A comparative evaluation of models to predict human intestinal metabolism from nonclinical data

Abstract

Extensive gut metabolism is often associated with the risk of low and variable bioavailability. The prediction of the fraction of drug escaping gut wall metabolism as well as transporter‐mediated secretion (F g) has been challenged by the lack of appropriate preclinical models. The purpose of this study is to compare the performance of models that are widely employed in the pharmaceutical industry today to estimate F g and, based on the outcome, to provide recommendations for the prediction of human F g during drug discovery and early drug development. The use of in vitro intrinsic clearance from human liver microsomes (HLM) in three mechanistic models – the ADAM, Q gut and Competing Rates – was evaluated for drugs whose metabolism is dominated by CYP450s, assuming that the effect of transporters is negligible. The utility of rat as a model for human F g was also explored. The ADAM, Q gut and Competing Rates models had comparable prediction success (70%, 74%, 69%, respectively) and bias (AFE = 1.26, 0.74 and 0.81, respectively). However, the ADAM model showed better accuracy compared with the Q gut and Competing Rates models (RMSE =0.20 vs 0.30 and 0.25, respectively). Rat is not a good model (prediction success =32%, RMSE =0.48 and AFE = 0.44) as it seems systematically to under‐predict human F g. Hence, we would recommend the use of rat to identify the need for F g assessment, followed by the use of HLM in simple models to predict human F g. © 2017 Merck KGaA. Biopharmaceutics & Drug Disposition Published by John Wiley & Sons, Ltd.

Absorption and Intestinal Metabolic Profile of Oleocanthal in Rats

“…The bioavailability of ingested phenolic compounds can be influenced by factors such as diet, genomic profile, enzymatic activity and colonic microflora [3], but it also depends on the extent of absorption and metabolism after ingestion. In this context, many in vitro and in vivo models for estimating human intestinal permeability and first-pass metabolism have been developed [10,11].…”

Requirements to Establishing Confidence in Physiologically Based Pharmacokinetic (PBPK) Models and Overcoming Some of the Challenges to Meeting Them

“…For example, if gut metabolism is known to be relevant for the NCE, then quantifying the metabolic contribution of the gut requires metabolite measured in intravenous and oral routes. For CYP3A substrates, reasonable quantification is possible even with in vitro data [19]. For non-CYP drivers of gut metabolism, the availability of PK data following intravenous administration is indispensable in the quantitative mechanistic understanding of gut bioavailability.…”

Revisiting the role of gut wall in the fate of orally administered drugs: Why now and to what effect?

“…These authors focus on discrepancies in methods to quantify gut wall metabolism . The second Theme issue deals more with strategies for the prediction of in vivo observations from non‐clinical data on an industrial scale by Yau et al , the provision of scaling factors for gut‐wall enzymes by Hatley et al , the critical assessment of predicting pediatric drug absorption by applying physiologically based pharmacokinetics (PBPK) modelling by Nicolas et al , and the ability to predict inhibitory effects on intestinal metabolism by employing PBPK models that account for variations of metabolism in different (enterocyte vs. serosal) regions of the gut (Pang et al . ).…”

“…A major problem with regard to the handling of in vitro or in vivo data is the presence of inter‐species differences in gut wall metabolism, making a direct comparison or animal scale‐up a virtual impossibility, although the concept of using animal studies to infer human gut metabolism is an attractive one. In the second issue, Yao et al appraised whether we can predict in vivo derived F G or F I (intestine availability) in humans from in vitro values or observations obtained in rats with the use of various models and assumptions. Nicolas et al extend such activity with respect to pediatric drug development, and the possibility of predicting gut drug absorption.…”

“…These violations are not always recognized and some investigators kept using f T as proposed by Yang et al , and failed to account for the process of drug reabsorption pursuant to secretion. The debate over the components of the Q Gut model will continue, particularly with respect to the use of f T in lieu of f B (as seen with the theme issue by Yau et al ). Hence, readers should note that the Q Gut model, at its best, is semi‐mechanistic and is not a true reflection of all gut attributes when it comes to defining gut metabolism.…”