Model-Based Rationale Could Inform First-in-Pediatric Dose Selection

A model-based framework could inform first-in-pediatric dose selection for marzeptacog alfa, activated (MarzAA) to treat episodic bleeding episodes in children with hemophilia A or hemophilia B with inhibitors in a registrational phase 3 trial.

“A run-in PK [pharmacokinetic] phase was agreed upon with regulators to confirm the dose, prior to initiation of efficacy evaluations, instead of a separate dedicated PK study in pediatrics,” the study’s authors explained in CPT: Pharmacometrics & Systems Pharmacology.

The results of the model-informed work suggest that a first-in-pediatric dose of 60 μg/kg of marzeptacog alfa, activated administered subcutaneously, 1 to 3 doses every 3 hours as needed, could stop an acute bleeding event in pediatric patients.

The analysis of exposure in pediatric age groups revealed that 60 μg/kg of marzeptacog alfa, activated given once, 2 times 3 hours apart, or 3 times 3 hours apart resulted in an area under the concentration curve over 24 hours and maximum concentrations over 24 hours close to the target adult matching range.

Read more about hemophilia therapies

Therefore, the study suggests that a single 60 μg/kg dose of marzeptacog alfa, activated might be sufficient to stop an acute bleeding event in pediatric patients. However, in case of failure, a second dose can be administered after 3 hours, as previous simulations indicated that it can lead to desirable levels of wild-type recombinant activated coagulation factor VII above target in more than 90% of adult patients.

“The work presented here shows how modeling and simulations coupled with an exposure matching strategy may be used in a rare disease setting to inform first-in-pediatric dose selection for a drug candidate that has not been studied in earlier pediatric trials,” the authors said.

Despite the utility of the model-informed framework for determining first-in-pediatric dose selection, the authors did reiterate that the exposure-matching strategy needs to be confirmed in a pharmacokinetic run-in part of the phase 3 trial before initiating efficacy evaluations.

Marzeptacog alfa, activated is a novel variant of human recombinant activated coagulation factor VII.

Reference

Faraj A, van Wijk RC, Neuman L, et al. Model-informed pediatric dose selection of marzeptacog alfa (activated): an exposure matching strategy. CPT Pharmacometrics Syst Pharmacol. Published online April 12, 2023. doi:10.1002/psp4.12967