Pharmacokinetics/Pharmacodynamics of caspofungin in plasma and peritoneal fluid of liver transplant recipients.

Background: The weaker diffusion of echinocandins in the peritoneal fluid (PF) could promote Candida resistant isolates. The aim of this study was to analyse the pharmacokinetics/pharmacodynamics (PK/PD) of caspofungin in plasma and PF of liver transplant recipients.Methods: Liver transplant patients received caspofungin as postoperative prophylaxis. Caspofungin concentrations were quantified in plasma and in PF on Days 1, 3 and 8. Data were analysed using non-linear mixed-effect modelling and Monte Carlo simulations. Area under curve (AUC) in plasma and PF were simulated under three dosing regimens. Probabilities of target attainment (PTA) were calculated using fAUC0-24/minimal inhibitory concentration (MIC) ratios with MICs ranging from 0.008 to 8 mg/litre. All the patients included were monitored weekly for Candida colonisation and for Candida infections.Results: Twenty patients were included. Median daily dose of caspofungin was 0.81 mg/kg. Plasma (n=395) and peritoneal (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 model produced an effective PK/PD relationship in plasma, achieving a PTA ≥90% and MIC ranging from 0.008 to 0.12 mg/L for C. albicans and glabrata. In PF, PTAs at D8 were only optimal for a MIC of 0.008 in patients weighing 60 kg under the three dosing regimens. Among the 16 patients colonized, all MIC values were below the maximal concentration (Cmax) in plasma but not in PF.Conclusion: Peritoneal concentrations of caspofungin were low. Simulations showed that the PTA for Candida spp. in PF were not optimal, that might suggesting a potential risk of resistance.