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

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_eff) 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_eff in rat and mouse have not been published. This work evaluates the predictive performance of the ‘MechPeff’ model to predict P_eff 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_eff. The jejunal and/or ileal P_eff 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_o:w, and compared with experimental P_eff obtained using SPIP. A key input is the intrinsic transcellular permeability (P_trans,0) which can be derived from modelling of appropriate in vitro permeability experiments or predicted from physicochemical properties. The P_eff predictions were reasonably good when experimentally derived P_trans,0 was used; from 42 P_eff,rat values, 24 (57%) were within 3-fold, and of 19 P_eff,mouse values, 12 (63%) were within 3-fold, of observed P_eff. Considering the lack of alternative models to predict P_eff in preclinical species, and the minimal drug-specific inputs required, this model provides a valuable tool within drug discovery and development programmes.