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A Phase I, Open-label, Randomized, Crossover Study of the Relative Bioavailability of Capsule and Granule
Sarit Cohen-Rabbie1, Alexandra Mattinson2, Karen So3
1Clinical Pharmacology and Safety Science Biopharmaceutics Research and Development, AstraZeneca, Cambridge, United Kingdom.
Insights
A new granule formulation of selumetinib (ARRY-142886) showed similar absorption and acceptable palatability compared to capsules. This oral medication is approved for neurofibromatosis type 1 in children.
Area of Science:
- Pharmacology
- Drug Formulation
- Pediatric Oncology
Background:
- Selumetinib (ARRY-142886) is an approved MEK inhibitor for pediatric neurofibromatosis type 1 (NF1).
- A new oral granule formulation aims to improve administration for patients unable to swallow capsules.
Purpose of the Study:
- Evaluate pharmacokinetic properties of selumetinib granules versus capsules.
- Assess safety, tolerability, and palatability of the new granule formulation.
Main Methods:
- Phase I crossover study in healthy volunteers.
- Randomized administration of selumetinib granules (25 mg) and capsules (50 mg).
- Primary endpoint: pharmacokinetic comparison; Secondary endpoints: safety and palatability.
Main Results:
- Dose-normalized Cmax and AUC0-∞ were comparable between formulations.
- Absorption was similar, with median Tmax of 1.73 hours (granules) and 1.14 hours (capsules).
- Low incidence of mild adverse events; granule palatability was acceptable.
Conclusions:
- The selumetinib granule formulation demonstrates favorable pharmacokinetic properties and palatability.
- Supports further investigation for use in younger children or those with swallowing difficulties.
- Potential to enhance treatment adherence for NF1 patients.
Purpose:
Selumetinib (ARRY-142886) is an oral, potent, and highly selective allosteric mitogen-activated protein kinase kinase 1/2 inhibitor approved for the treatment of pediatric patients (≥2 years of age) with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. This Phase I crossover study (NCT03649165) evaluated the pharmacokinetic properties and palatability of a new granule formulation of selumetinib.
Methods:
Healthy volunteers were randomized to 1 of 2 sequences; selumetinib granule (25 mg) followed by selumetinib capsules (50 mg [2 × 25 mg]) and vice versa. The primary end point was the pharmacokinetic properties of the 2 formulations. Secondary end points included safety and tolerability of single selumetinib doses and palatability of the granule formulation.
Findings:
Of the 24 enrolled volunteers (mean age, 33.2 years; range 23-44 years), all were male and 20 (83%) were Black/African American. Under fasted conditions for the granule versus capsule, geometric mean ratios for the dose-normalized Cmax and AUC0-∞ were 0.654 (90% CI, 0.581-0.736) and 0.865 (90% CI, 0.811-0.922), respectively. Absorption of selumetinib was similar between granule and capsule formulation, with a median time to Cmax of 1.73 hours and 1.14 hours, respectively. Adverse event incidence was low (n = 6 in both groups), and most events were mild. Palatability was acceptable, with volunteers indicating that they would take the granule formulation again.
Implications:
These findings support further research into the selumetinib granule formulation, with the aim of producing an alternative formulation for younger children or patients unable to swallow capsules.
Clinicaltrials:
gov identifier: NCT03649165.
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