Clinical Pharmacy, Saarland University, Campus C2 2, 66123, Saarbrücken, Germany.
Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, USA.
Pharm Res. 2020 Nov 25;37(12):250. doi: 10.1007/s11095-020-02964-z.
To provide whole-body physiologically based pharmacokinetic (PBPK) models of the potent clinical organic anion transporter (OAT) inhibitor probenecid and the clinical OAT victim drug furosemide for their application in transporter-based drug-drug interaction (DDI) modeling.
PBPK models of probenecid and furosemide were developed in PK-Sim®. Drug-dependent parameters and plasma concentration-time profiles following intravenous and oral probenecid and furosemide administration were gathered from literature and used for model development. For model evaluation, plasma concentration-time profiles, areas under the plasma concentration-time curve (AUC) and peak plasma concentrations (C) were predicted and compared to observed data. In addition, the models were applied to predict the outcome of clinical DDI studies.
The developed models accurately describe the reported plasma concentrations of 27 clinical probenecid studies and of 42 studies using furosemide. Furthermore, application of these models to predict the probenecid-furosemide and probenecid-rifampicin DDIs demonstrates their good performance, with 6/7 of the predicted DDI AUC ratios and 4/5 of the predicted DDI C ratios within 1.25-fold of the observed values, and all predicted DDI AUC and C ratios within 2.0-fold.
Whole-body PBPK models of probenecid and furosemide were built and evaluated, providing useful tools to support the investigation of transporter mediated DDIs.
构建强效临床有机阴离子转运体（OAT）抑制剂丙磺舒和临床 OAT 底物药物呋塞米的全身体生理药代动力学（PBPK）模型，以便将其应用于基于转运体的药物相互作用（DDI）模型中。
在 PK-Sim®中开发了丙磺舒和呋塞米的 PBPK 模型。从文献中收集了丙磺舒和呋塞米静脉注射和口服给药后的药物依赖性参数和血浆浓度-时间曲线下面积（AUC）以及峰浓度（C），并用于模型开发。为了进行模型评估，预测并比较了血浆浓度-时间曲线、AUC 和 C 的预测值与观察值。此外，还应用这些模型预测了临床 DDI 研究的结果。
所开发的模型准确描述了 27 项丙磺舒临床研究和 42 项呋塞米研究的报告血浆浓度。此外，将这些模型应用于预测丙磺舒-呋塞米和丙磺舒-利福平的 DDI 表明其具有良好的性能，6/7 的预测 DDI AUC 比值和 4/5 的预测 DDI C 比值在观察值的 1.25 倍以内，所有预测的 DDI AUC 和 C 比值均在 2.0 倍以内。
构建并评估了丙磺舒和呋塞米的全身体 PBPK 模型，为研究转运体介导的 DDI 提供了有用的工具。
