II-088 Jonas Langeraert

Small molecule drug absorption in inflammatory bowel disease and current implementation in PBPK models.

Jonas Langeraert, Elke Gasthuys, An Vermeulen

Laboratory for Medicinal Biochemistry and Clinical Analysis, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent

Introduction: Inflammatory bowel disease (IBD) is characterized by a chronic inflammation of the intestinal mucosa, with predominant localization in the colon in ulcerative colitis (UC) or affecting the entire length of the gastrointestinal tract in Crohn’s disease (CD) (1). The global prevalence rate of IBD has increased significantly between 1990 and 2017, with the highest rates found in the USA (2). Current mainstay treatment for this disease consists of immunomodulators and biologics, predominately anti-tumor necrosis factor alpha (TNF-α) monoclonal antibodies (3). However, initial nonresponse to anti-TNF biologics has been reported to range from 10% to as high as 80% with loss of response over time also having been observed in around one third of initial responders (4,5). Therefore, recent advances in the drug development space have been marked by a return to orally administered small molecules with novel mechanisms of action such as Janus kinase inhibitors (6). Additionally, the prevalence of certain chronic conditions is higher in IBD patients, many of which are treated with orally administered drugs (7,8). Given the pathophysiology and localization of IBD, altered drug absorption from the gastrointestinal tract can be expected (9).

Objectives: The aim of the current review was to:

  • Determine factors influencing oral drug absorption, and the impact of IBD
  • Assess available literature data which can be used as a test case in PBPK modelling
  • Identify shortcomings in currently published PBPK models that defined an IBD population

Methods: A literature search was performed in the Pubmed, Web of Science and Embase databases to determine factors influencing oral drug absorption in the small and large intestine as well as in healthy volunteers and IBD patients. Original research articles and reviews linking differences in physiology to oral absorption were included. The literature was also searched in the same databases for PBPK models describing oral drug absorption in an IBD population.

Results: The literature search revealed several physiological differences between the small and large intestine with the potential to influence drug absorption including pathophysiology related alterations associated with IBD. The main physiological parameters which are identified include luminal fluid volume, luminal pH, transit time, bile salt concentration, microbiome, absorptive surface area, permeability and metabolizing enzymes and transporters. Their potential influence on drug absorption is also discussed. Furthermore, only two articles were found which used PBPK modelling to describe the PK of an orally administered drug in an IBD population. The models allowed for incorporation of all the reported alterations simultaneously and provided mechanistic insight into the absorption of budesonide. These results seem to indicate that PBPK modelling using an IBD population built on literature data can be used to describe oral absorption of small molecule compounds. However, it must be noted that these models described the PK of BCS class I drugs for which absorption is not expected to be severely influenced by changes in the epithelial membrane or intestinal lumen given their high permeability and solubility.

Conclusions: The factors which can affect oral drug absorption are numerous and differ regionally even within the small and the large intestine. This review described the influence of IBD on these factors both in UC and CD. Reported data was often marked with a high degree of heterogeneity making it oftentimes difficult to unambiguously determine the impact of disease on a certain factor. Non-conformity in the reporting of disease states and the applied methodology in many studies further complicates these assessments. Two PBPK models were described in this review which attempted to describe the pharmacokinetics of midazolam and budesonide. Model performance would need to be assessed using other BCS class type drugs to determine whether membrane and luminal alterations in IBD are adequately incorporated into the model and capable of describing absorption kinetics for these low permeability and/or low solubility drugs as well.

References:

  1. Abraham C. Inflammatory Bowel Disease. N Engl J Med. 2009.
  2. The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2020 Jan 1;5(1):17–30.
  3. Aditi Kumar, Philip J Smith. Horizon scanning: new and future therapies in the management of inflammatory bowel disease. eGastroenterology. 2023 Oct 1;1(2):e100012.
  4. Papamichael K, Gils A, Rutgeerts P, Levesque BG, Vermeire S, Sandborn WJ, et al. Role for Therapeutic Drug Monitoring During Induction Therapy with TNF Antagonists in IBD: Evolution in the Definition and Management of Primary Nonresponse. Inflamm Bowel Dis. 2015 Jan 1;21(1):182–97.
  5. Qiu Y, Chen B li, Mao R, Zhang S hong, He Y, Zeng Z rong, et al. Systematic review with meta-analysis: loss of response and requirement of anti-TNFα dose intensification in Crohn’s disease. J Gastroenterol. 2017 May 1;52(5):535–54.
  6. Jefremow A, Neurath MF. Novel Small Molecules in IBD: Current State and Future Perspectives. Cells. 2023 Jan;12(13):1730.
  7. Xu F, Dahlhamer JM, Zammitti EP, Wheaton AG, Croft JB. Health-Risk Behaviors and Chronic Conditions Among Adults with Inflammatory Bowel Disease — United States, 2015 and 2016. Morb Mortal Wkly Rep. 2018 Feb 16;67(6):190–5.
  8. Alrubia S, Mao J, Chen Y, Barber J, Rostami-Hodjegan A. Altered Bioavailability and Pharmacokinetics in Crohn’s Disease: Capturing Systems Parameters for PBPK to Assist with Predicting the Fate of Orally Administered Drugs. Clin Pharmacokinet. 2022 Oct 1;61(10):1365–92.
  9. Effinger A, O’Driscoll CM, McAllister M, Fotaki N. Impact of gastrointestinal disease states on oral drug absorption – implications for formulation design – a PEARRL review. J Pharm Pharmacol. 2019;71(4):674–98.

Reference: PAGE 32 (2024) Abstr 11103 [www.page-meeting.org/?abstract=11103]

Poster: Drug/Disease Modelling - Absorption & PBPK

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