Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Department of Clinical Pharmacy, Jining No. 2 People's Hospital, Jining, China.
J Antimicrob Chemother. 2024 Oct 1;79(10):2678-2687. doi: 10.1093/jac/dkae276.
The optimal dosing regimen of caspofungin in adolescents undergoing allogeneic haematopoietic stem cell transplantation against Candida spp. is unknown. The study aimed to compare body surface area (BSA)-based and fixed dosing regimens through population pharmacokinetic (PPK) analysis and to optimize dosing regimens likely to achieve therapeutic exposures.
Opportunistic sampling was used to collect plasma concentrations through a prospective observational pharmacokinetic study. PPK analysis and Monte Carlo simulations (n = 1000) were performed using NONMEM.
A total of 86 samples of 30 adolescents (12-17 years old) were best described by a two-compartment pharmacokinetic model. BSA is the only covariate on clearance and central volume of distribution. For Candida glabrata and Candida albicans, a standard dosing regimen could achieve at least a 90% probability of target attainment for the indicator of AUC0-24/MIC90. Dosing regimen simulations identified a BSA cut-off value of 1.3 m2, where a fixed loading dose (LD) is preferred when BSA ≥ 1.3 m2 and a BSA-based LD is preferred when BSA < 1.3 m2. For maintenance dose (MD), however, the BSA-based dose was proposed, regardless of BSA. The current maximum dosing regimen of LD 70 mg/day and MD 70 mg/day could not result in sufficient antifungal exposure for Candida parapsilosis with MIC90 of 1 mg/L. Furthermore, an LD of 70 mg/day and MD of 60 mg/m2/day rendered 90.4% steady-state trough concentration (Ctrough) over 1 mg/L in the virtual population.
Our study proposed optimized dosing regimens of caspofungin based on AUC0-24/MIC90 or Ctrough, which may support further individualized treatment.
异体造血干细胞移植患者抗念珠菌治疗中卡泊芬净的最佳剂量方案尚不清楚。本研究旨在通过群体药代动力学（PPK）分析比较体表面积（BSA）剂量方案和固定剂量方案，并优化可能达到治疗暴露的剂量方案。
采用前瞻性观察性药代动力学研究，通过机会抽样采集血浆浓度。采用 NONMEM 进行 PPK 分析和蒙特卡罗模拟（n=1000）。
共采集了 30 例青少年（12-17 岁）的 86 个样本，最适合用双室药代动力学模型描述。BSA 是清除率和中央分布容积的唯一协变量。对于光滑念珠菌和白念珠菌，标准剂量方案可使 AUC0-24/MIC90 指标的达标概率至少达到 90%。剂量方案模拟确定了 BSA 截断值为 1.3 m2，BSA≥1.3 m2 时，首选固定负荷剂量（LD），BSA<1.3 m2 时，首选 BSA 为基础的 LD。然而，对于维持剂量（MD），建议使用基于 BSA 的剂量，无论 BSA 如何。目前，LD 70mg/天和 MD 70mg/天的最大剂量方案不能为 MIC90 为 1mg/L 的近平滑念珠菌提供足够的抗真菌暴露。此外，LD 70mg/天和 MD 60mg/m2/天的方案使虚拟人群中的 90.4%稳态谷浓度（Ctrough）超过 1mg/L。
本研究提出了基于 AUC0-24/MIC90 或 Ctrough 的卡泊芬净优化剂量方案，这可能为进一步的个体化治疗提供支持。
