Dose reduction of Caspofungin in Intensive care unit patients with child Pugh B will result in suboptimal exposure
Martial, Lisa C.; Brüggemann, Roger J. M.; Schouten, Jeroen A.; van Leeuwen, Henk J.; van Zanten, Arthur R.; de Lange, Dylan W.; Muilwijk, Eline W.; Verweij, Paul E.; Burger, David M.; Aarnoutse, Rob E.; Pickkers, Peter; Dorlo, Thomas P. C.
(2016) Clinical Pharmacokinetics, volume 55, issue 6, pp. 723 - 733
(Article)
Abstract
Background and Objectives: Caspofungin is an echinocandin antifungal agent used as first-line therapy for the treatment of invasive candidiasis. The maintenance dose is adapted to body weight (BW) or liver function (Child-Pugh score B or C). We aimed to study the pharmacokinetics of caspofungin and assess pharmacokinetic target attainment for
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various dosing strategies. Methods: Caspofungin pharmacokinetic data from 21 intensive care unit (ICU) patients was available. A population pharmacokinetic model was developed. Various dosing regimens (loading dose/maintenance dose) were simulated: licensed regimens (I) 70/50 mg (for BW 80 kg); and (II) 70/35 mg (for Child-Pugh score B); and adapted regimens (III) 100/50 mg (for Child-Pugh score B); (IV) 100/70 mg; and (V) 100/100 mg. Target attainment based on a preclinical pharmacokinetic target for Candida albicans was assessed for relevant minimal inhibitory concentrations (MICs). Results: A two-compartment model best fitted the data. Clearance was 0.55 L/h and the apparent volumes of distribution in the central and peripheral compartments were 8.9 and 5.0 L, respectively. The median area under the plasma concentration–time curve from time zero to 24 h on day 14 for regimens I–V were 105, 65, 93, 130, and 186 mg·h/L, respectively. Pharmacokinetic target attainment was 100 % (MIC 0.03 µg/mL) irrespective of dosing regimen but decreased to (I) 47 %, (II) 14 %, (III) 36 %, (IV) 69 %, and (V) 94 % for MIC 0.125 µg/mL. Conclusion: The caspofungin maintenance dose should not be reduced in non-cirrhotic ICU patients based on the Child-Pugh score if this classification is driven by hypoalbuminemia as it results in significantly lower exposure. A higher maintenance dose of 70 mg in ICU patients results in target attainment of >90 % of the ICU patients with species with an MIC of up to 0.125 µg/mL.
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Keywords: NCT01533558, caspofungin, adult, aged, area under the curve, article, Candida albicans, Child Pugh score, clinical article, clinical trial, compartment model, dose response, drug dose reduction, drug dose regimen, drug exposure, female, human, intensive care, intensive care unit, invasive candidiasis, loading drug dose, male, minimum inhibitory concentration, plasma concentration-time curve, priority journal
ISSN: 0312-5963
Publisher: Adis International Ltd
(Peer reviewed)