众所周知,胃酸度降低,例如伴随酸还原剂的给药,可导致可变的药代动力学和弱碱性药物的吸收减少。重要的是在开发早期识别减少和可变吸收的风险,以便可以考虑解决风险的产品设计选项。本文介绍了利用体外和硅工具来预测胃pH值的影响,以及添加pH调节剂的影响,减轻酸还原剂对弱碱药物溶解和吸收的影响。Palbociclib,一种弱碱性药物,在称为胃肠模拟器(GIS)的多室溶出装置中,在低和高的胃pH条件下进行评价。GIS允许以更好地评估生理相关pH条件下的溶出度的方式对药物产品进行测试。缓冲液浓度,配方添加剂,和生理变化,包括GIpH,缓冲液浓度,分泌物,胃排空率,在GI中的停留时间,和房水的管腔容积。为了预测GIS中的药物溶出度,使用分层传质模型,并使用体外实验数据进行验证.然后使用GastroPlus吸收模型将溶解结果与有和没有质子泵抑制剂的观察到的人类临床血浆数据进行比较,以预测palbociclib血浆谱和药代动力学参数。结果表明,在有和没有pH调节剂的情况下,在低和高胃液pH条件下,计算机模型成功地预测了palbociclib在GIS中的溶解。此外,GIS数据加上计算机工具预期(1)由于质子泵抑制剂共同给药而减少了palbociclib暴露,以及(2)pH调节剂的缓解作用。这项研究提供了工具,以帮助开发口服制剂,以克服胃pH升高的影响,特别是当与pH调节剂配制。
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.