Department of Pharmacy, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu 222000, China.
Department of Orthopaedics, The Affiliated Jiangyin Clinical College of Xuzhou Medical University, Jiangyin, Jiangsu 214400, China.
Curr Pharm Des. 2024;30(18):1419-1432. doi: 10.2174/0113816128307797240416053723.
Cyclosporin has been used for the treatment of pediatric refractory nephrotic syndrome (PRNS). However, the narrow therapeutic window and large pharmacokinetic variability make it difficult to individualize cyclosporin administration. Meanwhile, spironolactone has been reported to affect cyclosporin metabolism in PRNS patients. This study aims to explore the initial dosage optimization of cyclosporin in PRNS based on the impact of spironolactone co-administration.
Monte Carlo simulation based on a previously established cyclosporin population pharmacokinetic model for PRNS was used to design cyclosporin dosing regimen.
In this study, the probability of drug concentration reaching the target and the convenience of times of administration were considered comprehensively. The optimal administration regimen in PRNS without spironolactone was 6, 5, 4 and 3 mg/kg cyclosporin split into two doses for the body weight of 5-8, 8-18, 18-46 and 46-70 kg, respectively. The optimal administration regimen in PRNS with spironolactone was 4, 3, 2 mg/kg cyclosporin split into two doses for body weight of 5-14, 14-65, and 65-70 kg, respectively.
The cyclosporin dosing regimen for PRNS based on Monte Carlo simulation was systematically developed and the initial dosage optimization of cyclosporin in PRNS was recommended for the first time.
环孢素已被用于治疗小儿难治性肾病综合征（PRNS）。然而，其治疗窗狭窄且药代动力学变异性大，这使得个体化环孢素给药变得困难。同时，有报道称螺内酯会影响 PRNS 患者中环孢素的代谢。本研究旨在探索基于螺内酯联合用药影响的 PRNS 中环孢素的初始剂量优化。
基于之前建立的 PRNS 环孢素群体药代动力学模型进行蒙特卡罗模拟，以设计环孢素给药方案。
本研究综合考虑了药物浓度达到目标的概率和给药次数的便利性。无螺内酯的 PRNS 中，体重为 5-8kg、8-18kg、18-46kg 和 46-70kg 的患儿，分别采用 6、5、4 和 3mg/kg 环孢素，分两次给药，是最佳给药方案。螺内酯的 PRNS 中，体重为 5-14kg、14-65kg 和 65-70kg 的患儿，分别采用 4、3、2mg/kg 环孢素，分两次给药，是最佳给药方案。
本研究系统地开发了基于蒙特卡罗模拟的 PRNS 中环孢素给药方案，并首次推荐了 PRNS 中环孢素的初始剂量优化。
