Pharmacokinetics of Caspofungin in Critically Ill Patients in Relation to Liver Dysfunction: Differential Impact of Plasma Albumin and Bilirubin Levels

Abstract

Caspofungin has a liver-dependent metabolism. Reduction of the dose is recommended based on Child-Pugh (C-P) score. In critically ill patients, drug pharmacokinetics (PK) may be altered. The aim of this study was to investigate the prevalence of abnormal liver function tests, increased C-P scores, their effects on caspofungin PK, and whether pharmacokinetic-pharmacodynamic (PK/PD) targets were attained in patients with suspected candidiasis. Intensive care unit patients receiving caspofungin were prospectively included. PK parameters were determined on days 2, 5, and 10, and their correlations to the individual liver function tests and the C-P score were analyzed. Forty-six patients were included with C-P class A (n ϭ 5), B (n ϭ 40), and C (n ϭ 1). On day 5 (steady state), the median and interquartile range for area under the curve from 0 to 24 h (AUC 0 -24 ), clearance (CL), and central volume of distribution (V 1 ) were 57.8 (51.6 to 69.8) mg·h/liter, 0.88 (0.78 to 1.04) liters/h, and 11.9 (9.6 to 13.1) liters, respectively. The C-P score did not correlate with AUC 0 -24 (r ϭ 0.03; P ϭ 0.84), CL (r ϭ Ϫ0.07; P ϭ 0.68), or V 1 (r ϭ 0.19; P ϭ 0.26), but there was a bilirubin-driven negative correlation with the elimination rate constant (r ϭ Ϫ0.46; P ϭ 0.004). Hypoalbuminemia correlated with low AUC 0 -24 (r ϭ 0.45; P ϭ 0.005) and was associated with higher clearance (r ϭ Ϫ0.31; P ϭ 0.062) and somewhat higher V 1 (r ϭ Ϫ0.15; P ϭ 0.37), resulting in a negative correlation with the elimination rate constant (r ϭ Ϫ0.34; P ϭ 0.042). For Candida strains with minimal inhibitory concentrations of Ն0.064 g/ml, PK/PD targets were not attained in all patients. The caspofungin dose should not be reduced in critically ill patients in the absence of cirrhosis, and we advise against the use of the C-P score in patients with trauma-or sepsis-induced liver injury.

Caspofungin Weight-Based Dosing Supported by a Population Pharmacokinetic Model in Critically Ill Patients

“…3), and data from Muilwijk et al showed a fit of r ϭ 0.83 ( Fig. S1) (7,13). The normalized prediction distribution error (NPDE) plots are presented in Fig.…”

“…The prediction-and variability-corrected visual predictive checks (pcVPCs) were done to evaluate the performance of the final population pharmacokinetic model (32). The model was validated with two external digitized data sets from caspofungin pharmacokinetic studies on critically ill patients (7,13). The data were digitized using WebPlotDigitizer (https://automeris.io/WebPlotDigitizer/), and a uniform distribution was used to sample random numbers from the weight range reported in the publication.…”

Challenges in Antifungal Therapy in Diabetes Mellitus

“…This observation indicated that higher unbound voriconazole concentrations is associated with decreasing albumin concentrations. Kurland et al [ 23 ], on the other hand, found that hypoalbuminemia in critically ill patients was associated with higher caspofungin clearance ( r = −0.31; p = 0.062).…”

Commentary: Recommendation of Antimicrobial Dosing Optimization During Continuous Renal Replacement Therapy

“…Other pharmacokinetic modifications than CRRT may impact antimicrobial concentrations, as fluid balance variability, protein binding modifications and hepatic function. This may impact the PK-PD target attainment (Ulldemolins et al, 2011;Lewis and Mueller, 2014;Vanstraelen et al, 2014;Kurland et al, 2019). Some studies consider total antimicrobial concentration instead of active unbound concentration without possible interpretation of the target attainment (Roberts et al, 2013).…”