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Physiologically Based Pharmacokinetic Modeling of Oral Absorption, pH, and Food Effect in Healthy Volunteers to Drive Alpelisib Formulation Selection

Gajewska, Monika and Blumenstein, Lars and Kourentas, Alexandros and Mueller-Zsigmondy, Martin and Lorenzo, Sebastien and Heimbach, Tycho and Angela, Sinn and Maria, Velinova (2020) Physiologically Based Pharmacokinetic Modeling of Oral Absorption, pH, and Food Effect in Healthy Volunteers to Drive Alpelisib Formulation Selection. AAPS Journal, 22 (6). ISSN 15507416

Abstract

A physiologically based pharmacokinetic (PBPK) human model for alpelisib, an oral α-specific class I phosphatidylinositol-3-kinase (PI3K) inhibitor, was established to simulate oral absorption and plasma pharmacokinetics of healthy subjects to allow model-informed drug development. The GastroPlus™ model consisted of an advanced absorption gut model, which was linked to a 2-compartmental model. Systemic clearance and volume of distribution were estimated using population pharmacokinetics (popPK). Various food effect and pH-mediated absorption drug–drug interaction (DDI) scenarios were modeled. In fasted healthy subjects, simulated absorption was lower (ca. 70% for a 300-mg dose) due to pH and bile acid concentration-dependent solubility. Ranitidine showed a significant pH-mediated DDI effect only in the fasted but not fed state. The PBPK model identified that more drug is absorbed in the fed state, and alpelisib intestinal permeability is rate limiting to systemic exposure. Simulations for healthy subject showed a positive food effect with ca. 2-fold increase in plasma Cmax and 1.5-fold increase in AUC0-inf with a meal compared with fasted conditions. The PBPK model was verified using clinical food effect data with pivotal clinical formulation (PCF) and then applied to predict the performance of a commercial formulation (CF) in healthy volunteers. The model successfully predicted the outcome of a clinical bioequivalence study for PCF and CF with included in vitro dissolution data, both fasted and fed state. Estimated predictive errors (based on plasma Cmax, AUC0-t) were equal or below 30%. The alpelisib model for healthy subjects enables future bioequivalence formulation assessments, in fasted, fed, or altered pH conditions. [Figure not available: see fulltext.]

Item Type: Article
Keywords: alpelisib bioequivalence biopharmaceutics GastroPlus™ physiologically based pharmacokinetic(s) modeling proton pump inhibitor DDI
Date Deposited: 06 Apr 2021 00:45
Last Modified: 06 Apr 2021 00:45
URI: https://oak.novartis.com/id/eprint/42754

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