J Glob Antimicrob Resist. 2021 Apr 9:S2213-7165(21)00076-X. doi: 10.1016/j.jgar.2021.03.011. Online ahead of print.
BACKGROUND: Effective antifungal therapy is important for reducing the mortality of patients with invasive fungal diseases. Numerous factors affect the pharmacokinetic (PK)/pharmacodynamic (PD) parameters in critically ill patients. To guide the individualized administration of the antifungal drug caspofungin in critically ill patients, it is of great significance to investigate the population pharmacokinetics of caspofungin.
METHODS: A prospective study in 42 intensive care unit (ICU) patients with invasive fungal diseases was conducted in China. A population pharmacokinetic model of caspofungin was established using a nonlinear mixed-effects model, which was utilized to investigate the effects of demographic indices, liver function and kidney function on pharmacokinetics. In addition, the appropriate dosages of caspofungin under various scenarios were determined based on minimum inhibitory concentration (MIC) values and probability of target attainment (PTA) levels at specific dosages.
RESULTS: In critically ill Chinese patients, the clearance (CL), V and area under the curve (AUCss) at steady state of caspofungin were 0.32 L/h, 6.77 L, 135.47 mg•h/L, respectively. Blood albumin level and total bilirubin level were factors that affected CL, while body weight was the only factor that affected V among Chinese people with relatively low weight compared with other populations. A maintenance dose of 50 mg caspofungin achieved a high PTA for treating invasive fungal diseases caused by C. albicans (MIC ≤ 0.06 mg/L) and C. glabrata (MIC ≤ 0.125 mg/L). The maintenance dose of caspofungin should be adjusted to 70-200 mg to treat invasive fungal diseases caused by C. albicans (MIC, 0.06-0.125 mg/L). For invasive fungal diseases caused by C. parapsilosis, MIC greater than 0.03 mg/L is associated with a very low PTA, but whether higher doses of the caspofungin or replaced with other antifungal drugs need to be future studied.
CONCLUSION: The population pharmacokinetic model established in the present study well described the PK/PD characteristics of caspofungin in critically ill Chinese patients. These results could guide the formulation of individualized caspofungin dosing regimens for critically ill patients.