Caspofungin Population Pharmacokinetic Analysis in Plasma and Peritoneal Fluid in Septic Patients with Intra-Abdominal Infections: A Prospective Cohort Study.

Abstract

The aim of this study was to report the pharmacokinetics (PK) of caspofungin in plasma and peritoneal fluid and to identify optimal dosing strategies in septic patients with intra-abdominal infections. Eleven patients with secondary peritonitis with septic shock received the standard dosing regimen of caspofungin. Total caspofungin plasma and peritoneal concentrations were subject to a population PK analysis using Pmetrics®. Monte Carlo simulations were performed considering the ratio of 24-h total drug exposure above the minimum inhibitory concentration (AUC24/MIC) in plasma and comparing simulated concentrations versus MIC in peritoneal fluid. Fat-free mass (FFM) was retained in the final model of caspofungin, reporting a total clearance (standard deviation) of 0.78 (0.17)L/h and a central volume of distribution of 9.36 (2.61)L. The peritoneal fluid/plasma ratio of caspofungin was 33% on the first day of therapy (AUC24 73.92 (21.93) and 26.03 (9.88)mg*h/L for plasma and peritoneal data, respectively). Dosing simulations supported the use of standard dosing regimens for patients with an FFM <50kg for the most susceptible candida species (C. albicans and C. glabrata). For higher FFM, a loading dose of 70 or 100 mg, with a maintenance dose of 70 mg, reached AUC24/MIC ratios for these species. There is moderate penetration of caspofungin into the peritoneal cavity (33%). For empirical treatment, a dose escalation of 100 mg loading dose on the first day is suggested for higher FFM to ensure adequate concentrations into the abdominal cavity for the most susceptible candida species.