A Population-based PBPK Model for the Prediction of Time-Variant Bile Salt Disposition within GI Luminal Fluids

Stamatopoulos, Konstantinos; Pathak, Shriram; Marciani, Luca; Turner, David

Abstract

In vivo studies have shown cyclic bile salt (BS) outputs during fasting whereas higher amounts have been observed in fed states. This leads to fluctuations of intestinal BS concentrations ([BS]) that can affect the rate and extent of absorption of lipophilic drugs in particular. However, most PBPK models use fixed val-ues of [BS] in fasted and fed states albeit with different values in different regions of the GI tract. During fasting, there is a relationship between gallbladder volume (GBV) and the phase of the Interdigestive Mi-grating Motor Complex cycle (IMMCc), showing cyclic GBV changes with periodic filling and emptying. This relationship is also affected by the origin of the IMMCc (antral or duodenal). In fed states, meta-analysis indicated that GB residual volume (% of fasting maximum) was 46.4 ±27 %CV and 30.7 ±48 %CV for low- and high-fat meals respectively. The corresponding values for the duration of the emptying phase were for low fat meals 0.72h ±1%CV and for high fat meals 1.17h ±37%CV. The model, the Ad-vanced Dynamic Bile Salt Model (ADBSM), was built bottom-up and its parameters were not fitted against in vivo measurements of [BS]. It involved update of the dynamic luminal fluid volumes model based on meta-analysis of available imaging data. The ADBSM is incorporated into the Simcyp® (v18r2) PBPK simulator. The model predictivity was good (within 1.25 fold error for 11/20 of the clinical studies) and was assessed against clinical studies of luminal [BS] that provide only the type of meal (i.e., low- or high-fat), the timing of the meal and/or water intake events, and the number and age range of the study participants. The model is also an important component of models capturing enterohepatic recirculation of drug and metabolite. Further work is required to validate the current model and compare to simpler models with respect to drug absorption, especially of the lipophilic compounds.

Citation

Stamatopoulos, K., Pathak, S., Marciani, L., & Turner, D. (2020). A Population-based PBPK Model for the Prediction of Time-Variant Bile Salt Disposition within GI Luminal Fluids. Molecular Pharmaceutics, 17(4), 1310-1323. https://doi.org/10.1021/acs.molpharmaceut.0c00019

• Journal Article Type: Article
• Acceptance Date: Mar 16, 2020
• Online Publication Date: Mar 16, 2020
• Publication Date: Apr 6, 2020
• Deposit Date: Mar 21, 2020
• Publicly Available Date: Mar 17, 2021
• Journal: Molecular Pharmaceutics
• Print ISSN: 1543-8384
• Electronic ISSN: 1543-8392
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 17
• Issue: 4
• Pages: 1310-1323
• DOI: https://doi.org/10.1021/acs.molpharmaceut.0c00019
• Keywords: Molecular Medicine; Drug Discovery; Pharmaceutical Science
• Public URL: https://nottingham-repository.worktribe.com/output/4183486
• Publisher URL: https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.0c00019
• Additional Information: “This document is the Accepted Manuscript version of a Published Work that appeared in final form in Molecular Pharmaceutics copyright ©American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.0c00019