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

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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. ClinicalTrials.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). Researchers developed a new, child-friendly version of crizotinib, a medication used to treat cancer, because earlier versions tasted too unpleasant for children to tolerate. The researchers carried out six clinical studies over more than a decade that guided the development of a formulation of crizotinib that was both effective and tolerable for children with cancer. Here, we outline the key steps and results of the six clinical studies, explain the major challenges faced and how they were solved, and share lessons learned along the way. Early attempts to develop a crizotinib dosage for children, including a taste-masked liquid version, led to formulations that were still too bitter for the children to drink. Some formulations caused a burning feeling in the throat. Researchers then tested microscopic taste-masked particles containing the medicine, called microspheres. These microsphere versions tasted better but did not work well because the medicine was not properly absorbed by the body. To overcome this, the researchers developed another version with a new taste-masked coating, the Opadry SGR-coated microsphere, which had a better taste and allowed for proper absorption of the medicine. Overall, this work led to a dose-flexible, oral solid version of crizotinib that was tolerable and effective for children with anaplastic large cell lymphoma or inflammatory myofibroblastic tumors. This experience offers valuable lessons to help make future pediatric drug development faster and easier.

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