Model‐informed pediatric dose selection of marzeptacog alfa (activated): An exposure matching strategy

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

show abstract

Model‐informed pediatric dose selection of marzeptacog alfa (activated): An exposure matching strategy

Faraj

Wijk

Neuman

et al. 2023

CPT Pharmacom & Syst Pharma

Self Cite

View full text Add to dashboard Cite

show abstract

Getting the dose right using physiologically-based pharmacokinetic modeling: dexamethasone to prevent post-extubation stridor in children as proof of concept

van der Heijden,

de Hoop-Sommen,

Hoevenaars

et al. 2024

Front. Pediatr.

View full text Add to dashboard Cite

IntroductionCritically ill patients show large variability in drug disposition due to e.g., age, size, disease and treatment modalities. Physiologically-based pharmacokinetic (PBPK) models can be used to design individualized dosing regimens taking this into account. Dexamethasone, prescribed for the prevention post-extubation stridor (PES), is metabolized by the drug metabolizing enzyme CYP3A. As CYP3A4 undergoes major changes during childhood, we aimed to develop age-appropriate dosing recommendations for children of dexamethasone for PES, as proof of concept for PBPK modeling to individualize dosing for critically ill patients.MethodsAll simulations were conducted in Simcyp™ v21 (a population-based PBPK modeling platform), using an available dexamethasone compound model and pediatric population model in which CYP3A4 ontogeny is incorporated. Published pharmacokinetic (PK) data was used for model verification. Evidence for the dose to prevent post-extubation stridor was strongest for 2–6 year old children, hence simulated drug concentrations resulting from this dose from this age group were targeted when simulating age-appropriate doses for the whole pediatric age range.ResultsDexamethasone plasma concentrations upon single and multiple intravenous administration were predicted adequately across the pediatric age range. Exposure-matched predictions of dexamethasone PK indicated that doses (in mg/kg) for the 2–6 years olds can be applied in 3 month-2 year old children, whereas lower doses are needed in children of other age groups (60% lower for 0–2 weeks, 40% lower for 2–4 weeks, 20% lower for 1–3 months, 20% lower for 6–12 year olds, 40% lower for 12–18 years olds).DiscussionWe show that PBPK modeling is a valuable tool that can be used to develop model-informed recommendations using dexamethasone to prevent PES in children. Based on exposure matching, the dose of dexamethasone should be reduced compared to commonly used doses, in infants <3 months and children ≥6 years, reflecting age-related variation in drug disposition. PBPK modeling is an promising tool to optimize dosing of critically ill patients.

show abstract

scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.

Contact Info

customersupport@researchsolutions.com

10624 S. Eastern Ave., Ste. A-614

Henderson, NV 89052, USA

This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.

Blog Terms and Conditions API Terms Privacy Policy Contact Cookie Preferences Do Not Sell or Share My Personal Information

Made with 💙 for researchers

Part of the Research Solutions Family.

Model‐informed pediatric dose selection of marzeptacog alfa (activated): An exposure matching strategy

Cited by 2 publications

References 33 publications