胃酸异常,包括氨水,可以作为一个重要的来源的变异性在口服药物,特别是与pH敏感的溶解度曲线,比如弱碱,可能导致不良的治疗反应。这项研究旨在评估基于生理的药代动力学(PBPK)模型在通过使用伊曲康唑预测胃pH介导的药物暴露中的实用性,一个薄弱的基础,作为一个案例。伊曲康唑PBPK模型是在其吸收动力学的机理基础上从逐步的体内外推至体内精制的中间方式开发的。之后,我们进行了一项独立的前瞻性临床研究,评估在正常胃酸和埃索美拉唑诱导的胃酸量减少条件下的胃pH和伊曲康唑药代动力学(PKs),以进行模型验证.通过将预测数据与临床观察结果进行比较来进行验证。随后将有效的模型应用于预测氯氢化作用下的PK变化。开发的伊曲康唑PBPK模型对临床研究中观察到的胃pH介导的暴露显示出合理的可重复性。根据基于模型的模拟,伊曲康唑的暴露预计将减少高达65%,而且,胃pH介导的暴露可以根据总溶解度的顺序变化进行机械解释,溶出度,和吸收。这项研究表明PBPK模型在预测胃pH介导的暴露中的实用性,特别是对于吸收易受胃pH值影响的药物。我们的研究结果将作为一种领先的模型,用于根据各种药物的胃pH值对暴露进行进一步的机械评估。最终有助于个性化药物治疗。
Abnormal gastric acidity, including
achlorhydria, can act as a significant source of variability in orally administered drugs especially with pH-sensitive solubility profiles, such as weak bases, potentially resulting in an undesirable therapeutic response. This study aimed to evaluate the utility of physiologically-based pharmacokinetic (PBPK) modeling in the prediction of gastric pH-mediated drug exposure by using itraconazole, a weak base, as a case. An itraconazole PBPK model was developed on the mechanistic basis of its absorption kinetics in a middle-out manner from a stepwise in vitro-in vivo extrapolation to in vivo refinement. Afterward, an independent prospective clinical study evaluating gastric pH and itraconazole pharmacokinetics (PKs) under normal gastric acidity and esomeprazole-induced gastric hypoacidity was conducted for model validation. Validation was performed by comparing the predicted data with the clinical observations, and the valid model was subsequently applied to predict PK changes under
achlorhydria. The developed itraconazole PBPK model showed reasonable reproducibility for gastric pH-mediated exposure observed in the clinical investigation. Based on the model-based simulations, itraconazole exposure was expected to be decreased up to 65% under
achlorhydria, and furthermore, gastric pH-mediated exposure could be mechanistically interpreted according to sequential variation in total solubility, dissolution, and absorption. This study suggested the utility of PBPK modeling in the prediction of gastric pH-mediated exposure, especially for drugs whose absorption is susceptible to gastric pH. Our findings will serve as a leading model for further mechanistic assessment of exposure depending on gastric pH for various drugs, ultimately contributing to personalized pharmacotherapy.