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

Abstract

PurposeThis 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.MethodsA 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.ResultsIn 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 Cmax 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 (tmax) 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.ConclusionsThe 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.

Selumetinib Attenuates Skeletal Muscle Wasting in Murine Cachexia Model through ERK Inhibition and AKT Activation

“…The cumulative food intakes for vehicle-treated control and cancer cachexia mice were 512.4 and 496.5 g, while cumulative food intakes for selumetinib treatment control and cancer cachexia mice were 506.7 and 489.6 g, respectively. The results were consistent with the previous results showing that the CT26 tumor and selumetinib had little influence on appetite (27). Excessive production of proinflammatory cytokines, such as TNFa, IL1b and IL6, triggered proteolytic degradation of skeletal muscle clinically and in experimental animals with cancer cachexia.…”

Phase I Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of the MEK Inhibitor RO4987655 (CH4987655) in Patients with Advanced Solid Tumors

“…The pharmacokinetics of The influence of food on the absorption of RO4987655 remains to be determined. Data from recent studies with other MEK inhibitors are conflicting; although administration with a high-fat meal was shown to increase exposure to the oral inhibitor CI-1040, exposure to selumetinib was reduced when administered with food (28,29). Patients in this study were lightly fasted before dosing with RO4987655; the effect of food on the exposure to RO4987655 will be investigated during further development of this compound.…”

Selumetinib: A Promising Pharmacologic Approach for KRAS -Mutant Advanced Non-Small-Cell Lung Cancer

“…In more detail, cytochrome P450 1A2 is the enzyme responsible for the formation of the active metabolite N-desmethylselumetinib, which has shown in vitro three-to five-fold greater potency for MEK1 inhibition than selumetinib itself [25]. The main route of elimination of selumetinib relies on the formation of glucuronide conjugates, which happen to be excreted predominantly via the feces.…”