Low but Sufficient Anidulafungin Exposure in Critically Ill Patients

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...

Section: Discussionsupporting

confidence: 47%

“…In addition, V and CL may be subject to increased inter-and intrasubject variability due to altered plasma protein binding (15). Also, it has been hypothesized that disease severity might result in altered drug PK behavior (16).…”

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confidence: 99%

Altered Micafungin Pharmacokinetics in Intensive Care Unit Patients

Lempers

Schouten

Hunfeld

et al. 2015

“…The low AUC 0 -24 of caspofungin in our study is therefore most likely the result of a larger V. Fluid extravasation as a result of endothelial dysfunction and capillary leak, edema in sepsis, ascites, and other third spaces, fluid resuscitation, and hypoalbuminemia are factors that are frequently present in ICU patients and can all lead to an increased V and a lower drug concentration (18)(19)(20). Low AUC values and increased V in ICU patients are also seen with other antifungal drugs, such as fluconazole and anidulafungin (36,37). Although one study showed a lower response rate among patients with a higher acute physiology and chronic health evaluation II (APACHE II) score (38), the AUC 0 -24 of caspofungin was not associated with disease severity scores, which was in agreement with recent findings (34,36).…”

Section: Discussionmentioning

confidence: 90%

“…Low AUC values and increased V in ICU patients are also seen with other antifungal drugs, such as fluconazole and anidulafungin (36,37). Although one study showed a lower response rate among patients with a higher acute physiology and chronic health evaluation II (APACHE II) score (38), the AUC 0 -24 of caspofungin was not associated with disease severity scores, which was in agreement with recent findings (34,36). Hence, the use of disease severity scores does not seem appropriate to predict pharmacokinetic parameters.…”

Section: Discussionmentioning

confidence: 99%

Low Caspofungin Exposure in Patients in Intensive Care Units

Elst

Veringa

Zijlstra

et al. 2017

Self Cite

In critically ill patients, drug exposure may be influenced by altered drug distribution and clearance. Earlier studies showed that the variability in caspofungin exposure was high in intensive care unit (ICU) patients. The primary objective of this study was to determine if the standard dose of caspofungin resulted in adequate exposure in critically ill patients. A multicenter prospective study in ICU patients with (suspected) invasive candidiasis was conducted in the Netherlands from November 2013 to October 2015. Patients received standard caspofungin treatment, and the exposure was determined on day 3 of treatment. An area under the concentration-time curve from 0 to 24 h (AUC 0 -24 ) of 98 mg · h/liter was considered adequate exposure. In case of low exposure (i.e., Ͻ79 mg · h/liter, a Ն20% lower AUC 0 -24 ), the caspofungin dose was increased and the exposure reevaluated. Twenty patients were included in the study, of whom 5 had a positive blood culture. The median caspofungin AUC 0 -24 at day 3 was 78 mg · h/liter (interquartile range [IQR], 69 to 97 mg · h/liter). A low AUC 0 -24 (Ͻ79 mg · h/liter) was seen in 10 patients. The AUC 0 -24 was significantly and positively correlated with the caspofungin dose in mg/kg/day (P ϭ 0.011). The median AUC 0 -24 with a caspofungin dose of 1 mg/kg was estimated using a pharmacokinetic model and was 114.9 mg · h/liter (IQR, 103.2 to 143.5 mg · h/liter). In conclusion, the caspofungin exposure in ICU patients in this study was low compared with that in healthy volunteers and other (non)critically ill patients, most likely due to a larger volume of distribution. A weight-based dose regimen is probably more suitable for patients with substantially altered drug distribution. (This study has been registered at ClinicalTrials.gov under registration no. NCT01994096.)

“…More information is necessary to elucidate this relation. Determination of the anidulafungin AUC along with MIC values is therefore advisable for future research and possibly also in specific clinical situations, since anidulafungin exposure can be low in critically ill patients (4). Lack of response to the standard dose in the situation of an anidulafungin-susceptible tested isolate may prompt measurement of the anidulafungin concentration to detect whether drug exposure is too low.…”

mentioning

confidence: 99%

Limited-Sampling Strategies for Anidulafungin in Critically Ill Patients

Wanrooy

Proost

Rodgers

et al. 2015

Self Cite

e Efficacy of anidulafungin is driven by the area under the concentration-time curve (AUC)/MIC ratio. Determination of the anidulafungin AUC along with MIC values can therefore be useful. Since obtaining a full concentration-time curve to determine an AUC is not always feasible or appropriate, limited-sampling strategies may be useful in adequately estimating exposure. The objective of this study was to develop a model to predict the individual anidulafungin exposure in critically ill patients using limited-sampling strategies. Pharmacokinetic data were derived from 20 critically ill patients with invasive candidiasis treated with anidulafungin. These data were used to develop a two-compartment model in MW‫گ‬Pharm using an iterative 2-stage Bayesian procedure. Limited-sampling strategies were subsequently investigated using two methods, a Bayesian analysis and a linear regression analysis. The best possible strategies for these two methods were evaluated by a Bland-Altman analysis for correlation of the predicted and observed AUC from 0 to 24 h (AUC 0 -24 ) values. Anidulafungin exposure can be adequately estimated with the concentration from a single sample drawn 12 h after the start of the infusion either by linear regression (R 2 ‫؍‬ 0.99; bias, 0.05%; root mean square error [RMSE], 3%) or using a population pharmacokinetic model (R 2 ‫؍‬ 0.89; bias, ؊0.1%; RMSE, 9%) in critically ill patients and also in less severely ill patients, as reflected by healthy volunteers. Limited sampling can be advantageous for future studies evaluating the pharmacokinetics and pharmacodynamics of anidulafungin and for therapeutic drug monitoring in selected patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01047267.)