Dodd, Stephanie (2021) Use of PBPK Modeling for Predicting Drug-Food Interactions: Successful prediction using a middle-out approach. AAPS PharmSci, 23 (12). ISSN 1550-7416/21/0000-0001/0

Abstract

Over the last 10 years, 40% of approved oral drugs exhibited a significant effect of food on pharmacokinetics (PK) and currently the only method to characterize the effect of food on drug absorption which is recognized by the authorities, is to conduct a clinical evaluation. Within the pharmaceutical industry, there is a significant effort to predict the mechanism and clinical relevance of a food effect. Physiologically-based pharmacokinetic (PBPK) models combining both drug-specific and physiology-specific data have been used to interpret the effect of food on absorption and the underlying mechanisms. This manuscript provides detailed descriptions of how a middle-out modeling approach can be used to predict the magnitude and direction of food effect for three compounds: nefazodone, furosemide and aprepitant. For nefazodone, a mechanistic clearance for gut and liver was added, for furosemide, an absorption window was introduced and for aprepitant, the solubility, absorption scaling factors and volume needed adjustment. In all cases, these adjustments were supported by literature data and modelers judgement on the factors limiting absorption. Through this modelling, some differences in how software packages handle the data or make assumptions in default system parameters led to differences in the predicted food effect which is also presented for the three examples.

Item Type:	Article
Keywords:	PBPK, food effect, pharmacokinetics, modeling, middle out, optimization
Date Deposited:	19 Jan 2021 00:45
Last Modified:	19 Jan 2021 00:45
URI:	https://oak.novartis.com/id/eprint/43107