Gastrointestinal transfer: in vivo evaluation and implementation in in vitro and in silico predictive tools

The purpose of this study was to explore the transfer of drug solutions from stomach to small intestine and its impact on intraluminal drug concentrations in humans. The collected intraluminal data were used as reference to evaluate simulations of gastrointestinal transfer currently implemented in different in vitro and in silico absorption models.

Gastric and duodenal concentrations of the highly soluble and non-absorbable compound paromomycin were determined following oral administration to 5 healthy volunteers under the following conditions: fasted state, fed state and fed state in the presence of a transit-stimulating (domperidone) or transit-inhibiting (loperamide) agent. Based on the obtained intraluminal concentration-time profiles, gastrointestinal transfer (expressed as the half-life of gastric emptying) was analyzed using physiologically-based parameter estimation in Simcyp®. Subsequently, the observed transfer profiles were used to judge the implementation of gastrointestinal transfer in 2 in vitro simulation tools (the TNO Intestinal Model TIM-1 and a three-compartmental in vitro model) and the Simcyp® population-based PBPK modeling platform.

The observed duodenal concentration-time profile of paromomycin under fasting conditions, with a high average Cmax obtained after 15 min, clearly indicated a fast transfer of drug solutions from stomach to duodenum (estimated gastric half-life between 4 and 13 min). The three-compartmental in vitro model adequately reflected the in vivo fasted state gastrointestinal transfer of paromomycin. For both TIM-1 and Simcyp®, modifications in gastric emptying and dilutions were required to improve the simulation of the transfer of drug solutions. As expected, transfer from stomach to duodenum was delayed in the fed state, resulting in lower duodenal paromomycin concentrations and an estimated gastric half-life between 21 and 40 min. Administration of domperidone or loperamide as transit-stimulating and transit-inhibiting agent, respectively, did not affect the fed state gastric half-life of emptying.

For the first time, the impact of gastrointestinal transfer of solutions on intraluminal drug concentrations was directly assessed in humans. In vitro and in silico simulation tools have been validated and optimized using the in vivo data as reference.