Physiologically Based Biopharmaceutics Model for Selumetinib Food Effect Investigation and Capsule Dissolution Safe Space - Part I: Adults.

OBJECTIVE: A physiologically based biopharmaceutics model (PBBM) was developed to mechanistically investigate the effect of formulation and food on selumetinib pharmacokinetics. METHODS: Selumetinib is presented as a hydrogen sulfate salt, and in vitro and in vivo data were used to verify the precipitation rate to apply to simulations. Dissolution profiles observed for capsules and granules were used to derive product-particle size distributions for model input. The PBBM incorporated gut efflux and first-pass gut metabolism, based on intravenous and oral pharmacokinetic data, alongside in vitro data for the main enzyme isoform and P-glycoprotein efflux. The PBBM was validated across eight clinical scenarios. RESULTS: The quality-control dissolution method for selumetinib capsules was found to be clinically relevant through PBBM validation. A safe space for capsule dissolution was established using a virtual batch. The effect of food (low fat vs high fat) on capsules and granules was elucidated by the PBBM. For capsules, a lower amount was dissolved in the fed state due to a pH increase in the stomach followed by higher precipitation in the small intestine. First-pass gut extraction is higher for capsules in the fed state due to drug dilution in the stomach chyme and reduced concentration in the lumen. The enteric-coated granules dissolve more slowly than capsules after stomach emptying, attenuating the difference in first-pass gut extraction between prandial states. CONCLUSIONS: The PBBM was instrumental in understanding and explaining the different behaviors of the selumetinib formulations. The model can be used to predict the impact of food in humans.

A Phase I, Open-label, Randomized, Crossover Study of the Relative Bioavailability of Capsule and Granule Formulations of Selumetinib.

PURPOSE: Selumetinib (ARRY-142886) is an oral, potent, and highly selective allosteric mitogen-activated protein kinase kinase 1/2 inhibitor approved for the treatment of pediatric patients (≥2 years of age) with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. This Phase I crossover study (NCT03649165) evaluated the pharmacokinetic properties and palatability of a new granule formulation of selumetinib. METHODS: Healthy volunteers were randomized to 1 of 2 sequences; selumetinib granule (25 mg) followed by selumetinib capsules (50 mg [2 × 25 mg]) and vice versa. The primary end point was the pharmacokinetic properties of the 2 formulations. Secondary end points included safety and tolerability of single selumetinib doses and palatability of the granule formulation. FINDINGS: Of the 24 enrolled volunteers (mean age, 33.2 years; range 23-44 years), all were male and 20 (83%) were Black/African American. Under fasted conditions for the granule versus capsule, geometric mean ratios for the dose-normalized Cmax and AUC0-∞ were 0.654 (90% CI, 0.581-0.736) and 0.865 (90% CI, 0.811-0.922), respectively. Absorption of selumetinib was similar between granule and capsule formulation, with a median time to Cmax of 1.73 hours and 1.14 hours, respectively. Adverse event incidence was low (n = 6 in both groups), and most events were mild. Palatability was acceptable, with volunteers indicating that they would take the granule formulation again. IMPLICATIONS: These findings support further research into the selumetinib granule formulation, with the aim of producing an alternative formulation for younger children or patients unable to swallow capsules. CLINICALTRIALS: gov identifier: NCT03649165.

Effect of food on capsule and granule formulations of selumetinib.

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 (Tmax ) ranging from ~1-3 h. Geometric mean ratios (90% confidence interval [CI]) for maximum plasma concentration (Cmax ) 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 Cmax and longer Tmax 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.