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

Purpose: Selumetinib (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.

Methods: In this open-label, single-center, Phase I clinical trial, 6 subjects received a single 75-mg dose of [C]-selumetinib. Blood and excreta samples were collected for pharmacokinetic and radiometric analyses. Tolerability monitoring was performed throughout the study.

Findings: The C of plasma selumetinib was 1520 ng/mL at 1 hour postdose and declined with a t 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 AUC 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.

Implications: The findings from this study will inform the label and will contribute to the understanding of the clinical pharmacology of selumetinib. ClinicalTrials.gov identifier: NCT01931761.