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26.04.2021 | Original Article

Population pharmacokinetics and exposure–response of selumetinib and its N‐desmethyl metabolite in pediatric patients with neurofibromatosis type 1 and inoperable plexiform neurofibromas

verfasst von: Stein Schalkwijk, Li Zhou, Sarit Cohen‐Rabbie, Lokesh Jain, Tomoko Freshwater, Karen So, Zhongqing He, Ioanna Gioni, Helen Tomkinson, Karthick Vishwanathan, Diansong Zhou

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 2/2021

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Abstract

Purpose

Selumetinib (ARRY-142886) is a potent, selective, MEK1/2 inhibitor approved in the US for the treatment of children (≥ 2 years) with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas (PN). We characterized population pharmacokinetics (PK) of selumetinib and its active N‐desmethyl metabolite, evaluated exposure–safety/efficacy relationships, and assessed the proposed therapeutic dose of 25 mg/m² bid based on body surface area (BSA) in this patient population.

Methods

Population PK modeling and covariate analysis (demographics, formulation, liver enzymes, BSA, patients/healthy volunteers) were based on pooled PK data from adult healthy volunteers (n = 391), adult oncology patients (n = 83) and pediatric patients with NF1-PN (n = 68). Longitudinal selumetinib/metabolite exposures were predicted with the final model. Exposure–safety/efficacy analyses were applied to pediatric patients (dose levels: 20, 25, 30 mg/m² bid).

Results

Selumetinib and metabolite concentration–time courses were modeled using a joint compartmental model. Typical selumetinib plasma clearance was 11.6 L/h (95% CI 11.0–12.2 L/ h). Only BSA had a clinically relevant (> 20%) impact on exposure, supporting BSA-based administration in children. Selumetinib and metabolite exposures in responders (≥ 20% PN volume decrease from baseline) and non-responders were largely overlapping, with medians numerically higher in responders. No clear relationships between exposure and safety events were established; exposure was not associated with key adverse events (AEs) including rash acneiform, diarrhea, vomiting, and nausea.

Conclusion

Findings support continuous selumetinib 25 mg/m² bid in pediatric patients. Importantly, the updated dosing nomogram ensures that patients will receive a clinically active, yet tolerable, dose regardless of differences in BSA and allows dose reductions, if necessary.

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Titel: Population pharmacokinetics and exposure–response of selumetinib and its N‐desmethyl metabolite in pediatric patients with neurofibromatosis type 1 and inoperable plexiform neurofibromas
verfasst von: Stein Schalkwijk
Li Zhou
Sarit Cohen‐Rabbie
Lokesh Jain
Tomoko Freshwater
Karen So
Zhongqing He
Ioanna Gioni
Helen Tomkinson
Karthick Vishwanathan
Diansong Zhou
Publikationsdatum: 26.04.2021
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 2/2021
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-021-04274-6

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Population pharmacokinetics and exposure–response of selumetinib and its N‐desmethyl metabolite in pediatric patients with neurofibromatosis type 1 and inoperable plexiform neurofibromas