Metabolism, Excretion, and Pharmacokinetics of Selumetinib, an MEK1/2 inhibitor, in Healthy Adult Male Subjects

PurposeSelumetinib (AZD6244, ARRY-142886), an oral mitogen activated kinase 1/2 inhibitor, is in clinical development for the treatment of a variety of different tumor types. Herein, we report a study that determined the distribution, metabolism, and excretion of selumetinib in healthy male volunteers.MethodsIn this open-label, single-center, Phase I clinical trial, 6 subjects received a single 75-mg dose of [14C]-selumetinib. Blood and excreta samples were collected for pharmacokinetic and radiometric analyses. Tolerability monitoring was performed throughout the study.FindingsThe Cmax of plasma selumetinib was 1520 ng/mL at 1 hour postdose and declined with a t1/2 of 13.7 hours. Over a 216-hour postdose collection period, total dose recovery was 93% of the radioactive dose, with 59% recovered from feces and 33% from urine. Circulating drug-related material was primarily associated with plasma, with minimal distribution into red blood cells. Selumetinib was the major circulating drug-related component and accounted for 40% of the plasma radioactivity (mean of AUC0-72h pool). The major circulating metabolite (M2; accounting for 22% of the plasma radioactivity) resulted from multiple biotransformation pathways, including loss of the ethanediol moiety in combination with glucuronidation. A further 6 circulating metabolites were identified, each accounting for between 2% and 7% of plasma radioactivity. Selumetinib was a minor component in urine, accounting for ≤1% of the dose. M2 was the most abundant metabolite in urine, accounting for 10% of the dose, and there were 5 other metabolites accounting for between 1% and 10% of the dose. In feces, selumetinib accounted for a mean of 19% of the dose. Also present were 7 metabolites accounting for between 1% and 9% of the dose. The majority of the dose was recovered as metabolites, indicating that the liver is the major route of drug elimination. There were no tolerability concerns.ImplicationsThe findings from this study will inform the label and will contribute to the understanding of the clinical pharmacology of selumetinib. ClinicalTrials.gov identifier: NCT01931761.