Use of Gastrointestinal Simulator, Mass Transport Analysis, and Absorption Simulation to Investigate the Impact of pH Modifiers in Mitigating Weakly Basic Drugs' Performance Issues Related to Gastric pH: Palbociclib Case Study.

Abstract

It is well known that reduced gastric acidity, for example with concomitant administration of acid reducing agents, can result in variable pharmacokinetics and decreased absorption of weakly basic drugs. It is important to identify the risk of reduced and variable absorption early in development, so that product design options to address the risk can be considered. This article describes the utilization of in vitro and in silico tools to predict the effect of gastric pH, as well as the impact of adding pH modifiers, in mitigating the effect of acid reducing agents on weak base drugs' dissolution and absorption. Palbociclib, a weakly basic drug, was evaluated in low and high gastric pH conditions in a multicompartmental dissolution apparatus referred to as a gastrointestinal simulator (GIS). The GIS permits the testing of pharmaceutical products in a way that better assesses dissolution under physiologically relevant conditions of pH, buffer concentration, formulation additives, and physiological variations including GI pH, buffer concentrations, secretions, stomach emptying rate, residence time in the GI, and aqueous luminal volume. To predict drug dissolution in the GIS, a hierarchical mass transport model was used and validated using in vitro experimental data. Dissolution results were then compared to observed human clinical plasma data with and without proton pump inhibitors using a GastroPlus absorption model to predict palbociclib plasma profiles and pharmacokinetic parameters. The results showed that the in silico model successfully predicted palbociclib dissolution in the GIS under low and high gastric pH conditions with and without pH modifiers. Furthermore, the GIS data coupled with the in silico tools anticipated (1) the reduced palbociclib exposure due to proton pump inhibitor coadministration and (2) the mitigating effect of a pH-modifying agent. This study provides tools to help in the development of orally administered formulations to overcome the effect of elevated gastric pH, especially when formulating with pH modifiers.