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 Dec;68(6):1619-28. doi: 10.1007/s00280-011-1732-7. Epub 2011 Sep 28.


Purpose: This Phase I study assessed whether food influences the rate and extent of selumetinib absorption in patients with advanced solid malignancies and determined the safety, tolerability, and pharmacokinetic (PK) profile of selumetinib and its active metabolite N-desmethyl-selumetinib in fed and fasted states.

Methods: A single dose of 75 mg selumetinib was to be taken with food on Day 1 followed by a single dose of 75 mg after fasting for at least 10 h on Day 8, or vice versa, followed by twice daily dosing of 75 mg selumetinib from Day 10. Plasma concentrations and PK parameters were determined on Days 1 and 8. Patients could continue to receive selumetinib for as long as they benefitted from treatment.

Results: In total, 31 patients were randomized to receive selumetinib; 15 to fed/fasted sequence and 16 to fasted/fed sequence. Comprehensive PK sampling was performed on 11 and 10 patients, respectively. The geometric least-squares means of C(max) and AUC for selumetinib were reduced by 62% (ratio 0.38 90% CI 0.29, 0.50) and 19% (ratio 0.81 90% CI 0.74, 0.88), respectively, under fed compared with fasting conditions. The rate of absorption (t(max)) of selumetinib (fed) was delayed by approximately 2.5 h (median). The food effect was also observed for the active metabolite N-desmethyl-selumetinib. Selumetinib was well tolerated.

Conclusions: The presence of food decreased the extent of absorption of selumetinib. It is recommended that for further clinical studies, selumetinib be taken on an empty stomach. Selumetinib demonstrated an acceptable safety profile in the advanced cancer population.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Benzimidazoles / administration & dosage*
  • Benzimidazoles / adverse effects
  • Benzimidazoles / pharmacokinetics
  • Biological Availability
  • Cross-Over Studies
  • Female
  • Food*
  • Humans
  • MAP Kinase Kinase 1 / antagonists & inhibitors*
  • MAP Kinase Kinase 2 / antagonists & inhibitors*
  • Male
  • Middle Aged
  • Neoplasms / drug therapy*


  • AZD 6244
  • Benzimidazoles
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2