Mechanism‐Based Modeling of Gastric Emptying Rate and Gallbladder Emptying in Response to Caloric Intake

Abstract

Bile acids released postprandially modify the rate and extent of absorption of lipophilic compounds. The present study aimed to predict gastric emptying (GE) rate and gallbladder emptying (GBE) patterns in response to caloric intake. A mechanism‐based model for GE, cholecystokinin plasma concentrations, and GBE was developed on data from 33 patients with type 2 diabetes and 33 matched nondiabetic individuals who were administered various test drinks. A feedback action of the caloric content entering the proximal small intestine was identified for the rate of GE. The cholecystokinin concentrations were not predictive of GBE, and an alternative model linking the nutrients amount in the upper intestine to GBE was preferred. Relative to fats, the potency on GBE was 68% for proteins and 2.3% for carbohydrates. The model predictions were robust across a broad range of nutritional content and may potentially be used to predict postprandial changes in drug absorption.

Effect of Protein Binding on Exposure of Unbound and Total Mycophenolic Acid: A Population Pharmacokinetic Analysis in Chinese Adult Kidney Transplant Recipients

“…Several assumptions were made to ensure the model was structurally identifiable [40]: (1) MMF is completely and quickly absorbed, (2) the conversion ratio from MMF to MPAG is fixed at 100%, (3) MPAG secreted from the gallbladder to intestines is completely deconjugated to MPA and reabsorbed, (4) the rate constants associated with each compartment are all first-order and unaffected by the recycling, and (5) gallbladder emptying is triggered by meals. Additionally, the gallbladder emptying rate constant (k GB ) was fixed at 3.708 /h based on previous study [42]. The duration (D GB ) of gallbladder release was fixed at 0.5 h to ensure that over 90% gallbladder contents would be released after each trigger.…”

Prior information for population pharmacokinetic and pharmacokinetic/pharmacodynamic analysis: overview and guidance with a focus on the NONMEM PRIOR subroutine

“…covariate effects on clearance) to physiologically plausible values, because no data were available for children younger than one year old [ 20 ]. Eight articles used the PRIOR subroutine in NONMEM to inform mechanistic popPK models [ 4 , 8 , 11 , 15 , 22 , 32 – 34 ]. Amongst them, three were Physiologically-Based Pharmacokinetic (PBPK) models [ 4 , 8 , 11 ] (see Sect.…”

“…In our review, only two out of 32 articles analyzing sparse data used TNPRI [ 15 , 29 ]: in both articles, the previous analysis had been done by the same team. Eighteen articles [ 4 – 14 , 23 , 25 , 27 , 30 , 32 – 34 ] used NWPRI; in the remaining 12 articles the method was not specified [ 16 – 22 , 24 , 26 , 28 , 31 , 35 ], among which six used prior only on THETA [ 19 , 20 , 22 , 24 , 28 , 35 ], the distribution attributed to the OMEGA consequently having no impact.…”

“…Eight out of 32 articles analyzing sparse data reviewed implemented informative priors on all parameters [ 5 , 10 , 12 , 15 , 23 , 29 – 31 ], 18 implemented informative priors, and/or so-called “weakly informative” (when they are associated to 10% [ 20 ] or 50% [ 24 , 28 ] uncertainty) only on a part of the parameters [ 7 – 9 , 13 , 16 – 22 , 24 , 25 , 28 , 32 – 35 ], and three implemented uninformative priors on some of the parameters while had informative priors on the rest of the parameters [ 4 , 6 , 11 ]. The latter included the study using MCMC [ 6 ] and the study comparing FOCE to MCMC [ 4 ].…”

A Physiology-Based Model of Bile Acid Distribution and Metabolism Under Healthy and Pathologic Conditions in Human Beings

“…Early work by Hofmann et al 15,16 and Molino et al 17 included a detailed mechanistic description of the dynamics of the major human BAs, cholic acid (CA), chenodeoxycholic acid (CDCA), and deoxycholic acid (DCA) in the EHC, hepatobiliary tract, and gastrointestinal tract. In more recent work, Guiastrennec et al 18 developed and applied a nonlinear mixed-effects model, with a simplified description of EHC, to study the effects of meal composition on the distribution of the total BA pool. Likewise, a mechanistic model by Sips et al 19 has been used to identify determinants of BA pool composition.…”