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 values 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 Migrating 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 Advanced 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.
Highlights
Along with other parameters, such as stability, permeability and first-pass metabolism, solubility in luminal fluids is considered to be a key factor for the prediction of oral drug bioavailability
644 studies were excluded according to exclusion criteria as described in the methodology
After constructing all the equations describing the time-variant enterohepatic circulation (EHC) of bile salts coupled to time-dependent luminal fluid volumes, simulated luminal [Bile salts (BS)] were obtained and compared to the observed data
Summary
Along with other parameters, such as stability, permeability and first-pass metabolism, solubility in luminal fluids is considered to be a key factor for the prediction of oral drug bioavailability. Several studies have been conducted in the past to characterize fasting and fed duodenal, jejunal and colonic aspirates in healthy and non-healthy (e.g., with ulcerative colitis) subjects. These studies have been used to design simulated biorelevant media (FaSSIF, FeSSIF) enabling in vivo prediction of drug solubility.. These studies have been used to design simulated biorelevant media (FaSSIF, FeSSIF) enabling in vivo prediction of drug solubility.33 This information has been implemented in in-silico platforms; e.g., SimCYP, as a part of the Advanced Dissolution Absorption and Metabolism (ADAM) model, GastroPlus and GISIM.. The Guiastrennec et al., mechanistic model describes GB motility only in the fed state and is based on a single in vivo study. A different approach for mechanistically modelling
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