Drug co-administration

TIM® Predicts the effect of co-administration of drugs

 

 

About the project

Many patients take multiple medications, making drug–drug interaction (DDI) studies essential and required during clinical drug development. DDIs can affect absorption and exposure of investigational drugs. A key interaction involves acid-reducing agents (ARAs), such as proton pump inhibitors (PPI), which raise gastric pH and can reduce the solubility of weakly basic oral drugs. Early prediction of these effects is challenging but crucial to avoid delays and costly formulation changes. This project used the Tiny-TIM gastrointestinal model to simulate human GI conditions and assess its ability to predict ARA-related absorption effects for representative compounds.

 

Predict the impact of ARAs

tiny-TIM’s was used to predict the impact of acid-reducing agents (ARAs) on oral drug absorption. Twelve development and approved compounds were tested, selected for their known susceptibility to ARAs due to their physicochemical properties. The effect of co-administration was assessed by comparing bioaccessibility under the standard fasted state protocol (gastric pH 3.0–1.5) versus a fasted state + ARA protocol, in which gastric acid secretion (HCl) was omitted to elevate gastric pH, simulating ARA-induced conditions.

Keywords

PPI Drug-Drug Interaction TIM Upper GI

The results

  • tiny-TIM reliably predicted whether or not ARAs impact drug bioavailability, even for salt forms and low doses
  • Scale and directionality of ARA effect was successfully predicted and in agreement with in vivo results
  • In addition to the extent of bioavailability, tiny-TIM was also able to capture the effect of ARA on rate of dissolution
  • The commonly used risk indicator D0 showed limited ability to predict ARA effect for free bases, while tiny-TIM did offer predictive value

tiny-TIM is a very reliable and promising GI model to successfully predict the nature of DDI... 

Liu et al., J. Pharm. Sci. (2021)

Full reference

Liu, J., Nagapudi, K., Dolton, M. J., & Chiang, P. C. (2021). Utilizing Tiny-TIM to Assess the Effect of Acid-Reducing Agents on the Absorption of Orally Administered Drugs. Journal of Pharmaceutical Sciences, 110(8), 3020–3026. https://doi.org/10.1016/j.xphs.2021.04.017

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