Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (S.N.S., F.O.C., D.G.); School of Pharmacy, University of Waterloo, Kitchener, ON, Canada (A.N.E.); Duke Clinical Research Institute, Durham, NC, USA (M.C.-W.); Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina (M.C.-W.).
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (S.N.S., F.O.C., D.G.); School of Pharmacy, University of Waterloo, Kitchener, ON, Canada (A.N.E.); Duke Clinical Research Institute, Durham, NC, USA (M.C.-W.); Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina (M.C.-W.)
Drug Metab Dispos. 2021 Sep;49(9):844-855. doi: 10.1124/dmd.120.000318. Epub 2021 Jun 21.
Solithromycin is a novel fluoroketolide antibiotic that is both a substrate and time-dependent inhibitor of CYP3A. Solithromycin has demonstrated efficacy in adults with community-acquired bacterial pneumonia and has also been investigated in pediatric patients. The objective of this study was to develop a framework for leveraging physiologically based pharmacokinetic (PBPK) modeling to predict CYP3A-mediated drug-drug interaction (DDI) potential in the pediatric population using solithromycin as a case study. To account for age, we performed in vitro metabolism and time-dependent inhibition studies for solithromycin for CYP3A4, CYP3A5, and CYP3A7. The PBPK model included CYP3A4 and CYP3A5 metabolism and time-dependent inhibition, glomerular filtration, P-glycoprotein transport, and enterohepatic recirculation. The average fold error of simulated and observed plasma concentrations of solithromycin in both adults (1966 plasma samples) and pediatric patients from 4 days to 17.9 years (684 plasma samples) were within 0.5- to 2.0-fold. The geometric mean ratios for the simulated area under the concentration versus time curve (AUC) extrapolated to infinity were within 0.75- to 1.25-fold of observed values in healthy adults receiving solithromycin with midazolam or ketoconazole. DDI potential was simulated in pediatric patients (1 month to 17 years of age) and adults. Solithromycin increased the simulated midazolam AUC 4- to 6-fold, and ketoconazole increased the simulated solithromycin AUC 1- to 2-fold in virtual subjects ranging from 1 month to 65 years of age. This study presents a systematic approach for incorporating CYP3A in vitro data into adult and pediatric PBPK models to predict pediatric CYP3A-mediated DDI potential. SIGNIFICANCE STATEMENT: Using solithromycin, this study presents a framework for investigating and incorporating CYP3A4, CYP3A5, and CYP3A7 in vitro data into adult and pediatric physiologically based pharmacokinetic models to predict CYP3A-mediated DDI potential in adult and pediatric subjects during drug development. In this study, minor age-related differences in inhibitor concentration resulted in differences in the magnitude of the DDI. Therefore, age-related differences in DDI potential for substrates metabolized primarily by CYP3A4 can be minimized by closely matching adult and pediatric inhibitor concentrations.
索利霉素是一种新型氟酮内酯类抗生素，同时也是 CYP3A 的底物和时间依赖性抑制剂。索利霉素已被证明对成人社区获得性细菌性肺炎有效，也已在儿科患者中进行了研究。本研究的目的是建立一个框架，利用基于生理学的药代动力学（PBPK）模型来预测儿科人群中 CYP3A 介导的药物相互作用（DDI）潜力，以索利霉素作为案例研究。为了考虑年龄因素，我们对索利霉素进行了 CYP3A4、CYP3A5 和 CYP3A7 的体外代谢和时间依赖性抑制研究。该 PBPK 模型包括 CYP3A4 和 CYP3A5 代谢和时间依赖性抑制、肾小球滤过、P-糖蛋白转运和肠肝循环。在成人（1966 个血浆样本）和 4 天至 17.9 岁的儿科患者（684 个血浆样本）中，模拟和观察到的索利霉素血浆浓度的平均倍差在 0.5 到 2.0 倍之间。接受索利霉素与咪达唑仑或酮康唑治疗的健康成年人的模拟 AUC 与时间曲线下面积（AUC）的几何均值比值在观察值的 0.75 到 1.25 倍之间。在 1 个月至 17 岁的儿科患者和成人中模拟了 DDI 潜力。在 1 个月至 65 岁的虚拟受试者中，索利霉素使模拟咪达唑仑 AUC 增加了 4 到 6 倍，酮康唑使模拟索利霉素 AUC 增加了 1 到 2 倍。本研究提出了一种将 CYP3A 体外数据纳入成人和儿科 PBPK 模型的系统方法，以预测儿科 CYP3A 介导的 DDI 潜力。 意义声明：本研究使用索利霉素，提出了一种框架，用于研究和将 CYP3A4、CYP3A5 和 CYP3A7 的体外数据纳入成人和儿科基于生理学的药代动力学模型，以预测药物开发过程中成人和儿科受试者中 CYP3A 介导的 DDI 潜力。在本研究中，抑制剂浓度的微小年龄相关差异导致 DDI 程度的差异。因此，通过密切匹配成人和儿科抑制剂浓度，可以最小化主要由 CYP3A4 代谢的底物的 DDI 潜力的年龄相关差异。
