure Matching Strategy [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 1). https://abstracts.isth.org/abstract/dose-selection-of-marzeptacog-alfa-activated-in-children-with-hemophilia-a-population-pharmacokinetic-exposure-matching-strategy/. Accessed September 24, 2021.
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