Low but Sufficient Anidulafungin Exposure in Critically Ill Patients (original) (raw)
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Limited-sampling strategies for anidulafungin in critically ill patients
Antimicrobial agents and chemotherapy, 2015
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 MW\Pharm 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 c...
Antimicrobial Agents and Chemotherapy, 2017
Echinocandins, such as anidulafungin, are the first-line treatment for candidemia or invasive candidiasis in critically ill patients. There are conflicting data on the pharmacokinetic properties of anidulafungin in intensive care unit (ICU) patients. Adult ICU patients (from 3 hospitals) receiving anidulafungin for suspected or proven fungal infections were included in the present study. Patients were considered evaluable if a pharmacokinetic curve for day 3 could be completed. Twentythree of 36 patients (7 female and 16 male) were evaluable. The median (range) age and body weight were 66 (28 to 88) years and 76 (50 to 115) kg, respectively. Pharmacokinetic sampling on day 3 (n ϭ 23) resulted in a median anidulafungin area under the concentration-time curve from 0 to 24 h (AUC 0-24) of 72.1 (interquartile range [IQR], 61.3 to 94.0) mg • h • liter Ϫ1 , a median daily trough concentration (C 24) of 2.2 (IQR, 1.9 to 2.9) mg/liter, a median maximum concentration of drug in serum (C max) of 5.3 (IQR, 4.1 to 6.0) mg/liter, a median volume of distribution (V) of 46.0 (IQR, 32.2 to 60.2) liters, and a median clearance (CL) of 1.4 (IQR, 1.1 to 1.6) liters • h Ϫ1. Pharmacokinetic sampling on day 7 (n ϭ 13) resulted in a median AUC 0-24 of 82.7 (IQR, 73.0 to 129.5) mg • h • liter Ϫ1 , a median minimum concentration of drug in serum (C min) of 2.8 (IQR, 2.2 to 4.2) mg/liter, a median C max of 5.9 (IQR, 4.6 to 8.0) mg/liter, a median V of 39.7 (IQR, 32.2 to 54.4) liters, and a median CL of 1.2 (IQR, 0.8 to 1.4) liters • h Ϫ1. The geometric mean ratio for the AUC day7 /AUC day3 term was 1.13 (90% confidence interval [CI], 1.03 to 1.25). The exposure in the ICU patient population was in accordance with previous reports on anidulafungin pharmacokinetics in ICU patients but was lower than that for healthy volunteers or other patient populations. Larger cohorts of patients or pooled data analyses are necessary to retrieve relevant covariates. (This study has been registered at ClinicalTrials.gov under identifier NCT01438216.) KEYWORDS antifungal drugs, echinocandins, pharmacokinetics, intensive care unit, invasive fungal infections E chinocandins are deployed as primary treatment for patients with invasive candidiasis or candidemia. Anidulafungin is one of three available echinocandins currently on the market. Both the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) and Infectious Diseases Society of America (IDSA) guidelines have argued that with respect to therapeutic efficacy, all echinocandins are equally effective when it comes to treatment of invasive candidiasis or candidemia (1-3). Nevertheless, there are subtle differences in regard to pharmacokinetics (PK).
Anidulafungin dosing in critically ill patients with continuous venovenous haemodiafiltration
The Journal of antimicrobial chemotherapy, 2014
Background: Anidulafungin is indicated as a first-line treatment for invasive candidiasis in critically ill patients. In the intensive care unit, sepsis is the main cause of acute renal failure, and treatment with continuous renal replacement therapy (CRRT) has increased in recent years. Antimicrobial pharmacokinetics is affected by CRRT, but few studies have addressed the optimal dosage for anidulafungin during CRRT.
Analytical and Bioanalytical Chemistry, 2012
Anidulafungin is a semi-synthetic echinocandin with antifungal activity, usually administered as an intravenous infusion. In order to determine the pharmacokinetics (PK) of anidulafungin in pediatric patients, a sensitive high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) bioanalytical method (M1) was developed and validated for quantification of anidulafungin in plasma. During analysis of incurred samples (samples collected from patients enrolled in a clinical study) an isobaric chromatographic interference was observed. The source of interference was identified as an anidulafungin open-ring form (D1) and its impact on the quantification of anidulafungin was investigated. It was found that accurately quantifying anidulafungin in incurred samples required chromatographic separation of the open-ring form from anidulafungin. The method was redeveloped to achieve the appropriate baseline separation and to avoid experimental conditions that favored opening the anidulafungin ring. The extraction of anidulafungin from plasma by protein precipitation remained unchanged, but the changes in chromatography warranted validation of a new method, M2, 2 years after M1 was validated. Incurred samples from three studies that were previously analyzed by M1 and were within confirmed long-term frozen stability were then reanalyzed by M2. Although the incurred sample reproducibility tests on those samples passed for each of the two methods, comparison of concentrations from the same samples obtained by M1 and M2 revealed that an overestimation of anidulafungin following the M1 method exceeded acceptance criteria. The new HPLC-MS/MS method (M2) is applicable for quantification of anidulafungin within a nominal range 50-20,000 ng/mL and requires a 50 μL human plasma aliquot. A linear, 1/concentration squared weighted, leastsquares regression algorithm was used to generate the calibration curve and its parameters were used to quantitate the incurred samples. The inter-assay accuracy in heparin human plasma validation ranged from −4.33 to 0.0386 % and precision was ≤7.32 %. The method M2 was validated for use in regulated bioanalysis and is presently used to quantitate anidulafungin in plasma samples from clinical studies.
Multiple-dose pharmacokinetics of anidulafungin during continuous venovenous haemofiltration
Journal of Antimicrobial Chemotherapy, 2011
Background: Clinical studies support a role for anidulafungin as first-line treatment of invasive candidiasis in critically ill patients and postulate no need for dose adjustments in mild to severe renal failure. Although intensive care patients requiring renal replacement therapy are at particular risk of invasive fungal infection, no pharmacokinetic data on anidulafungin during continuous venovenous haemofiltration (CVVHF) are available. Patients and methods: Ten patients with CVVHF due to acute renal failure were included. Anidulafungin was infused on 3 consecutive days starting with a loading dose of 200 mg on day 1, followed by doses of 100 mg on each of days 2 and 3. During the 72 h study phase of CVVHF, blood and ultrafiltrate samples were collected at corresponding times. Anidulafungin concentrations were determined by HPLC. Results: Peak plasma concentrations were reached 3 h after the start of infusion and were 8.5+3.6 mg/L at the pre-filter port. The mean arterial area under the curve (AUC 0-24) of the study population was 109.9+49.82 mg. h/L, the total clearance was 1.08+0.41 L/h, the volume of distribution was 41.97+22.64 L and the elimination half-life was 28.78+10.40 h. Anidulafungin was not filtered, but CVVHF resulted in a substance loss of 20%, due to adherence to synthetic surfaces. Conclusions: Pharmacokinetics of anidulafungin during CVVHF resembled findings in healthy adults and adults with fungal infections. Therefore we recommend a loading dose of 200 mg intravenous anidulafungin on the first day and 100 mg on consecutive treatment days in patients during CVVHF.
International Journal of Antimicrobial Agents, 2012
Post hoc analysis of a non-comparative, prospective, multicentre, phase IIIb study was performed to compare efficacy and safety of anidulafungin in elderly (≥65 years) versus non-elderly (<65 years) Intensive Care Unit (ICU) patients with candidaemia/invasive candidiasis (C/IC). Adult ICU patients with confirmed C/IC meeting ≥1 of the following criteria were enrolled: post-abdominal surgery; solid tumour; renal/hepatic insufficiency; solid organ transplantation; neutropenia; age ≥65 years. Patients received anidulafungin (200 mg on Day 1, 100 mg/day thereafter) for ≥10 days followed by optional azole stepdown therapy for a total treatment duration of 14-56 days. The primary efficacy endpoint was global (clinical and microbiological) response at the end of all therapy (EOT). Primary efficacy analysis was performed in the modified intent-to-treat (mITT) population (n = 170), excluding unknown and missing responses. In total, 80 patients (47.1%) were aged ≥65 years and 90 (52.9%) were aged <65 years; the mean age difference between the two groups was 21.9 years. Global success at EOT in mITT patients was similar in elderly (68.1%) and non-elderly (70.7%) patients (P = 0.719). However, global success rates were significantly lower in elderly versus non-elderly patients at 2 and 6 weeks after EOT (P = 0.045 and P = 0.016, respectively). Ninety-day survival was significantly lower (P = 0.006) for elderly (42.8%) versus non-elderly patients (63.3%). The incidence and profile of adverse events were similar in elderly and non-elderly patients. Anidulafungin was effective and safe for treatment of C/IC in elderly ICU patients, despite higher baseline severity of illness scores.
Low caspofungin exposure in patients in the Intensive Care Unit
Antimicrobial Agents and Chemotherapy, 2016
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 over 24 hours (AUC 0-24h ) of 98 mg*h/L was considered adequate exposure. In case of low exposure (i.e. <79 mg*h/L; ≥20% lower AUC 0-24h ), the caspofungin dose was increased and the exposure re-evaluated. Twenty patients were included in the study, of which 5 had a positive blood culture. The median caspofungin AUC 0-24h ...