Clin Pharmacokinet
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Despite recent advances in understanding of the role of the gut as a metabolizing organ, recognition of gut wall metabolism and/or other factors contributing to intestinal loss of a compound has been a challenging task due to the lack of well characterized methods to distinguish it from first-pass hepatic extraction. The implications of identifying intestinal loss of a compound in drug discovery and development can be enormous. Physiologically based pharmacokinetic (PBPK) simulations of pharmacokinetic profiles provide a simple, reliable and cost-effective way to understand the mechanisms underlying pharmacokinetic processes. The purpose of this article is to demonstrate the application of PBPK simulations in bringing to light intestinal loss of orally administered drugs, using two example compounds: verapamil and an in-house compound that is no longer in development (referred to as compound A in this article). ⋯ Mechanistic insights provided by PBPK simulations can be very valuable in answering vital questions in drug discovery and development. However, such applications of PBPK models are limited by the lack of accurate inputs for clearance and distribution. This article demonstrates a successful application of PBPK simulations to identify and quantify intestinal loss of two model compounds in rats and humans. The limitation of inaccurate inputs for the clearance and distribution parameters was overcome by optimizing these parameters through fitting intravenous profiles. The study also demonstrated that the large interspecies differences associated with gut wall metabolism and gastric emptying, evident for the compounds studied, make animal model extrapolations to humans unreliable. It is therefore important to do PBPK simulations of human pharmacokinetic profiles to understand the relevance of intestinal loss of a compound in humans.
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The mechanistic framework of physiologically based pharmacokinetic (PBPK) models makes them uniquely suited to hypothesis testing and lineshape analysis, which help provide valuable insights into mechanisms that contribute to the observed concentration-time profiles. The aim of this article is to evaluate the utility of PBPK models for simulating oral lineshapes by optimizing clearance and distribution parameters through fitting observed intravenous pharmacokinetic profiles. ⋯ The validation of the generic PBPK model built in-house demonstrated that as long as the absorption profile of a compound is determined solely by solubility and paracellular or transcellular permeability, the PBPK simulations of oral profiles using optimized parameters from intravenous simulations provide reasonably good agreement with the observed profile with respect to both the lineshape fit and prediction of pharmacokinetic parameters. Therefore, any lineshape mismatch between PBPK simulated and observed oral profiles can be interpreted suitably to gain mechanistic insights into the pharmacokinetic processes that have resulted in the observed lineshape. A strategy has been proposed to identify involvement of carrier-mediated transport; clearance saturation; enterohepatic recirculation of the parent compound; extra-hepatic, extra-gut elimination; higher in vivo solubility than predicted in vitro; drug-induced gastric emptying delays; gut loss and regional variation in gut absorption.