背景:卡泊芬净是一种棘白菌素抗真菌药,通常用作侵袭性念珠菌病的一线疗法,侵袭性曲霉病的抢救治疗,和推测的真菌感染的经验性治疗。据报道,卡泊芬净的药代动力学(PK)变化和次优暴露,增加疗效不足的风险。
目的:这项工作旨在开发卡泊芬净群体药代动力学(popPK)文库,并通过评估在不同环境中达到目标的可能性来证明其实用性。
方法:经过严格的文献回顾,我们建立了卡泊芬净popPK模型库,使用rxode2在R中重新实现选定的模型。质量控制程序包括不同研究的比较和评估协变量的影响。模型库主要用于进行蒙特卡洛模拟以估计目标实现并指导念珠菌感染中的个性化给药。
结果:总共13个模型,一个或两个隔间的模型,包括在内。最重要的协变量是体型(体重和体表面积),肝功能,和白蛋白水平。结果表明,儿童和成人在药代动力学方面表现出相当大的差异。对于白色念珠菌和近扁平念珠菌,没有一个人群在各自的易感MIC值下达到≥90%的PTA。相比之下,对于C.glabrata,70%的成人研究达到≥90%的PTA,而所有儿科研究均达到相同的PTA水平。
结论:在推荐剂量下,与儿科患者相比,成年患者的卡泊芬净暴露量明显较低。考虑到车身尺寸,肝功能,在确定卡泊芬净剂量方案时,血清白蛋白至关重要。此外,需要进一步研究以全面了解卡泊芬净在儿科患者体内的药代动力学。
BACKGROUND: Caspofungin is an echinocandin antifungal agent commonly used as the first-line therapy for invasive candidiasis, salvage therapy for invasive aspergillosis, and empirical therapy for presumed fungal infections. Pharmacokinetic (PK) variabilities and suboptimal exposure have been reported for caspofungin, increasing the risk of insufficient efficacy.
OBJECTIVE: This work aimed to develop a caspofungin population pharmacokinetic (popPK) library and demonstrate its utility by assessing the probability of target attainment across diverse settings.
METHODS: We established a caspofungin popPK model library following a rigorous literature review, re-implementing selected models in R with rxode2. Quality control procedures included a comparison of different studies and assessing covariate impacts. Model libraries were primarily used to perform Monte Carlo simulations to estimate target attainment and guide personalized dosing in Candida infections.
RESULTS: A total of 13 models, one- or two-compartment models, were included. The most significant covariates were body size (weight and body surface area), liver function, and albumin level. The results show that children and adults showed considerable differences in pharmacokinetics. For C. albicans and C. parapsilosis, none of the populations achieved a PTA of ≥90% at their respective susceptible MIC values. In contrast, for C. glabrata, 70% of the adult studies reached a PTA of ≥90%, while all pediatric studies achieved the same PTA level.
CONCLUSIONS: At the recommended dosage, adult patients showed notably lower exposure to caspofungin compared to pediatric patients. Considering body size, liver function, and serum albumin is crucial when determining caspofungin dosage regimens. Furthermore, further research is required to comprehensively understand the pharmacokinetics of caspofungin in pediatric patients.