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Population-Based PBPK Model for the Prediction of Time-Variant Bile Salt Disposition within GI Luminal Fluids
journal contribution
posted on 2020-03-23, 19:34 authored by Konstantinos Stamatopoulos, Shriram M. Pathak, Luca Marciani, David B. TurnerIn
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.
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ADBSMv 18r PBPK simulatorvivo measurementsdrug absorptionBSlipophilic drugsPopulation-Based PBPK Modellipophilic compoundsstudy participantsvivo studiesAdvanced Dynamic Bile Salt ModelGI tractmodel predictivityimaging dataage rangecyclic GBV changesCVPBPK models usehigh-fat mealsGI Luminal Fluidsgallbladder volumeenterohepatic recirculationluminal fluid volumes modelfastingTime-Variant Bile Salt DispositionInterdigestive Migrating Motor Complex cyclecyclic bile salt
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