Nonstationary Pharmacokinetics of Caspofungin in ICU Patients

Abstract

Standard dosing of caspofungin in critically ill patients has been reported to result in lower drug exposure, which can lead to subtherapeutic AUC0–24/MIC ratios. The aim of the study was to investigate the population pharmacokinetics of caspofungin in a cohort of 30 ICU patients with a suspected invasive fungal infection, with a large proportion of patients requiring extracorporeal therapies including ECMO and CRRT. Caspofungin was administered as empirical antifungal therapy 70 mg i.v. on the first day and 50 mg i.v. on the consecutive days once daily and the concentrations were measured after 3 subsequent doses. Population pharmacokinetic data were analysed by nonlinear mixed-effects modeling. The pharmacokinetics of caspofungin was described by 2-compartment model. A particular drift of individual CL and V1 values with time was discovered and described by including three separate typical values of CL and V1 in the final model. The typical CL values at day one, two and three were 0.563 L/h (6.7 %RSE), 0.737 L/h (6.1 %RSE) and 1.01 L/h (9.1 %RSE), respectively. The change in parameters with time was not explained by any of the recorded covariates. Increasing clearance with subsequent doses was associated with a clinically relevant decrease in caspofungin exposure (>20%). The use of ECMO, CRRT, albumin concentration, and other covariates did not significantly affect caspofungin pharmacokinetics. Additional pharmacokinetic studies are urgently required to assess the possible lack of acquiring steady-state and suboptimal concentrations of the drug in critically ill patients.

Population Pharmacokinetics of Caspofungin and Dose Simulations in Heart Transplant Recipients

“…Märtson et al ( 25 ) proposed a weight-based dose regimen for caspofungin. However, several other studies ( 26 , 31 – 33 ) have found no significant effect of weight on the pharmacokinetic parameters of caspofungin, similar to our research. Our study had a small sample size and a small range of changes in body weight.…”

New Formulations Loading Caspofungin for Topical Therapy of Vulvovaginal Candidiasis

“…This is essential for fungal infections because fungi, mainly Candida spp., colonize the mucosal surface [ 67 ]. Therefore, a certain degree of permeation and retention of the drug in the tissue is necessary without reaching or exceeding systemic therapeutic levels, C min = 3.55 µg/mL and C max = 11.73 µg/mL [ 68 , 69 , 70 ]. Porcine and human vaginal mucosas are substantially similar.…”

“…The calculated permeation kinetics parameters and CSP retained amount are reported in Table 4 . Taking into account an application surface area of 62.8 cm 2 for the vaginal cavity [ 74 ], and a plasmatic clearance ( Cl p ) of 0.55 L/h [ 68 , 69 , 70 ], the theoretical human plasmatic steady-state concentration ( Cl ss ) that CSP would achieve was also calculated, being 1.65 ± 0.01 μg/mL, 0.95 ± 0.22 μg/mL and 1.43 ± 0.12 μg/mL for CSP-CTS, CSP-P407 and CSP-CTS/P407, respectively. Therefore, no systemic side effects related to the use of CSP are expected.…”

“…The predicted drug steady-state plasma concentration (C ss , μg/mL) that would penetrate after topical application was calculated using the equation: C ss = J × A/Cl p where C ss is the plasma steady-state concentration, J the flux determined in this study, A the hypothetical area of application (62.8 cm 2 ) and Cl p the plasmatic clearance (0.55 L/h) [ 68 , 69 , 70 ].…”

Effects of ex vivo Extracorporeal Membrane Oxygenation Circuits on Sequestration of Antimicrobial Agents

“…A case report (22) observed that the standard dose of caspofungin failed to reach the target plasma concentration level during ECMO support. However, other in vivo studies (23)(24)(25) have suggested that ECMO does not affect the pharmacokinetic characteristics of caspofungin. Caspofungin is hydrophilic (log P −2.798) but has a high protein binding rate (97%), which may lead to significant differences in its recovery in different types of ECMO circuits.…”