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Model-based prediction of plasma concentration and enterohepatic circulation of total bile acids in humans
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
University of Copenhagen, Copenhagen, Denmark.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Pharmetheus AB, Uppsala, Sweden.ORCID iD: 0000-0002-0295-1227
University of Copenhagen, Copenhagen, Denmark.
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2018 (English)In: CPT: pharmacometrics and systems pharmacology, E-ISSN 2163-8306, Vol. 7, no 9, p. 603-612Article in journal (Refereed) Published
Abstract [en]

Bile acids released postprandially can modify the rate and extent of lipophilic compounds’ absorption. This study aimed to predict the enterohepatic circulation (EHC) of total bile acids (TBAs) in response to caloric intake from their spillover in plasma. A model for TBA EHC was combined with a previously developed gastric emptying (GE) model. Longitudinal gallbladder volumes and TBA plasma concentration data from 30 subjects studied after ingestion of four different test drinks were supplemented with literature data. Postprandial gallbladder refilling periods were implemented to improve model predictions. The TBA hepatic extraction was reduced with the high‐fat drink. Basal and nutrient‐induced gallbladder emptying rates were altered by type 2 diabetes (T2D). The model was predictive of the central trend and the variability of gallbladder volume and TBA plasma concentration for all test drinks. Integration of this model within physiological pharmacokinetic modeling frameworks could improve the predictions for lipophilic compounds’ absorption considerably.

Place, publisher, year, edition, pages
2018. Vol. 7, no 9, p. 603-612
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-340234DOI: 10.1002/psp4.12325ISI: 000445602000009OAI: oai:DiVA.org:uu-340234DiVA, id: diva2:1178118
Funder
EU, FP7, Seventh Framework Programme, 115369Available from: 2018-01-28 Created: 2018-01-28 Last updated: 2018-10-25Bibliographically approved
In thesis
1. Mechanism-based modeling of biological processes involved in oral absorption
Open this publication in new window or tab >>Mechanism-based modeling of biological processes involved in oral absorption
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

For orally administered drugs, the rate and extent of absorption are governed by the physiology of the gastrointestinal tract, the characteristics of the dosage form and the physico-chemical properties of the drug. This thesis primarily aimed to improve the mechanistic understanding and the predictability of processes involved in the absorption of orally administered drugs using a population modeling approach. A secondary aim was to propose an optimized dosing regimen for first line anti-tuberculosis drugs in underweight Indian children.

A model characterized the effect of pH, mechanical stress and formulation on in vitro extended release (ER) tablet erosion. The model was further used in combination with anatomical tablet location data to predict the in vivo erosion dynamics. The proposed approach could help address challenges related to the development of future ER formulations.

Gastric emptying regulates the rate of entry of nutrients into the small intestine. Bile acids are essential for the intestinal absorption of lipophilic drugs, but the determination of their local intestinal concentrations is difficult. A modeling framework was developed to characterize the relationships between nutritional intake, rate of gastric emptying, gallbladder emptying–refilling patterns and plasma concentrations of bile acids. This modeling framework could be used in combination with systems pharmacology models to predict the drug-drug interactions and food effects associated with gastric emptying, as well as to link the postprandial changes in plasma bile acid concentrations to the variability in drugs’ absorption.

Optimal doses of first-line antituberculosis drugs have not been firmly established. In an underweight Indian children population, the pharmacokinetic-pharmacodynamic model identified rifampin as single predictor of unfavorable treatment outcome. Children with low body weight and/or HIV coinfection had a higher probability of unfavorable treatment outcome. Doses increase were proposed and could provide crucial information for future guidelines.

In summary, the developed models enabled the prediction of the in vivo erosion profile of ER formulations based on in vitro dissolution data. A modeling framework predicted the postprandial gastric emptying rate and enterohepatic circulation of bile acids. Finally, a model-based approach was used to identify risk factors and propose optimized dose recommendations in tuberculosis-infected Indian children.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 64
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 246
Keywords
absorption, bile acids, enterohepatic circulation, food effect, gallbladder, in vitro in vivo correlation; NONMEM, pediatrics, pharmacometrics, tuberculosis
National Category
Health Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-340238 (URN)978-91-513-0225-6 (ISBN)
Public defence
2018-03-16, A1:111a, Biomedicinskt centrum, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2018-02-22 Created: 2018-01-29 Last updated: 2018-03-07

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Guiastrennec, BenjaminBergstrand, MartinKarlsson, Mats O

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