Altered Micafungin Pharmacokinetics in Intensive Care Unit Patients

Abstract

gMicafungin is considered an important agent for the treatment of invasive fungal infections in the intensive care unit (ICU). Little is known on the pharmacokinetics of micafungin. We investigated micafungin pharmacokinetics (PK) in ICU patients and set out to explore the parameters that influence micafungin plasma concentrations. ICU patients receiving 100 mg of intravenous micafungin once daily for suspected or proven fungal infection or as prophylaxis were eligible. Daily trough concentrations and PK curves (days 3 and 7) were collected. Pharmacokinetic analysis was performed using a standard two-stage approach. Twenty patients from the ICUs of four hospitals were evaluated. On day 3 (n ‫؍‬ 20), the median (interquartile range [IQR]) area under the concentration-time curve from 0 to 24 h (AUC 0 -24 ) was 78.6 (65.3 to 94.1) mg · h/liter, the maximum concentration of drug in serum (C max ) was 7.2 (5.4 to 9.2) mg/liter, the concentration 24 h after dosing (C 24 ) was 1.55 (1.4 to 3.1) mg/liter, the volume of distribution (V) was 25.6 (21.3 to 29.1) liters, the clearance (CL) was 1.3 (1.1 to 1.5) liters/h, and the elimination half-life (t 1/2 ) was 13.7 (12.2 to 15.5) h. The pharmacokinetic parameters on day 7 (n ‫؍‬ 12) were not significantly different from those on day 3. Daily trough concentrations (day 3 to the end of therapy) showed moderate interindividual (57.9%) and limited intraindividual variability (12.9%). No covariates of the influence on micafungin exposure were identified. Micafungin was considered safe and well tolerated. We performed the first PK study with very intensive sampling on multiple occasions in ICU patients, which aided in resolving micafungin PK. Strikingly, micafungin exposure in our cohort of ICU patients was lower than that in healthy volunteers but not significantly different from that of other reference populations. The clinical consequence of these findings must be investigated in a pharmacokinetic-pharmacodynamic (PK-PD) study incorporating outcome in a larger cohort. (This study is registered at ClinicalTrials.gov under registration no. NCT01783379.) T he incidence of fungal infections continues to pose a serious threat in the intensive care unit (ICU) and is associated with a high mortality rate and prolonged duration of ICU and hospital stay (1-4). Almost 20% of all isolated pathogens in ICU patients are determined to be fungi, with Candida species accounting for the majority of fungal infections (1).Echinocandins are currently considered the primary treatment for patients with invasive candidiasis or candidemia (5, 6). Micafungin is an intravenous antifungal agent of the echinocandin class that exerts potent in vitro and in vivo activity against both Candida and Aspergillus species (7-10). In the clinical setting, micafungin has demonstrated efficacy in treating invasive candidiasis and candidemia (11,12).ICU patients may be subject to severely altered pharmacokinetic (PK) characteristics compared to those of non-critically ill patients. In this population, physiological...

Pharmacokinetics of Anidulafungin in Critically Ill Intensive Care Unit Patients with Suspected or Proven Invasive Fungal Infections

“…We can hypothesize a number of reasons for the lower exposure in the cohort of ICU patients. These reasons are identical to the possible causes of lower micafungin exposure previously reported in another study from our group (15). These possible causes include (i) altered protein binding, (ii) impacts of disease severity, and (iii) a higher average body weight for this cohort than for reference populations.…”

“…Anidulafungin showed interpatient variability similar to those for other echinocandins (15,16). The intrapatient variability was limited and was comparable to those for other echinocandins as well (15,16). This limited intrapatient variability must be considered a beneficial drug property, as it confirms that the pharmacokinetic behavior is not influenced by many factors present in critically ill patients.…”

“…This corroborates previous publications in which the variability in exposure was higher for ICU patients than for reference populations, such as healthy volunteers and a general patient population (as might be expected). Anidulafungin showed interpatient variability similar to those for other echinocandins (15,16). The intrapatient variability was limited and was comparable to those for other echinocandins as well (15,16).…”

Comparative Population Plasma and Tissue Pharmacokinetics of Micafungin in Critically Ill Patients with Severe Burn Injuries and Patients with Complicated Intra-Abdominal Infection

“…The plasma exposure to micafungin in our whole cohort (median AUC 0 -24 for plasma on day 1, 48. Regarding the PK parameters, the estimated clearance for all patients (burn and intra-abdominal infection patients) was similar to that reported in patients with invasive candidiasis and candidemia (1.44 Ϯ 0.73 liters/h) (26) and also in other critically ill patients (1.3 Ϯ 1.1 to 1.5 liters/h) (12).…”

“…Critically ill patients with severe burn injuries may present with various pathophysiologies (burns with various sizes and depths, sepsis, hypoalbuminemia, altered capillary permeability, altered renal function, various degrees of hydration, and the need for renal replacement therapies) that can significantly alter antifungal pharmacokinetics (PKs) (10). A high interindividual variability in the PKs of fluconazole, anidulafungin, caspofungin, and micafungin has been observed in this population (11,12).…”