PBPK Modeling as a Tool for Predicting and Understanding Intestinal Metabolism of Uridine 5'-Diphospho-glucuronosyltransferase Substrates.

Uridine 5'-diphospho-glucuronosyltransferases (UGTs) are expressed in the small intestines, but prediction of first-pass extraction from the related metabolism is not well studied. This work assesses physiologically based pharmacokinetic (PBPK) modeling as a tool for predicting intestinal metabolism due to UGTs in the human gastrointestinal tract. Available data for intestinal UGT expression levels and in vitro approaches that can be used to predict intestinal metabolism of UGT substrates are reviewed. Human PBPK models for UGT substrates with varying extents of UGT-mediated intestinal metabolism (lorazepam, oxazepam, naloxone, zidovudine, cabotegravir, raltegravir, and dolutegravir) have demonstrated utility for predicting the extent of intestinal metabolism. Drug-drug interactions (DDIs) of UGT1A1 substrates dolutegravir and raltegravir with UGT1A1 inhibitor atazanavir have been simulated, and the role of intestinal metabolism in these clinical DDIs examined. Utility of an in silico tool for predicting substrate specificity for UGTs is discussed. Improved in vitro tools to study metabolism for UGT compounds, such as coculture models for low clearance compounds and better understanding of optimal conditions for in vitro studies, may provide an opportunity for improved in vitro-in vivo extrapolation (IVIVE) and prospective predictions. PBPK modeling shows promise as a useful tool for predicting intestinal metabolism for UGT substrates.

Application of physiologically based biopharmaceutics modeling to understand the impact of dissolution differences on in vivo performance of immediate release products: The case of bisoprolol.

Merck KGaA observed slight differences in the dissolution of Concor® (bisoprolol) batches over the years. The purpose of this work was to assess the impact of in vitro dissolution on the simulated pharmacokinetics of bisoprolol using in vitro-in vivo relationship established with available in vitro dissolution and corresponding plasma concentrations-time data for several bisoprolol batches. A mechanistic absorption model/physiologically based pharmacokinetics model linked with a biopharmaceutics tool such as dissolution testing, namely, physiologically based biopharmaceutics modeling (PBBM), can be valuable in determining a dissolution "safe space." A PBBM for bisoprolol was built using in vitro, in silico, and clinical data. We evaluated potential influences of variability in dissolution of bisoprolol batches on its clinical performance through PBBM and virtual bioequivalence (BE) trials. We demonstrated that in vitro dissolution was not critical for the clinical performance of bisoprolol over a wide range of tested values. Based on virtual BE trials, safe space expansion was explored using hypothetical dissolution data. A formulation with in vitro dissolution reaching 70% dissolved in 15 min and 79.5% in 30 min was shown to be BE to classical fast dissolution of bisoprolol (>85% within 15 min), as point estimates and 90% confidence intervals of the maximum plasma concentration and area under the concentration-time curve were within the BE limits (0.8-1.25).