Development of a Taste-Masked, Dose-Flexible, Multiparticulate Pediatric Dosage Form: Case Study of Crizotinib, a...

Developing pediatric dosage forms remains challenging, particularly for poorly palatable drugs, which can limit tolerability and adherence. Crizotinib, an anaplastic lymphoma kinase inhibitor used to treat rare pediatric cancers, was initially available only as an oral solution or capsules, with the solution demonstrating unacceptable taste in pediatric patients.

The objectives of this work were to outline results from clinical studies supporting the crizotinib pediatric formulation development and commercialization process, summarize key clinical and formulation challenges encountered, and present lessons learned from an over-a-decade-long development process.

Six clinical studies conducted in pediatric patients and healthy adult participants were collectively used to evaluate palatability, tolerability, pharmacokinetics, and bioequivalence of multiple crizotinib formulations. These studies assessed an oral solution and taste-masked microsphere formulations under fasted, fed, and proton pump inhibitor coadministration conditions, using validated palatability assessments and pharmacokinetic endpoints.

Early oral solution formulations showed poor palatability, contributing to reduced tolerability and discontinuation in some pediatric patients. Taste-masked microsphere formulations improved palatability but initially showed reduced drug absorption under elevated gastric pH conditions. Reformulation with a pH-independent Opadry SGR coating resulted in a microsphere formulation that achieved acceptable palatability and consistent pharmacokinetic performance and demonstrated bioequivalence to the commercial adult capsule.

This over-a-decade-long clinical development program led to the commercialization of a palatable, dose-flexible, oral solid multiparticulate pediatric formulation of crizotinib for patients with anaplastic large cell lymphoma or inflammatory myofibroblastic tumors. The clinical outcomes and development strategy described herein provide a practical framework to support future pediatric formulation development programs.

gov trial registration number (date of registration): NCT00939770 (15 Jul 2009), NCT01606878 (28 May 2012), NCT02006277 (10 Dec 2013), NCT03137134 (02 May 2017), NCT03978143 (06 Jun 2019), NCT04856293 (23 Apr 2021, retrospectively registered).