Marzeptacog alfa (activated) (MarzAA) is an activated recombinant human rFVII variant intended for subcutaneous (s.c.) administration to treat or prevent bleeding in individuals with hemophilia A (HA) or B (HB) with inhibitors, and other rare bleeding disorders. The s.c. administration provides benefits over i.v. injections. The objective of the study was to support the first-in-pediatric dose selection for s.c. MarzAA to treat episodic bleeding episodes in children up through 11 years in a registrational phase III trial. Assuming the same exposure-response relationship as in adults, an exposure matching strategy was used with a population pharmacokinetics model. A sensitivity analysis evaluating the impact of doubling in absorption rate and age-dependent allometric exponents on dose selection was performed. Subsequently, the probability of trial success, defined as the number of successful trials for a given pediatric dose divided by the number of simulated trials (n = 1000) was studied. A successful trial was defined as outcome where four, three, or two out of 24 pediatric subjects per trial were allowed to fall outside the adult exposures after s.c. administration of 60 μg/kg. A dose of 60 μg/kg in children with HA/HB was supported by the clinical trial simulations to match exposures in adults. The sensitivity analyses further supported selection of the 60 μg/kg dose level in all age groups. Moreover, the probability of trial success evaluations given a plausible design confirmed the potential of a 60 μg/kg dose level. Taken together, this work demonstrates the utility of model-informed drug development and could be helpful for other pediatric development programs for rare diseases.
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