Pharmacokinetics/Pharmacodynamics of Caspofungin in Plasma and Peritoneal Fluid of Liver Transplant Recipients

Abstract

The weaker diffusion of echinocandins in the peritoneal fluid (PF) could promote Candida-resistant isolates. The aim of this study was to analyze the pharmacokinetics (PK)/pharmacodynamics (PD) of caspofungin in plasma and PF samples from liver transplant recipients. Liver transplant patients received caspofungin as postoperative prophylaxis. Caspofungin concentrations were quantified in plasma and PF samples on days 1, 3, and 8. Data were analyzed using nonlinear mixed-effect modeling and Monte Carlo simulations. Area under the curve (AUC) values for plasma and PF were simulated under three dosing regimens. Probabilities of target attainment (PTAs) were calculated using area under the unbound plasma concentration-time curve from 0 to 24 h at steady state (fAUC_0-24)/MIC ratios, with MICs ranging from 0.008 to 8 mg/L. All of the patients included were monitored weekly for Candida colonization and for Candida infections. Twenty patients were included. The median daily dose of caspofungin was 0.81 mg/kg. Plasma (n = 395) and PF (n = 50) concentrations at steady state were available. A two-compartment model with first-order absorption and elimination was described. Our two-compartment model with first-order absorption and elimination produced an effective PK/PD relationship in plasma, achieving a PTA of ≥90% with MICs ranging from 0.008 to 0.12 mg/L for Candida albicans and Candida glabrata. In PF, PTAs at D8 were optimal only for a MIC of 0.008 mg/L in patients weighing 60 kg under the three dosing regimens. Among the 16 patients colonized, all MIC values were below the maximal concentration (C_max) in plasma but not in PF. PF concentrations of caspofungin were low. Simulations showed that the PTAs for Candida spp. in PF were not optimal, which might suggest a potential risk of resistance.

Keywords: Candida; caspofungin; liver transplantation; peritoneal fluid; pharmacodynamics; pharmacokinetics.

FIG 1

Concentration-time curves for caspofungin in plasma (A) and PF (B).

FIG 2

Plasma AUC_0–24 values on D8 for our patients and after Monte Carlo simulations for two regimens, i.e., 70/70 mg and 100/100 mg (loading dose/maintenance dose). The horizontal dotted line represents the mean AUC_0–24 described for ICU patients.

FIG 3

PTAs depending on the dosage used. (A) PTAs for Candida albicans (AUC/MIC of >25.9) in plasma (left) and PF (right) under the two regimens with body weights of 60, 80, and 100 kg. (B) PTAs for Candida glabrata (AUC/MIC of >13.5) in plasma (left) and PF (right) under the two regimens with body weights of 60, 80, and 100 kg. (C) PTAs for Candida parapsilosis (AUC/MIC of >35.5) in plasma (left) and PF (right) under the two regimens with body weights of 60, 80, and 100 kg. 70/50, 70 mg loading dose/50 mg maintenance dose; 70/70, 70 mg loading dose/70 mg maintenance dose; 100/100, 100 mg loading dose/100 mg maintenance dose.