Original Research| Volume 44, ISSUE 4, P565-576, April 2022

A Phase I, Open-label, Randomized, Crossover Study of the Relative Bioavailability of Capsule and Granule Formulations of Selumetinib



      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.


      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.


      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.


      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. identifier: NCT03649165.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Clinical Therapeutics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Chappell WH
        • Steelman LS
        • Long JM
        • et al.
        Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health.
        Oncotarget. 2011; 2: 135-164
        • Wang J
        • Wang B
        • Chu H
        • Yao Y.
        Intrinsic resistance to EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer with activating EGFR mutations.
        Onco Targets Ther. 2016; 9: 3711-3726
        • Yeh TC
        • Marsh V
        • Bernat BA
        • et al.
        Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor.
        Clin Cancer Res. 2007; 13: 1576-1583
        • Banerji U
        • Camidge DR
        • Verheul HM
        • et al.
        The first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer.
        Clin Cancer Res. 2010; 16: 1613-1623
        • Denton CL GD
        Pharmacokinetics and pharmacodynamics of AZD6244 (ARRY-142886) in tumor-bearing nude mice.
        J Clin Oncol. 2014; 32: 10018
        • Dombi E
        • Baldwin A
        • Marcus LJ
        • et al.
        Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas.
        N Engl J Med. 2016; 375: 2550-2560
        • Gross AM
        • Wolters PL
        • Dombi E
        • et al.
        Selumetinib in children with inoperable plexiform neurofibromas.
        N Engl J Med. 2020; 382: 1430-1442
      1. US Food & Drug Administration. Prescribing Information KOSELUGO (selumetinib). Accessed September 28, 2020.

        • Adjei AA
        • Cohen RB
        • Franklin W
        • et al.
        Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers.
        J Clin Oncol. 2008; 26: 2139-2146
        • Leijen S
        • Soetekouw PM
        • Jeffry Evans TR
        • et al.
        A phase I, open-label, randomized crossover study to assess the effect of dosing of the MEK 1/2 inhibitor selumetinib (AZD6244; ARRY-142866) in the presence and absence of food in patients with advanced solid tumors.
        Cancer Chemother Pharmacol. 2011; 68: 1619-1628
        • Tomkinson H
        • McBride E
        • Martin P
        • et al.
        Comparison of the pharmacokinetics of the Phase II and Phase III capsule formulations of selumetinib and the effects of food on exposure: results from two randomized crossover trials in healthy male subjects.
        Clin Ther. 2017; 39 (e2261): 2260-2275
        • Dymond AW
        • Elks C
        • Martin P
        • et al.
        Pharmacokinetics and pharmacogenetics of the MEK1/2 inhibitor, selumetinib, in Asian and Western healthy subjects: a pooled analysis.
        Eur J Clin Pharmacol. 2017; 73: 717-726
        • Dymond AW
        • Martin P
        • So K
        • et al.
        Pharmacokinetics of a single oral dose of the MEK1/2 inhibitor selumetinib in subjects with end-stage renal disease or varying degrees of hepatic impairment compared with healthy subjects.
        J Clin Pharmacol. 2017; 57: 592-605
        • Schalkwijk S
        • Zhou L
        • Cohen-Rabbie S
        • et al.
        Population pharmacokinetics and exposure-response of selumetinib and its N-desmethyl metabolite in pediatric patients with neurofibromatosis type 1 and inoperable plexiform neurofibromas.
        Cancer Chemother Pharmacol. 2021; 88: 189-202
      2. European Medicines Agency. Koselugo (selumetinib) Summary of Product Characteristics. Accessed February 1, 2022.