Anidulafungin Does Not Require Dosage Adjustment in Subjects With Varying Degrees of Hepatic or Renal Impairment

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.)

Section: Discussionsupporting

confidence: 92%

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

Brüggemann

Middel-Baars

Lange

et al. 2017

“…Furthermore, intact parent drug, as well as metabolites, appear to be eliminated via biliary excretion, without involvement of the kidneys. The conclusion that anidulafungin is not a substrate for phase 1 and phase 2 metabolic pathways is strongly supported by the results of our in vitro metabolism studies and is further substantiated by previous reports indicating that hepatic impairment, regardless of severity, does not increase the systemic exposure to anidulafungin (6).…”

Section: Discussionsupporting

confidence: 89%

“…Due to the difficulty in obtaining a stable degradation product(s) of anidulafungin, similar experiments assessing the potential action of drug transport proteins on these metabolites have not been conducted to date, and the exact nature of the biliary excretion of the degradation products, therefore, remains unclear. The assumed lack of renal and hepatic involvement in the elimination of anidulafungin is also supported by pharmacokinetic studies in renal or hepatic impairment subjects (6). These studies indicated that the pharmacokinetics of anidulafungin were not significantly affected by impaired renal or hepatic function, regardless of severity, and suggested that dose adjustment of anidulafungin is not necessary in these patient populations.…”

Section: Discussionmentioning

confidence: 82%

In Vitro and In Vivo Studies To Characterize the Clearance Mechanism and Potential Cytochrome P450 Interactions of Anidulafungin

Damle

Dowell

Walsky

et al. 2009

Self Cite

Anidulafungin is a novel semisynthetic echinocandin with potent activity against Candida (including azoleresistant isolates) and Aspergillus spp. and is used for serious systemic fungal infections. The purpose of these studies was to characterize the clearance mechanism and potential for drug interactions of anidulafungin. Experiments included in vitro degradation of anidulafungin in buffer and human plasma, a bioassay for antifungal activity, in vitro human cytochrome P450 inhibition studies, in vitro incubation with rat and human hepatocytes, and mass balance studies in rats and humans. Clearance of anidulafungin appeared to be primarily due to slow chemical degradation, with no evidence of hepatic-mediated metabolism (phase 1 or 2). Under physiological conditions, further degradation of the primary degradant appears to take place. The primary degradation product does not retain antifungal activity. Anidulafungin was not an inhibitor of cytochrome P450 enzymes commonly involved in drug metabolism. Mass balance studies showed that anidulafungin was eliminated in the feces predominantly as degradation products, with only a small fraction (10%) eliminated as unchanged drug; fecal elimination likely occurred via biliary excretion. Only negligible renal involvement in the drug's elimination was observed. In conclusion, the primary biotransformation of anidulafungin is mediated by slow chemical degradation, with no evidence for hepatic enzymatic metabolism or renal elimination.The echinocandins are a relatively new class of parenterally administered antifungal agents that have been developed for the treatment of serious systemic fungal infections. Members of this class include caspofungin, micafungin, and anidulafungin; the latter is a novel semisynthetic echinocandin with potent in vitro and in vivo activities against Candida spp. and Aspergillus spp., the major causes of deep-seated mycoses (4,5,24). Anidulafungin is approved in the United States and Europe for the treatment of candidemia in nonneutropenic patients and other forms of invasive Candida infections (11,25). Anidulafungin ( Fig. 1) has distinct pharmacokinetic characteristics, activity against azole-resistant Candida spp., and a favorable safety profile, all of which support its use for systemic fungal infections (26).Echinocandins mediate their antifungal activity by noncompetitive inhibition of (1,3)-␤-D-glucan synthase, a fungus-specific enzyme essential for the synthesis of cell wall glucan (5). While this mode of action is common to all members of the class, there appear to be some differences among echinocandins with respect to their pharmacokinetic properties, including drug disposition (3,5,26). Some of these differences may have implications for the concomitant use of these agents with other drugs and for their use in special patient populations, particularly those under intensive care.To this end, the studies described here were designed to characterize the clearance mechanism and disposition of anidulafungin in rats and humans, as well as to...

“…Although the three echinocandins are from the same class, differences in the route of metabolism, the requirement for a loading dose, dose adjustments in patients with moderate-to-severe hepatic disease, and the dosing schedules for different types of Candida infections exist (9). As no dose adjustment of anidulafungin is required for patients with renal/ hepatic impairment and no clinically relevant drug-drug interactions are known (10,11), anidulafungin might be a particularly valuable treatment option in ICU patients. So far, no studies have formally evaluated the pharmacokinetic profile of anidulafungin in critically ill patients.…”

mentioning

confidence: 99%

Pharmacokinetics of Anidulafungin in Critically Ill Patients with Candidemia/Invasive Candidiasis

Liu

Ruhnke

Meersseman

et al. 2013

Self Cite

fThe pharmacokinetics of intravenous anidulafungin in adult intensive care unit (ICU) patients were assessed in this study and compared with historical data from a general patient population and healthy subjects. Intensive plasma sampling was performed over a dosing interval at steady state from 21 ICU patients with candidemia/invasive candidiasis. All patients received the recommended dosing regimen (a 200-mg loading dose on day 1, followed by a daily 100-mg maintenance dose), except for a 54-yearold 240-kg female patient (who received a daily 150-mg maintenance dose instead). Plasma samples were assayed for anidulafungin using a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters in ICU patients were calculated by a noncompartmental method. With the exclusion of the 240-kg patient, the median (minimum, maximum) age, weight, and body mass index (BMI) of 20 ICU patients were 57 (39, 78) years, 65 (48, 106) kg, and 23.3 (16.2, 33.8) kg/m 2 , respectively. The average anidulafungin area under the curve over the 24-hour dosing interval (AUC 0-24 ), maximum concentration (C max ), and clearance (CL) in 20 ICU patients were 92.7 mg · h/liter, 7.7 mg/liter, and 1.3 liters/h, respectively. The exposure in the 240-kg patient at a daily 150-mg dose was within the range observed in ICU patients overall. The average AUC 0-24 and C max in the general patient population and healthy subjects were 110.3 and 105.9 mg · h/liter and 7.2 and 7.0 mg/liter, respectively. The pharmacokinetics of anidulafungin in ICU patients appeared to be comparable to those in the general patient population and healthy subjects at the same dosing regimen.