Application of the MechPeff model to predict passive effective intestinal permeability in the different regions of the rodent small intestine and colon

Abstract

A major component of physiologically based pharmacokinetic (PBPK) models is the prediction of the rate and extent of absorption of orally dosed drugs for which knowledge of effective passive intestinal permeability (P ) is essential. Single-pass intestinal perfusion (SPIP) studies are used to establish effective permeability in vivo but are difficult to perform in rodents, while mechanistic models to predict drug P in rat and mouse have not been published. This work evaluates the predictive performance of the 'MechPeff' model to predict P in the rodent intestine based upon knowledge of regional gut physiology and drug-specific physicochemical parameters. The 'MechPeff' model, built-in to the Simcyp Rat and Mouse Simulators, predicts transcellular, paracellular and mucus layer permeabilities and combines these to give the overall P . The jejunal and/or ileal P was predicted for 12 (4) acidic, 13 (12) basic, 10 (8) neutral and 2 (0) ampholytic drugs in the rat (mouse), spanning a wide range of MW and logP , and compared with experimental P obtained using SPIP. A key input is the intrinsic transcellular permeability (P ) which can be derived from modelling of appropriate in vitro permeability experiments or predicted from physicochemical properties. The P predictions were reasonably good when experimentally derived P was used; from 42 P values, 24 (57%) were within 3-fold, and of 19 P values, 12 (63%) were within 3-fold, of observed P . Considering the lack of alternative models to predict P in preclinical species, and the minimal drug-specific inputs required, this model provides a valuable tool within drug discovery and development programmes. Copyright © 2017 John Wiley & Sons, Ltd.

Prediction of the Pharmacokinetics of Pravastatin as an OATP Substrate Using Plateable Human Hepatocytes With Human Plasma Data and PBPK Modeling

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Mechanistic Physiologically Based Pharmacokinetic Modeling of the Dissolution and Food Effect of a Biopharmaceutics Classification System IV Compound—The Venetoclax Story

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Assessing Potential Drug–Drug Interactions Between Dabigatran Etexilate and a P‐Glycoprotein Inhibitor in Renal Impairment Populations Using Physiologically Based Pharmacokinetic Modeling

“…In the initial model without P-gp-mediated efflux in the intestine, the effective permeability in humans (P eff,man ) for DABE was estimated using the mechanistic permeability model, which was developed for predicting the regional passive intestinal permeability of drugs in humans based on the knowledge of regional gut physiology and drug-specific physicochemical parameters. 20 Regional P eff,man values were optimized by the scale-down of values estimated from the mechanistic permeability model when assuming that bioavailability was equivalent to the observed value (7.2%). 2 Drug distribution was modeled using a full-PBPK distribution model that uses a number of time-based differential equations to simulate concentrations in various organ compartments.…”