Effect of food on capsule and granule formulations of selumetinib

Abstract

Selumetinib is an oral, potent, and highly selective allosteric MEK1/2 inhibitor approved for the treatment of pediatric patients (aged ≥2 years) with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. A granule formulation of selumetinib is under development to improve dosing precision for younger pediatric patients who may be unable to swallow capsules. This phase I crossover study investigated the effect of food on the pharmacokinetic (PK) properties of selumetinib capsule and granule formulations. Healthy male volunteers were randomized to receive selumetinib granules (25 mg) or capsules (50 mg [2 × 25 mg]) under fasted or fed conditions (a low‐fat meal). Plasma concentrations and PK parameters were determined less than or equal to 48 h postdose. Safety and tolerability were assessed. Across 24 volunteers, selumetinib was absorbed quickly, with a time to maximum concentration (T max ) ranging from ~1–3 h. Geometric mean ratios (90% confidence interval [CI]) for maximum plasma concentration (C max ) in the fed versus fasted state were 0.61 (90% CI 0.51–0.72) and 0.40 (90% CI 0.33–0.48) for the granule and capsule formulations, respectively, whereas geometric mean ratios (90% CI) for area under the plasma drug concentration‐time curve in the fed versus fasted state were 0.97 (90% CI 0.91–1.02) and 0.62 (90% CI 0.55–0.70), respectively. Levels of less than 10% conversion to the N‐desmethyl selumetinib metabolite were observed. Selumetinib was well‐tolerated, with only a few adverse events of mild intensity reported. Selumetinib administration with a low‐fat meal resulted in lower C max and longer T max for both formulations versus fasted conditions. However, area under the curve for selumetinib granules was similar under fasted and fed conditions. Overall, these findings support further development of this formulation for pediatric patients.

Effect of food on selumetinib pharmacokinetics and gastrointestinal tolerability in adolescents with neurofibromatosis type 1-related plexiform neurofibromas

“…Dermatitis acneiform was the most commonly reported non-GI AE, and this AE has also been frequently reported in previous selumetinib studies. 11 , 16 , 18 , 29 No new safety signals for selumetinib were identified; the AEs reported were similar in both the fed and fasted treatment periods and were comparable to previous studies. 11 , 17 …”

“… 17 A further study conducted in healthy adults showed that consumption of a low-fat, low-calorie meal reduced both the rate and extent of absorption after a single dose of selumetinib; C max was reduced by 60%, T max was delayed by 2.5 h, and AUC was reduced by 38%. 18 Therefore, administration in the fed rather than the fasted state could affect exposure to, and absorption of, selumetinib.…”

A Population Pharmacokinetic Assessment of the Effect of Food on Selumetinib in Patients with Neurofibromatosis Type 1‐Related Plexiform Neurofibromas and Healthy Volunteers

“…23,24 Data from 3 previous phase 1, single-dose, foodeffect PK studies have indicated that administration with a meal may reduce selumetinib absorption compared with administration during a fasted state. 12,13,25 Specifically, a study conducted in healthy male adults (D1532C00069) demonstrated that consumption of a high-fat meal reduced the rate of absorption of selumetinib, as demonstrated by a 50% reduction in maximum concentration (C max ) and a 1.5-hour delay in time to reach C max (T max ), but did not cause a clinically relevant reduction in the extent of absorption of selumetinib (area under the concentration-time curve [AUC] was reduced by 16%), versus administration under fasted conditions. 13 Similar findings were reported in another study (D1532C00020) in which adults with advanced solid tumors were administered selumetinib with a high-fat meal (C max was reduced by 62%, T max was delayed by 2.5 hours, and AUC was reduced by 19% versus administration under fasted conditions).…”

“…12 In study D1532C00089, which was conducted in healthy adults, administration of a single dose of selumetinib after a low-fat meal reduced the rate of absorption, as demonstrated by a 60% reduction in C max and a 2.5-hour delay in T max , and the extent of absorption, as demonstrated by a 38% reduction in AUC. 25 Therefore, further investigations are warranted to assess whether the current recommended dose of selumetinib can maintain an acceptable efficacy and safety profile if taken with food.…”

“…One of the additional studies was a phase 1, open-label, single-center, relative bioavailability, and food-effect trial of the new granule and current capsule formulations of selumetinib in healthy male volunteers (D1532C00089). 25 The other additional study was a phase 1, single-arm, sequential trial performed to evaluate the effect of food on the gastrointestinal tolerability and PK of selumetinib in adolescent children with NF1-related PN (D1346C00015). The aim of the current analysis was to evaluate the effect of food, in the form of both low-and high-fat meals, on the PK parameters of selumetinib and its active metabolite.…”