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. 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\u2009=\u20095), B (n\u2009=\u200940), and C (n\u2009=\u20091). On day 5 (steady state), the median and interquartile range for area under the curve from 0 to 24 h (AUC0–24), clearance (CL), and central volume of distribution (V1) 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 AUC0–24 (r\u2009=\u20090.03; P\u2009=\u20090.84), CL (r\u2009=\u2009−0.07; P\u2009=\u20090.68), or V1 (r\u2009=\u20090.19; P\u2009=\u20090.26), but there was a bilirubin-driven negative correlation with the elimination rate constant (r = −0.46; P\u2009=\u20090.004). Hypoalbuminemia correlated with low AUC0–24 (r\u2009=\u20090.45; P\u2009=\u20090.005) and was associated with higher clearance (r = −0.31; P\u2009=\u20090.062) and somewhat higher V1 (r = −0.15; P\u2009=\u20090.37), resulting in a negative correlation with the elimination rate constant (r = −0.34; P\u2009=\u20090.042). For Candida strains with minimal inhibitory concentrations of ≥0.064\u2009μg/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.