Population Pharmacokinetic Model and Pharmacokinetic Target Attainment of Micafungin in Intensive Care Unit Patients

Abstract

Objective: To study the pharmacokinetics of micafungin in intensive care patients and assess pharmacokinetic (PK) target attainment for various dosing strategies.

Methods: Micafungin PK data from 20 intensive care unit patients were available. A population-PK model was developed. Various dosing regimens were simulated: licensed regimens (I) 100 mg daily; (II) 100 mg daily with 200 mg from day 5; and adapted regimens 200 mg on day 1 followed by (III) 100 mg daily; (IV) 150 mg daily; and (V) 200 mg daily. Target attainment based on a clinical PK target for Candida as well as non-Candida parapsilosis infections was assessed for relevant minimum inhibitory concentrations [MICs] (Clinical and Laboratory Standards Institute). Parameter uncertainty was taken into account in simulations.

Results: A two-compartment model best fitted the data. Clearance was 1.10 (root square error 8%) L/h and V ₁ and V ₂ were 17.6 (root square error 14%) and 3.63 (root square error 8%) L, respectively. Median area under the concentration-time curve over 24 h (interquartile range) on day 14 for regimens I-V were 91 (67-122), 183 (135-244), 91 (67-122), 137 (101-183) and 183 (135-244) mg h/L, respectively, for a typical patient of 70 kg. For the MIC/area under the concentration-time curve >3000 target (all Candida spp.), PK target attainment was >91% on day 14 (MIC 0.016 mg/L epidemiological cut-off) for all of the dosing regimens but decreased to (I) 44%, (II) 91%, (III) 44%, (IV) 78% and (V) 91% for MIC 0.032 mg/L. For the MIC/area under the concentration-time curve >5000 target (non-C. parapsilosis spp.), PK target attainment varied between 62 and 96% on day 14 for MIC 0.016.

Conclusions: The licensed micafungin maintenance dose results in adequate exposure based on our simulations with a clinical PK target for Candida infections but only 62% of patients reach the target for non-C. parapsilosis. In the case of pathogens with an attenuated micafungin MIC, patients may benefit from dose escalation to 200 mg daily. This encourages future study.

Keywords: Intensive Care Unit Patient; Invasive Candidiasis; Micafungin; Sequential Organ Failure Assessment; Sequential Organ Failure Assessment Score.

Fig. 1

Area under the concentration–time curve (AUC) over 24 h on day 14 based on Monte-Carlo simulations. The horizontal line represents the AUC over 24 h for healthy volunteers. Licensed regimens, I 100 mg daily (QD) and II 100 mg QD followed by 200 mg QD from day 5. Alternative regimens, III a 200-mg loading dose followed by 100 mg maintenance; IV a 200-mg loading dose followed by 150 mg maintenance; and V 200 mg QD

Fig. 2

Predicted target attainment at day 3 vs. minimal inhibitory concentration (MIC) for all five simulated regimens based on a clinical target area under the concentration–time curve over 24 h/MIC ratio of ≥3000 (valid for all Candida spp.). Bars represent the wild-type population distribution of Candida albicans for micafungin, as gathered from [22]

Fig. 3

Predicted target attainment at day 3 vs. minimal inhibitory concentration (MIC) for all five simulated regimens based on a clinical target area under the concentration–time curve over 24 h/MIC ratio of ≥5000 (valid for non-Candida parapsilosis spp.). Bars represent the wild-type population distribution of Candida albicans for micafungin, as gathered from [22]