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

Abstract

ObjectiveTo study the pharmacokinetics of micafungin in intensive care patients and assess pharmacokinetic (PK) target attainment for various dosing strategies.MethodsMicafungin 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.ResultsA 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.ConclusionsThe 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-017-0509-5) contains supplementary material, which is available to authorized users.

Pharmacokinetics and probability of target attainment for micafungin in normal-weight and morbidly obese adults

“…A two-compartment model with first order elimination best described the micafungin plasma concentrations, which is in line with previous reports. 5,12,[18][19][20] In our study, body weight was the size descriptor best explaining the inter-individual variability in clearance, where individual clearance (in L/h) is predicted using the power function 0.69 * (weight / 70) 0.74 . This relation is supported by previously reported clearances in normal-weight healthy subjects.…”

“…These patients show an increased micafungin clearance and an augmented dose of 200 mg has been proposed previously. 12,20 In obese critically ill patients, a significant lower probability of target attainment was reported compared to normal-weight critically ill patients. 19 Although a 300 mg dose was not investigated in this study, this should be considered in critically ill obese patients, if possible under the guidance of therapeutic drug monitoring.…”

“…Micafungin plasma concentrations were quantified using a validated ultra performance liquid chromatography with fluorescence detection and a range in plasma of 0.01 to 32.40 mg/L. This assay has been used for previous reports on micafungin PK [10][11][12] . Before injection, proteins were precipitated using 50% acetonitrile, 50% methanol, and 0.1% formic acid.…”

Management of infected pancreatic necrosis in the intensive care unit: a narrative review

“…Are sensitive to azoles, therapy with an echinocandin is recommended as it was shown to be superior in a septic ICU population with invasive candidiasis and candidaemia [53,54]. Several population pharmacokinetic studies in a general ICU population suggested that echinocandins are probably underdosed and no dose reduction is required for patients on CRRT [55,56].…”

Clinical Pharmacokinetics and Pharmacodynamics of Micafungin

“…Simulations show that only 62% of patients reach the MIC/AUC target for non- C. parapsilosis spp. ; therefore, these patients could benefit from a dose escalation to micafungin 200 mg, as indicated in the manufacturer’s label information [ 62 ].…”