Department of Pharmaceutical Sciences, Center for Clinical Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania, USA.
Department of Pharmacy and Therapeutics, Center for Clinical Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania, USA.
J Clin Pharmacol. 2021 Jun;61(6):769-781. doi: 10.1002/jcph.1818. Epub 2021 Feb 16.
The aim of this study was to apply individualized, physiologically based pharmacokinetic modeling of CO production rates (iPBPK-R) measured by the erythromycin breath test to characterize the effect of hemodialysis on the function of nonrenal clearance pathways in patients with end-stage renal disease. Twelve patients previously received C-erythromycin intravenously pre- and post-hemodialysis. Serial breath samples were collected after each dose over 2 hours. Eight PBPK parameters were co-estimated across periods, whereas activity of cytochrome P450 (CYP) 3A4 clearance was independently estimated for each period. Inhibition coefficients for organic anion transporting polypeptide (OATP), P-glycoprotein, and multidrug resistance-associated protein 2 activities were also estimated. Nonrenal clearance parameter estimates were explored regarding sex differences and correlations with uremic toxins and were used in hierarchical cluster analysis (HCA). Relationships between the function of nonrenal clearance pathways and uremic toxin concentrations were explored. Mean CYP 3A4 clearance increased by 2.2% post-hemodialysis. Uptake transporter activity was highly intervariable across hemodialysis. Females had 22% and 30% higher median CYP3A4 activity than males pre- and post-hemodialysis, respectively. Exploratory HCA indicated that using both CYP3A4 and OATP activity parameters at pre- and post-hemodialysis best identifies heterogeneous patients. This is the first study to use the iPBPK-R approach to simultaneously estimate multiple in vivo nonrenal elimination pathways in individual patients with kidney disease and to assess the effect of hemodialysis.
本研究旨在应用基于生理的个体化药代动力学模型（iPBPK-R）来测量红霉素呼气试验中 CO 生成率，以描述血液透析对终末期肾病患者非肾清除途径功能的影响。12 例患者先前接受过静脉内 C-红霉素，在血液透析前后进行。每次给药后 2 小时内连续采集呼吸样本。8 个 PBPK 参数在各时期共同估算，而细胞色素 P450（CYP）3A4 清除率则分别在各时期独立估算。有机阴离子转运多肽（OATP）、P-糖蛋白和多药耐药相关蛋白 2 活性的抑制系数也被估算。还探讨了非肾清除参数估计值与性别差异的相关性，以及与尿毒症毒素的相关性，并用于层次聚类分析（HCA）。探讨了非肾清除途径的功能与尿毒症毒素浓度之间的关系。血液透析后 CYP3A4 清除率平均增加 2.2%。血液透析过程中摄取转运体活性存在高度的变异性。女性在血液透析前后的 CYP3A4 活性中位数分别比男性高 22%和 30%。探索性 HCA 表明，在血液透析前后同时使用 CYP3A4 和 OATP 活性参数可以更好地识别异质性患者。这是第一项应用 iPBPK-R 方法同时估计个体肾病患者多种体内非肾消除途径，并评估血液透析效果的研究。
