Alasmari Fawaz, Alasmari Mohammed S, Muwainea Hussa Mubarak, Alomar Hatun A, Alasmari Abdullah F, Alsanea Sary, Alshamsan Aws, Rasool Muhammad F, Alqahtani Faleh
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Front Pharmacol. 2023 Jul 20;14:1200828. doi: 10.3389/fphar.2023.1200828. eCollection 2023.
Ceftriaxone is one of commonly prescribed beta-lactam antibiotics with several label and off-label clinical indications. A high fraction of administered dose of ceftriaxone is excreted renally in an unchanged form, and it may accumulate significantly in patients with impaired renal functions, which may lead to toxicity. In this study, we employed a physiologically-based pharmacokinetic (PBPK) modeling, as a tool for precision dosing, to predict the biological exposure of ceftriaxone in a virtually-constructed healthy and chronic kidney disease patient populations, with subsequent dosing optimizations. We started developing the model by integrating the physicochemical properties of the drug with biological system information in a PBPK software platform. A PBPK model in an adult healthy population was developed and evaluated visually and numerically with respect to experimental pharmacokinetic data. The model performance was evaluated based on the fold error criteria of the predicted and reported values for different pharmacokinetic parameters. Then, the model was applied to predict drug exposure in CKD patient populations with various degrees of severity. The developed PBPK model was able to precisely describe the pharmacokinetic behavior of ceftriaxone in adult healthy population and in mild, moderate, and severe CKD patient populations. Decreasing the dose by approximately 25% in mild and 50% in moderate to severe renal disease provided a comparable exposure to the healthy population. Based on the simulation of multiple dosing regimens in severe CKD population, it has been found that accumulation of 2 g every 24 h is lower than the accumulation of 1 g every 12 h dosing regimen. In this study, the observed concentration time profiles and pharmacokinetic parameters for ceftriaxone were successfully reproduced by the developed PBPK model and it has been shown that PBPK modeling can be used as a tool for precision dosing to suggest treatment regimens in population with renal impairment.
头孢曲松是一种常用的β-内酰胺类抗生素，有多种标签注明和未注明的临床适应症。头孢曲松给药剂量的很大一部分以原形经肾脏排泄，在肾功能受损的患者中可能会显著蓄积，这可能导致毒性。在本研究中，我们采用基于生理的药代动力学（PBPK）建模作为精准给药的工具，来预测头孢曲松在虚拟构建的健康和慢性肾脏病患者群体中的生物暴露情况，并随后进行给药优化。我们通过在一个PBPK软件平台中将药物的物理化学性质与生物系统信息相结合来开始构建模型。在成年健康人群中开发了一个PBPK模型，并根据实验药代动力学数据进行了直观和数值评估。基于不同药代动力学参数的预测值和报告值的误差倍数标准对模型性能进行了评估。然后，将该模型应用于预测不同严重程度的慢性肾脏病患者群体中的药物暴露情况。所开发的PBPK模型能够精确描述头孢曲松在成年健康人群以及轻度、中度和重度慢性肾脏病患者群体中的药代动力学行为。轻度肾功能不全患者剂量降低约25%，中度至重度肾功能不全患者剂量降低50%，可使药物暴露情况与健康人群相当。基于对重度慢性肾脏病群体中多种给药方案的模拟，发现每24小时给予2g的蓄积量低于每12小时给予1g的给药方案的蓄积量。在本研究中，所开发的PBPK模型成功再现了头孢曲松的观察到的浓度-时间曲线和药代动力学参数，并且表明PBPK建模可作为精准给药的工具，为肾功能受损人群推荐治疗方案。
