Population Pharmacokinetics of Caspofungin and Dosing Optimization in Children With Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

Caspofungin is the first echinocandin antifungal agent that licented for pediatric use in invasive candidiasis and aspergillosis. In this study, we evaluated the population pharmacokinetics of caspofungin and investigate appropriate dosing optimization against Candida spp. in children with allogeneic hematopoietic stem cell transplantation (allo-HSCT) in order to improve therapeutic efficacy. All participants received a recommended caspofungin 70 mg/m 2 loading dose followed by 50 mg/m 2 maintenance dose. A one-compartment model with first-order elimination was best fitted the data from 48 pediatric patients. Body surface area and aspartate aminotransferase had significant influence on caspofungin clearance from covariate analysis. Our results reviewed that dose adjustment is not necessary in patients with mild liver dysfunction. Monte Carlo simulations were performed using pharmacokinetic data from our study to evaluate the probability of target attainment (PTA) of caspofungin regimen in terms of AUC 24 /MIC targets against Candida spp. The results of simulations predicted that a caspofungin 70 mg/m 2 at first dose, 50 mg/m 2 of daily dose may have a high probability of successful outcome against C. albicans and C. glabrata whilst 60 mg/m 2 maintenance dose was required for fungistatic target against C. parapsilosis but may be not sufficient to achieve optimal fungicidal activity. Caspofungin standard regimen had high probability of successful outcome against C. albicans (MIC ⩽ 0.25 mg/L) and C. glabrata (MIC ⩽ 0.5 mg/L) but insufficient for C. parapsilosis with MIC > 0.25 mg/L. That may provide an evidence based support to caspofungin individualized administration and decrease the risk of therapeutic failure in allo-HSCT pediatric patients.

Development and Quality Control of a Population Pharmacokinetic Model Library for Caspofungin

“…Three studies enrolled a pediatric population between three months and 18 years, while the rest included adults only. Five studies focused on transplant patients, including allogeneic hematopoietic stem cell transplant [ 25 , 32 ], heart transplant [ 29 ], lung transplant [ 30 ], and liver transplant [ 26 ]. While most studies collected only plasma concentrations, Pressiat et al [ 26 ] collected plasma and peritoneal fluid samples.…”

“…All studies incorporated between-subject variability (BSV), with a median of 27.5% (range: 11.8–42.3%) in CL across the 13 studies. Residual unexplained variability was described by proportional [ 11 , 23 , 25 , 26 , 27 , 28 , 31 , 32 , 33 , 34 ], additive [ 12 , 30 ], or combined models [ 29 ]. Proportional errors with coefficients of variation ranged from 12.2% to 36% in eleven studies, while three studies [ 12 , 29 , 30 ] included addictive errors ranging from 0.0941 to 0.73 mg/L.…”

“…All included popPK models conducted internal validation, including goodness-of-fit tests, a visual predictive check, a predicted–corrected visual predictive check, and normalized prediction distribution error plots. Additionally, ten [ 11 , 12 , 25 , 27 , 28 , 29 , 30 , 32 , 33 , 34 ] out of thirteen studies presented results of bootstrap analyses. Würthwein et al [ 28 ] used external validation to further verify their model.…”

“…Ten studies [ 11 , 12 , 23 , 25 , 26 , 27 , 29 , 31 , 33 , 34 ] performed Monte Carlo simulations to evaluate existing dosing regimens or optimize caspofungin therapy, comparing different dosage regimens or evaluating caspofungin PKs and drug interaction in specific patient populations. In nine [ 11 , 12 , 23 , 25 , 26 , 29 , 31 , 33 , 34 ] of these studies, the simulation targeted AUC 0–24 h /MIC as the PK/PD.…”

“…Ten studies [ 11 , 12 , 23 , 25 , 26 , 27 , 29 , 31 , 33 , 34 ] performed Monte Carlo simulations to evaluate existing dosing regimens or optimize caspofungin therapy, comparing different dosage regimens or evaluating caspofungin PKs and drug interaction in specific patient populations. In nine [ 11 , 12 , 23 , 25 , 26 , 29 , 31 , 33 , 34 ] of these studies, the simulation targeted AUC 0–24 h /MIC as the PK/PD. Pressiat et al [ 26 ] concluded that the standard caspofungin dose was sufficient, while five studies [ 11 , 12 , 23 , 29 , 34 ] explicitly advocated for adjusting dosing regimens based on covariates, suggesting higher doses (70–150 mg) considering factors like disease condition, albumin (ALB) levels [ 29 ], fungal colony type, and liver function.…”