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

Overview

Journal Pharm Res

Specialties Pharmacology
Pharmacy

Date 2022 Aug 24

PMID 36002614

Authors

Xavier J H Pepin

Maria Hammarberg

Alexandra Mattinson

Andrea Moir

Affiliations

Soon will be listed here.

Abstract

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.

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