Departments of Pharmaceutical Sciences (Y.F.) and Pharmacy and Therapeutics (T.D.N.), Center of Clinical Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania.
Departments of Pharmaceutical Sciences (Y.F.) and Pharmacy and Therapeutics (T.D.N.), Center of Clinical Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania
J Pharmacol Exp Ther. 2019 Oct;371(1):151-161. doi: 10.1124/jpet.119.257212. Epub 2019 Aug 9.
Erythromycin is a substrate of cytochrome P4503A4 (CYP3A4) and multiple drug transporters. Although clinical evidence suggests that uptake transport is likely to play a dominant role in erythromycin's disposition, the relative contributions of individual pathways are unclear. Phenotypic evaluation of multiple pathways generally requires a probe drug cocktail. This approach can result in ambiguous conclusions due to imprecision stemming from overlapping specificity of multiple drugs. We hypothesized that an individualized physiologically based pharmacokinetic modeling approach incorporating CO production rates (iPBPK-R) of the erythromycin breath test (ERMBT) would enable us to differentiate the contribution of metabolic and transporter pathways to erythromycin disposition. A seven-compartmental physiologically based pharmacokinetic (PBPK) model was built for C-erythromycin administered intravenously. Transporter clearance and CYP3A4 clearance were embedded in hepatic compartments. CO production rates were simulated taking the first derivative of by-product CO concentrations. Parameters related to nonrenal elimination pathways were estimated by model fitting the ERMBT data of 12 healthy subjects individually. Optimized iPBPK-R models fit the individual rate data well. Using one probe, nine PBPK parameters were simultaneously estimated per individual. Maximum velocity of uptake transport, CYP3A4 clearance, total passive diffusion, and others were found to collectively control CO production rates. The median CYP3A4 clearance was 12.2% of the input clearance. Male subjects had lower CYP3A4 activity than female subjects by 11.3%. We applied iPBPK-R to ERMBT data to distinguish and simultaneously estimate the activity of multiple nonrenal elimination pathways in healthy subjects. The iPBPK-R framework is a novel tool for delineating rate-limiting and non-rate-limiting elimination pathways using a single probe. SIGNIFICANCE STATEMENT: Our developed individualized physiologically based pharmacokinetic modeling approach incorporating rate data (iPBPK-R) enabled us to distinguish and simultaneously estimate the activity of multiple nonrenal elimination pathways of erythromycin in healthy subjects. A new interpretation of erythromycin breath test (ERMBT) data was also obtained via iPBPK-R. We found that rate data have rich information allowing estimation of per-person PBPK parameters. This study serves as proof of principle that the iPBPK-R framework is a novel tool for delineating rate-limiting and non-rate-limiting elimination pathways using a single probe. iPBPK-R can be applied to other rate-derived data beyond ERMBT. Potential areas of application include drug-drug interaction, pathophysiological effects on drug disposition, and the role of biomarkers on hemodialysis efficiency utilizing estimated adjustment factors with correlation analysis.
红霉素是细胞色素 P4503A4（CYP3A4）和多种药物转运体的底物。尽管临床证据表明摄取转运可能在红霉素处置中起主导作用，但各途径的相对贡献尚不清楚。多途径的表型评估通常需要探针药物混合物。由于多种药物的特异性重叠导致不精确，这种方法可能会得出模棱两可的结论。我们假设，纳入红霉素呼吸试验（ERMBT）的 CO 产生率（iPBPK-R）的个体化基于生理的药代动力学建模方法将使我们能够区分代谢和转运途径对红霉素处置的贡献。建立了一个七室基于生理的药代动力学（PBPK）模型，用于静脉内给予 C-红霉素。转运体清除率和 CYP3A4 清除率嵌入在肝室中。通过对副产物 CO 浓度的一阶导数模拟 CO 产生率。通过对 12 名健康受试者的 ERMBT 数据进行模型拟合，估计了与非肾消除途径相关的参数。优化的 iPBPK-R 模型很好地拟合了个体速率数据。每个个体同时估计了 9 个 PBPK 参数和 1 个探针。发现摄取转运的最大速度、CYP3A4 清除率、总被动扩散等共同控制 CO 产生率。中位数 CYP3A4 清除率为输入清除率的 12.2%。男性受试者的 CYP3A4 活性比女性受试者低 11.3%。我们将 iPBPK-R 应用于 ERMBT 数据，以区分和同时估计健康受试者中多种非肾消除途径的活性。iPBPK-R 框架是使用单个探针区分限速和非限速消除途径的新工具。意义声明：我们开发的个体化基于生理的药代动力学建模方法，纳入速率数据（iPBPK-R），使我们能够区分和同时估计健康受试者中红霉素的多种非肾消除途径的活性。还通过 iPBPK-R 获得了红霉素呼吸试验（ERMBT）数据的新解释。我们发现速率数据具有丰富的信息，允许估计每个人的 PBPK 参数。这项研究证明了 iPBPK-R 框架是使用单个探针区分限速和非限速消除途径的新工具。iPBPK-R 可应用于 ERMBT 以外的其他源自速率的数据。潜在的应用领域包括药物相互作用、药物处置的病理生理效应以及利用估计的调整因素和相关分析在血液透析效率上的生物标志物作用。
