Dose Reduction of Caspofungin in Intensive Care Unit Patients with Child Pugh B Will Result in Suboptimal Exposure


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 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) 7050 mg (for BW <80 kg) or 7070 mg (for BW <80 kg); and (II) 7035 mg (for Child-Pugh score B); and adapted regimens (III) 10050 mg (for Child-Pugh score B); (IV) 10070 mg; and (V) 100100 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 24h on day 14 for regimens I-V were 105, 65, 93, 130, and 186 mg*h/L, respectively. Pharmacokinetic target attainment was 100% (MIC 0.03ug/mL) irrespective of dosing regimen but decreased to (I) 47%, (II) 14%, (III) 36%, (IV) 69%, and (V) 94% for MIC 0.125ug/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 ug/mL.

Clinical Pharmacokinetics