Impact of gastrointestinal tract variability on oral drug absorption and pharmacokinetics: An UNGAP review

Vinarov, Zahari; Abdallah, Mohammad; Agundez, Jos� A.G.; Allegaert, Karel; Basit, Abdul W.; Braeckmans, Marlies; Ceulemans, Jens; Corsetti, Maura; Griffin, Brendan T.; Grimm, Michael; Keszthelyi, Daniel; Koziolek, Mirko; Madla, Christine M.; Matthys, Christophe; McCoubrey, Laura E.; Mitra, Amitava; Reppas, Christos; Stappaerts, Jef; Steenackers, Nele; Trevaskis, Natalie L.; Vanuytsel, Tim; Vertzoni, Maria; Weitschies, Werner; Wilson, Clive; Augustijns, Patrick

Abstract

The absorption of oral drugs is frequently plagued by significant variability with potentially serious therapeutic consequences. The source of variability can be traced back to interindividual variability in physiology, differences in special populations (age- and disease-dependent), drug and formulation properties, or food-drug interactions. Clinical evidence for the impact of some of these factors on drug pharmacokinetic variability is mounting: e.g. gastric pH and emptying time, small intestinal fluid properties, differences in pediatrics and the elderly, and surgical changes in gastrointestinal anatomy. However, the link of colonic factors variability (transit time, fluid composition, microbiome), sex differences (male vs. female) and gut-related diseases (chronic constipation, anorexia and cachexia) to drug absorption variability has not been firmly established yet. At the same time, a way to decrease oral drug pharmacokinetic variability is provided by the pharmaceutical industry: clinical evidence suggests that formulation approaches employed during drug development can decrease the variability in oral exposure. This review outlines the main drivers of oral drug exposure variability and potential approaches to overcome them, while highlighting existing knowledge gaps and guiding future studies in this area.

Citation

Vinarov, Z., Abdallah, M., Agundez, J. A., Allegaert, K., Basit, A. W., Braeckmans, M., Ceulemans, J., Corsetti, M., Griffin, B. T., Grimm, M., Keszthelyi, D., Koziolek, M., Madla, C. M., Matthys, C., McCoubrey, L. E., Mitra, A., Reppas, C., Stappaerts, J., Steenackers, N., Trevaskis, N. L., …Augustijns, P. (2021). Impact of gastrointestinal tract variability on oral drug absorption and pharmacokinetics: An UNGAP review. European Journal of Pharmaceutical Sciences, 162, Article 105812. https://doi.org/10.1016/j.ejps.2021.105812

• Journal Article Type: Review
• Acceptance Date: Mar 16, 2021
• Online Publication Date: Mar 20, 2021
• Publication Date: Jul 1, 2021
• Deposit Date: Apr 10, 2021
• Publicly Available Date: Apr 21, 2021
• Journal: European Journal of Pharmaceutical Sciences
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 162
• Article Number: 105812
• DOI: https://doi.org/10.1016/j.ejps.2021.105812
• Public URL: https://nottingham-repository.worktribe.com/output/5445068
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0928098721001147