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. Conclusion: 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.

Background: Fluoxetine is widely prescribed to treat depression but exhibits high inter-individual and inter-ethnic pharmacokinetic (PK) variability. Most published population pharmacokinetic (PopPK) models were derived from Western patients, and their applicability to Chinese patients remains uncertain. Methods: A systematic review of the published fluoxetine PopPK models was carried, and the relevant demographic and model parameters were extracted. A retrospective real-world dataset from Chinese psychiatric patients was then collected. External evaluation was conducted to assess the model’s predictive performance. Subsequently, a joint parent–metabolite PopPK model was developed to better characterize fluoxetine and its active metabolite norfluoxetine in Chinese patients. Finally, Monte Carlo simulations were performed to evaluate once-daily dosing regimens of 10–60 mg for 30 days, focusing on the probability of achieving target (PTA) steady-state trough concentrations (C_min,ss). Results: Two published PopPK models were identified and externally evaluated using data from 198 Chinese patients with 241 fluoxetine and 241 norfluoxetine plasma concentrations. Both models were shown to have prediction discrepancy. The parent drug–metabolite model was used to describe the characteristics of fluoxetine and norfluoxetine in the Chinese population. Sex was identified as the significant covariate, and males exhibited a 16.5% higher clearance than females. The simulation results indicate that the maximum effective dose for females is 30 mg once daily, and for males, it is 40 mg once daily. Conclusions: This study provides the first comprehensive external evaluation of published fluoxetine PopPK models and establishes a tailored joint model that incorporates sex effects to explain trough variability in Chinese psychiatric patients. The findings support 30–40 mg once daily as a practical dosing range for Chinese adults and adolescents, with males more likely to require the higher dose.

While caspofungin is increasingly used to treat invasive fungal infections in pediatric intensive care unit (PICU) patients, its pharmacokinetic profile in this population remains poorly understood, and current dosing regimens are not firmly supported by scientific evidence. This study aimed to characterize the population pharmacokinetics of caspofungin in critically ill children and to identify dosing strategies for optimal exposure. The prospective clinical study was conducted among pediatrics in PICU. Population pharmacokinetic analysis and Monte Carlo simulations were performed. A total of 138 plasma samples collected from 29 pediatric patients (0.33–16 years) were included in the final analysis. The two-compartment model with allometric scaling on body surface area (BSA, exponential 1 for volume of distribution and 0.66 for clearance) accurately described time courses of caspofungin. Extracorporeal membrane oxygenation (ECMO) significantly increased the central volume of distribution (effect coefficient 18.2). There was no significant difference in area under the concentration curve (AUC) between patients with and without ECMO support. Simulations demonstrated that tAUC _ss,24h /MIC-based PTA results showed no significant differences between ECMO and non-ECMO groups and supported the current dosing regimen. A fixed maintenance dose (MD) is appropriate for patients with BSA ≥ 1.4 m², while the standard BSA-based MD remains preferable for those with BSA <1.4 m². Our study confirmed the recommended caspofungin dosing regimen in Chinese critically ill PICU patients. Although the number of patients receiving ECMO in this study was limited, future studies with a larger ECMO population are warranted to further validate these findings. This study is registered with ClinicalTrials.gov as NCT04961593.

Caspofungin is an echinocandin antifungal commonly used as the first-line therapy for invasive candidiasis, salvage therapy for invasive aspergillosis. Pharmacokinetic variabilities and suboptimal exposure have been reported for caspofungin, increasing the risk of insufficient efficacy. We aimed to consolidate information from population pharmacokinetic studies, compare model performance, identify significant covariates affecting caspofungin’s PKs, evaluate probability of target attainment in different studies and assemble pharmacokinetic/pharmacodynamic target to address existing knowledge gaps that may warrant further investigation in future. We performed a systematic search strategy to review the PPK studies of caspofungin. Four databases were searched. We extracted information for the comparison of models, evaluation of the impact of covariates on clearance and apparent volume and the calculation of probability of target attainment under specific minimum inhibitory concentration. Thirteen studies were included. The simulation results showed that under labeled dose, pediatrics exhibited notably higher exposure than adults. Body size was the most identified covariate that affected both clearance and volume of distribution. For C. albicans and C. parapsilosis, none of the populations achieved a PTA of ≥ 90%. In contrast, for C. glabrata, 70% of the adult patients reached a PTA of ≥ 90%, while all pediatric patients achieved the same PTA level. At the recommended dosage, adults showed lower exposure to caspofungin compared to pediatrics. It is crucial to consider body size, liver function and serum albumin when determining caspofungin dosage regimens. Furthermore, further research is required to comprehensively understand the pharmacokinetics of caspofungin in pediatrics.