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Pharmacokinetics of Caspofungin in Critically Ill Patients in Relation to Liver Dysfunction: Differential Impact of Plasma Albumin and Bilirubin Levels
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
Karolinska Inst, Karolinska Univ Hosp, Dept Lab Med, Clin Pharmacol, Stockholm, Sweden.
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2019 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 63, no 6, article id e02466-18Article in journal (Refereed) Published
Abstract [en]

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 = 5), B (n = 40), and C (n = 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 = 0.03; P = 0.84), CL (r = -0.07; P = 0.68), or V-1 (r = 0.19; P = 0.26), but there was a bilirubin-driven negative correlation with the elimination rate constant (r = -0.46; P = 0.004). Hypoalbuminemia correlated with low AUC(0-24) (r = 0.45; P = 0.005) and was associated with higher clearance (r = -0.31; P = 0.062) and somewhat higher V-1 (r = -0.15; P = 0.37), resulting in a negative correlation with the elimination rate constant (r = -0.34; P = 0.042). For Candida strains with minimal inhibitory concentrations of >= 0.064 mu 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.

Place, publisher, year, edition, pages
AMER SOC MICROBIOLOGY , 2019. Vol. 63, no 6, article id e02466-18
Keywords [en]
Child-Pugh score, caspofungin, critically ill, pharmacokinetics
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-386442DOI: 10.1128/AAC.02466-18ISI: 000468935100054PubMedID: 30962329OAI: oai:DiVA.org:uu-386442DiVA, id: diva2:1330376
Funder
Stockholm County Council, ALF20160331Available from: 2019-06-25 Created: 2019-06-25 Last updated: 2019-06-25Bibliographically approved

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Kurland, SiriFurebring, MiaLöwdin, ElisabethNielsen, Elisabet I.Sjölin, Jan

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Kurland, SiriFurebring, MiaLöwdin, ElisabethNielsen, Elisabet I.Sjölin, Jan
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