Developing in vitro and in silico tools to predict the impact of gastrointestinal disease states on drug product performance

  • Angela Effinger

Student thesis: Doctoral ThesisPhD

Abstract

Gastrointestinal (GI) diseases affect a large number of people and drug treatment in this patient population includes the treatment of the GI condition, of associated systemic symptoms and of concomitant conditions. Preferably, drugs are administered via the oral route and the respective pharmaceutical formulations are designed to overcome physiological challenges before reaching the systemic circulation. Pathophysiological changes in GI disease patients can affect the absorption, distribution, metabolism and excretion of drugs but clinical studies are rarely performed in patients with GI diseases. In the absence of those studies, in vitro and in silico tools can be used to identify drugs at risk of altered performance in this patient population and were developed as aim of this thesis.
To simulate the solubility and dissolution of drugs in the GI fluids of patients with Crohn’s disease (CD), Ulcerative colitis (UC) and Coeliac disease (CED) compared to healthy subjects, biorelevant media were developed based on pathophysiological differences in these patient populations using a Design of Experiment (DoE) approach. The characterisation of the GI disease media revealed differences compared to healthy biorelevant media, mostly in terms of surface tension, osmolality and buffer capacity. Solubility studies in the respective media indicated that a risk of altered drug solubility in patients with GI diseases was in the majority of cases related to the drugs’ lipophilicity or ionisation properties.
To predict the performance of a controlled-release budesonide formulation in healthy subjects and CD patients, in vitro dissolution studies representative of CD and healthy conditions were performed and integrated in a physiologically-based pharmacokinetic (PBPK) model. The developed PBPK model revealed a higher drug exposure for CD patients compared to healthy subjects as observed in vivo, mainly due to differences in drug metabolism and distribution.
The performance of complex formulations in GI disease patients was investigated using a complex GI simulator (TIM-1, TNO). The simulation of dynamic conditions to which a lipid-based formulation of ciprofloxacin is exposed to after oral administration in healthy subjects and CD patients revealed a similar drug performance in this specific case. A delayed and reduced lipid digestion was observed in CD, indicating a possible impact for other drugs.
Overall, this thesis provides a range of in vitro and in silico tools that can be used in combination or separately to identify drugs and formulations at risk of altered performance in patients with GI diseases.
Date of Award19 Feb 2020
Original languageEnglish
Awarding Institution
  • University of Bath
SponsorsEU - Horizon 2020
SupervisorNikoletta Fotaki (Supervisor), Caitriona M. O'Driscoll O'Driscoll (Supervisor), Mark McAllister (Supervisor) & Lorenzo Caggiano (Supervisor)

Keywords

  • Gastrointestinal disease
  • Inflammatory bowel disease
  • Crohn's disease
  • Ulcerative colitis
  • Coeliac disease
  • Dissolution
  • Solubility
  • PBPK modeling

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