Population pharmacokinetics of caspofungin in critically ill patients receiving extracorporeal membrane oxygenation-an ASAP ECMO study

Abstract

This study aimed to describe the population pharmacokinetics of caspofungin in critically ill patients receiving extracorporeal membrane oxygenation (ECMO) and to identify dosing regimens with a high likelihood of achieving effective exposures. Serial blood samples were collected over a single-dosing interval during ECMO. Total plasma concentrations were measured by a validated chromatographic assay. A population pharmacokinetic model was built and Monte Carlo dosing simulations were performed using Monolix. The probability of target attainment (PTA) and fractional target attainment (FTA) rates were simulated for various caspofungin dosing regimens against Candida albicans, Candida glabrata, and Candida parapsilosis. In all, 64 plasma concentration-time points were obtained from 8 critically ill patients receiving ECMO. Plasma concentration-time data for caspofungin were best described by a one-compartment model with first-order elimination. Lean body weight was identified as a significant covariate of volume of distribution. The typical volume of distribution and clearance of caspofungin in this cohort were 8.13 L and 0.55 L/h, respectively. The licensed caspofungin dosing regimen (a loading dose of 70 mg on day 1 followed by a maintenance dose of either 50 mg/day or 70 mg/day) demonstrated optimal PTA rates (≥90%) against C. albicans with an MIC of ≤0.064 mg/L, C. glabrata with an MIC of ≤0.125 mg/L, and C. parapsilosis with an MIC of ≤0.064 mg/L. The FTA analysis suggested that the licensed dosing regimen is only optimal (≥95%) against Candida glabrata, regardless of lean body weight. A higher-than-standard empirical dosing regimen (e.g., a loading dose of 100 mg on day 1, followed by a maintenance dose of 100 mg daily) is likely advantageous for critically ill patients receiving ECMO.

Keywords: caspofungin; critically ill patients; extracorporeal membrane oxygenation; population pharmacokinetics.

Fig 1

Goodness-of-fit plots associated with the final population pharmacokinetic model for caspofungin in critically ill patients receiving extracorporeal membrane oxygenation. (A) Observed versus population predicted concentrations; (B) observed versus individual predicted concentrations; (C) IWRES versus time; (D) IWRES versus predicted concentrations; (E) NPDE versus time; and (F) NPDE versus population predicted concentrations. The solid red line represents the spline line.

Fig 2

Visual predictive check plot associated with the final population pharmacokinetic model for caspofungin. The circles represent the observed data. The solid black line represents the 50th percentile of the simulated data, and the dashed black lines represent the 5th and 95th percentiles of the simulated data. The shaded areas represent the 95% confidence intervals of the 5th, 50th, and 95th percentiles of the simulated data.

Fig 3

The PTA on Day 2 for simulated caspofungin dosing regimens to achieve AUC_0–24/MIC ratio of ≥450 for Candida glabrata in patients with an LBW of 40 kg, 50 kg, 60 kg, and 80 kg. The dashed black lines denote optimal dosing regimen, that is, achieving ≥90% PTA.

Fig 4

The PTA on Day 2 for simulated caspofungin dosing regimens to achieve AUC_0–24/MIC ratio of ≥865 for Candida albicans in patients with a LBW of 40 kg, 50 kg, 60 kg, and 80 kg. The dashed black lines denote optimal dosing regimen, that is, achieving ≥90% PTA.

Fig 5

The PTA on Day 2 for simulated caspofungin dosing regimens to achieve AUC_0–24/MIC ratio of ≥1,185 for Candida parapsilosis in patients with a LBW of 40 kg, 50 kg, 60 kg, and 80 kg. The dashed black lines denote the optimal dosing regimen, that is, achieving ≥90% PTA.