Related Experiment Video
Updated: Jun 29, 2025

An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment
Published on: December 3, 2020
The Use of Global Sensitivity Analysis to Assess the Oral Absorption of Weakly Basic Compounds: A Case Example of
Siddharth S Kesharwani1, Guillaume Louit2, Fady Ibrahim3
1US Early Development Biopharmacy, Synthetics Platform, Sanofi, 350 Water St, Cambridge, MA, 02141, USA.
Objective:
To utilize the global system analysis (GSA) in oral absorption modeling to gain a deeper understanding of system behavior, improve model accuracy, and make informed decisions during drug development.
Methods:
GSA was utilized to give insight into which drug substance (DS), drug product (DP), and/or physiological parameter would have an impact on peak plasma concentration (Cmax) and area under the curve (AUC) of dipyridamole as a model weakly basic compound. GSA guided the design of in vitro experiments and oral absorption risk assessment using FormulatedProducts v2202.1.0. The solubility and precipitation profiles of dipyridamole in different bile salt concentrations were measured. The results were then used to build a mechanistic oral absorption model.
Results:
GSA warranted further investigation into the precipitation kinetics and its link to the levels of bile salt concentrations. Mechanistic modeling studies demonstrated that a precipitation-integrated modeling approach appropriately predicted the mean plasma profiles, Cmax, and AUC from the clinical studies.
Conclusions:
This work shows the value of GSA utilization in early development to guide in vitro experimentation and build more confidence in identifying the critical parameters for the mathematical models.
More Related Videos
Related Concept Videos
Factors Influencing Drug Absorption: Drug Dissolution
Factors Affecting Dissolution: Drug pKa, Lipophilicity and GI pH
A drug's pKa and the pH of the gastrointestinal (GI) tract play crucial roles...
Factors Affecting Dissolution: Drug Permeability, Stability and Stereochemistry
Factors Influencing Drug Absorption: Physicochemical Parameters
Enhanced drug absorption can be achieved by reducing particle sizes and increasing surface areas, thereby facilitating...
Factors Influencing Drug Absorption: Disease States and Pharmacology
Substances such as alcohol and specific drugs, including antineoplastics, can also negatively impact drug absorption. For instance,...
Methods for Studying Drug Absorption: In situ
The Doluisio method involves perfusing a prepared segment of a rat's small intestine with a solution of radiolabeled drug and a non-absorbable marker. This helps to differentiate between absorbed and non-absorbed drug concentrations. The intestinal segment is connected at both ends using tubing and syringes,...

