Pharmacotherapeutic Group: Antimycotics for systemic use, other antimycotics. ATC Code: JO2 AX 06.
Pharmacology: Pharmacodynamics: Mode of Action: Anidulafungin is a semi-synthetic echinocandin, a lipopeptide synthesised from a fermentation product of Aspergillus nidulans.
Anidulafungin selectively inhibits 1,3-β-D glucan synthase, an enzyme present in fungal, but not mammalian cells. This results in inhibition of the formation of 1,3-β-D-glucan, an essential component of the fungal cell wall. Anidulafungin has shown fungicidal activity against Candida species and activity against regions of active cell growth of the hyphae of Aspergillus fumigatus.
Activity in vitro: Anidulafungin is active in vitro against Candida spp. including C. albicans, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis, C. dubliniensis, C. lusitaniae, C. guilliermondii and Aspergillus species including A. fumigatus, A. flavus, A. niger, and A. terreus. Its activity is not affected by resistance to other classes of antifungal agents.
MICs were determined according to the Clinical and Laboratory Standard Institute (CLSI) approved standard reference methods M27 and M38. The relationship between clinical response and in vitro activity remains to be elucidated.
There have been reports of Candida isolates with reduced susceptibility to echinocandins including anidulafungin, but the clinical significance of this observation is unknown.
Activity in vivo: Parenterally administered anidulafungin was effective against Candida spp. in immunocompetent and immunocompromised mouse and rabbit models. Anidulafungin treatment prolonged survival and also reduced the organ burden of Candida spp.
Experimental infections included disseminated C. albicans infection in neutropenic rabbits, esophageal/oropharyngeal infection of neutropaenic rabbits with fluconazole-resistant C. albicans and disseminated infection of neutropaenic mice with fluconazole-resistant C. glabrata.
Anidulafungin has also demonstrated activity against Aspergillus fumigatus in mouse and rabbit infection models.
In combination with other antifungal agents: In vitro studies of anidulafunginin combination with fluconazole, itraconazole and amphotericin B suggest no antagonism of antifungal activity against Candida species. The clinical significance of these results is unknown. In vitro studies have evaluated the activity of anidulafungin in combination with itraconazole, voriconazole, and amphotericin B against Aspergillus spp. The combination of anidulafungin and amphotericin B showed indifference for 16 of 26 isolates, while anidulafungin in combination with either itraconazole or voriconazole showed synergy against 18 of 26 isolates. The clinical significance of these results is unknown.
Information from Clinical Studies: Candidemia and other forms of invasive candidiasis: The safety and efficacy of anidulafungin were evaluated in a pivotal, Phase 3, randomised, double-blind, multicentre, multinational study of patients with candidemia. Patients were randomised to receive once daily i.v. anidulafungin (200 mg loading dose followed by 100 mg maintenance dose) or i.v. fluconazole (800 mg loading dose followed by 400 mg maintenance dose). Patients were stratified by APACHE II score (≤20 and >20) and the presence or absence of neutropenia. Patients with Candida endocarditis, osteomyelitis or meningitis, or those with infection due to C. krusei, were excluded from the study. Treatment was administered for at least 14 and not more than 42 days. Patients in both study arms were permitted to switch to oral fluconazole after at least 10 days of intravenous therapy, provided that they were able to tolerate oral medication, were afebrile for at least 24 hours, and the most recent blood cultures were negative for Candida species.
Patients who received at least one dose of study medication and who had a positive culture for Candida species from a normally sterile site before entry into the study (modified intent-to-treat [MITT] population) were included in the primary analysis of global response at the end of i.v. therapy. A successful global response required clinical improvement and microbiological eradication. Patients were followed for six weeks beyond the end of all therapy.
Two hundred and fifty-six patients (aged 16 to 91 years) were randomised to treatment and received at least one dose of study medication. Two hundred and forty-five patients (127 anidulafungin, 118 fluconazole) met the criteria for inclusion in the MITT population. Of these, 219 patients (116 anidulafungin (91.3%), 103 fluconazole (87.3%)) had candidemia only; 5.5% patients in the anidulafungin arm and 9.3% patients in the fluconazole arm had infections at other normally sterile sites; finally 3.1% patients in the anidulafungin arm and 3.4% patients in the fluconazole arm had both (candidemia and infections at other normally sterile sites). The most frequent species isolated at baseline were C. albicans (63.8% anidulafungin, 59.3% fluconazole), followed by C. glabrata (15.7%, 25.4%), C. parapsilosis (10.2%, 13.6%) and C. tropicalis (11.8%, 9.3%). The majority (97%) of patients were nonneutropenic (ANC >500) and 81% had APACHE II scores less than or equal to 20.
At the end of i.v. therapy, anidulafungin was superior to fluconazole in the treatment of patients with candidemia and/or other forms of invasive candidiasis. In the anidulafungin arm, 96 patients (75.6%) had global success versus 71 patients (60.2%) in the fluconazole arm. The between group difference in global success rate (anidulafungin global success rate minus fluconazole global success rate) was 15.4% (95% CI: 3.9, 27.0).
Candida infections in neutropenic patients: The efficacy of anidulafungin (200 mg intravenous loading dose followed by 100 mg intravenous daily) in adult neutropenic patients (defined as absolute neutrophil count ≤500 cells/mm3, WBC ≤500 cells/mm3 or classified by the investigator as neutropenic at baseline) with microbiologically confirmed invasive candidiasis was assessed in an analysis of pooled data from 5 prospective studies (1 comparative versus caspofungin and 4 open-label, non-comparative). Patients were treated for at least 14 days. In clinically stable patients, a switch to oral azole therapy was permitted after at least 5 to 10 days of treatment with anidulafungin. A total of 46 patients were included in the analysis. The majority of patients had candidemia only (84.8%; 39/46). The most common pathogens isolated at baseline were C. tropicalis (34.8%; 16/46), C. krusei (19.6%; 9/46), C. parapsilosis (17.4%; 8/46), C. albicans (15.2%; 7/46), and C. glabrata (15.2%; 7/46). The successful global response rate at End of Intravenous Treatment (primary endpoint) was 26/46 (56.5%) and End of All Treatment was 24/46 (52.2%). All-cause mortality up to the end of the study (6 Week Follow-up Visit) was 21/46 (45.7%).
The efficacy of anidulafungin in adult neutropenic patients (defined as absolute neutrophil count ≤500 cells/mm3 at baseline) with invasive candidiasis was assessed in a prospective, double-blind, randomized, controlled trial. Eligible patients received either anidulafungin (200 mg intravenous loading dose followed by 100 mg intravenous daily) or caspofungin (70 mg intravenous loading dose followed by 50 mg intravenous daily) (2:1 randomization). Patients were treated for at least 14 days. In clinically stable patients, a switch to oral azole therapy was permitted after at least 10 days of study treatment. A total of 14 neutropenic patients with microbiologically confirmed invasive candidiasis (MITT population) were enrolled in the study (11 anidulafungin; 3 caspofungin). The majority of patients had candidemia only. The most common pathogens isolated at baseline were C. tropicalis (4 anidulafungin, 0 caspofungin), C. parapsilosis (2 anidulafungin, 1 caspofungin), C. krusei (2 anidulafungin, 1 caspofungin), and C. ciferrii (2 anidulafungin, 0 caspofungin). The successful global response rate at the End of Intravenous Treatment (primary endpoint) was 8/11 (72.7%) for anidulafungin and 3/3 (100.0%) for caspofungin (difference -27.3, 95% CI -80.9, 40.3); the successful global response rate at the End of All Treatment was 8/11 (72.7%) for anidulafungin and 3/3 (100.0%) for caspofungin (difference -27.3, 95% CI -80.9, 40.3). All-cause mortality up to the 6 Week Follow-Up visit for anidulafungin (MITT population) was 4/11 (36.4%) and 2/3 (66.7%) for caspofungin.
Patients with microbiologically confirmed invasive candidiasis (MITT population) and neutropenia were identified in an analysis of pooled data from 4 similarly designed prospective, open-label, noncomparative studies. The efficacy of anidulafungin (200 mg intravenous loading dose followed by 100 mg intravenous daily) was assessed in 35 adult neutropenic patients defined as absolute neutrophil count ≤500 cells/mm3 or WBC ≤500 cells/mm3 in 22 patients or classified by the investigator as neutropenic at baseline in 13 patients. All patients were treated for at least 14 days. In clinically stable patients, a switch to oral azole therapy was permitted after at least 5 to 10 days of treatment with anidulafungin. The majority of patients had candidemia only (85.7%). The most common pathogens isolated at baseline were C. tropicalis (12 patients), C. albicans (7 patients), C. glabrata (7 patients), C. krusei (7 patients), and C. parapsilosis (6 patients). The successful global response rate at the End of Intravenous Treatment (primary endpoint) was 18/35 (51.4%) and 16/35 (45.7%) at the End of All Treatment. All-cause mortality by Day 28 was 10/35 (28.6%). The successful global response rate at End of Intravenous Treatment and End of All Treatment were both 7/13 (53.8%) in the 13 patients with neutropenia assessed by investigators at baseline.
Deep tissue infections: The efficacy of anidulafungin (200 mg intravenous loading dose followed by 100 mg intravenous daily) in adult patients with microbiologically confirmed deep tissue candidiasis was assessed in an analysis of pooled data from 5 prospective studies (1 comparative and 4 open-label). Patients were treated for at least 14 days. In the 4 open-label studies, a switch to oral azole therapy was permitted after at least 5 to 10 days of treatment with anidulafungin. A total of 129 patients were included in the analysis. Twenty one (16.3%) had concomitant candidemia. The mean APACHE II score was 14.9 (range, 2 - 44). The most common sites of infection included the peritoneal cavity (54.3%; 70 of 129), hepatobiliary tract (7.0%; 9 of 129), pleural cavity (5.4%; 7 of 129) and kidney (3.1%; 4 of 129). The most common pathogens isolated from a deep tissue site at baseline were C. albicans (64.3%; 83 of 129), C. glabrata (31.0%; 40 of 129), C. tropicalis (11.6%; 15 of 129), and C. krusei (5.4%; 7 of 129). The successful global response rate at the end of intravenous treatment (primary endpoint) and end of all treatment and all-cause mortality up to the 6 week follow-up visit is shown in Table 1. (See Table 1.)
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Pharmacokinetics: The pharmacokinetics of anidulafungin have been characterized by a rapid distribution half-life (0.5-1 hour) and a volume of distribution of 30-50 L that is similar to total body fluid volume. Anidulafungin is extensively bound (>99%) to human plasma proteins.
Biotransformation: Hepatic metabolism of anidulafungin has not been observed. Anidulafungin is not clinically relevant substrate, inducer, or inhibitor of cytochrome P450 isoenzymes. It is unlikely that anidulafungin will have clinically relevant effects on the metabolism of drugs metabolized by cytochrome P450 isoenzymes.
Anidulafungin undergoes slow chemical degradation at physiologic temperature and pH to a ring-opened peptide that lacks antifungal activity. The degradation half-life of anidulafungin under physiologic conditions is approximately 24 hours. In vivo, the ring-opened product is subsequently converted to peptidic degradants and eliminated mainly through biliary excretion.
Elimination: The clearance of anidulafungin is about 1 L/h. Anidulafungin has a predominant elimination half-life of approximately 24 hours that characterizes the majority of the plasma concentration-time profile and a terminal half-life of 40-50 hours that characterizes the terminal elimination phase of the profile.
In a single-dose clinical study, radiolabeled (14C) anidulafungin (~88 mg) was administered to healthy subjects. Approximately 30% of the administered radioactive dose was eliminated in the faeces over 9 days, of which less than 10% was intact drug. Less than 1% of the administered radioactive dose was excreted in the urine. Anidulafungin concentrations fell below the lower limits of quantitation 6 days post-dose. Negligible amounts of drug-derived radioactivity were recovered in blood, urine, and faeces 8 weeks post-dose.
Linearity: Anidulafungin displays linear pharmacokinetics across a wide range of once daily doses (15-130 mg).
Special Populations: Patients with fungal infections: The pharmacokinetics of anidulafungin in patients with fungal infections are similar to those observed in healthy subjects based on population pharmacokinetic analyses. With the 200/100 mg daily dose regimen at an infusion rate of 1 mg/min, the steady state Cmax and trough concentrations Cmin could reach approximately 7 and 3 mg/L, respectively, with an average steady state AUC of approximately 110 mg·h/L.
Weight: Though weight was identified as a source of variability in clearance in the population pharmacokinetic analysis, weight has little clinical relevance on the pharmacokinetics of anidulafungin.
Gender: Plasma concentrations of anidulafungin in healthy men and women were similar. In multiple-dose patient studies, drug clearance was slightly faster (approximately 22%) in men.
Elderly: The population pharmacokinetic analysis showed that median clearance differed slightly between the elderly group (patients ≥65, median CL = 1.07 L/h) and the non-elderly group (patients <65, median CL = 1.22 L/h), however, the range of clearance was similar.
Ethnicity: Anidulafungin pharmacokinetics were similar among Caucasian, Blacks, Asians, and Hispanics.
HIV Positivity: Dosage adjustments are not required based on HIV positivity, irrespective of concomitant anti-retroviral therapy.
Hepatic Insufficiency: Anidulafungin is not hepatically metabolised. Anidulafungin pharmacokinetics were examined in subjects with Child-Pugh class A, B or C hepatic insufficiency. Anidulafungin concentrations were not increased in subjects with any degree of hepatic insufficiency. Although a slight decrease in AUC was observed in patients with Child-Pugh C hepatic insufficiency, the decrease was within the range of population estimates noted for healthy subjects.
Renal Insufficiency: Anidulafungin has negligible renal clearance (<1%). In a clinical study of subjects with mild, moderate, severe or end stage (dialysis-dependent) renal insufficiency, anidulafungin pharmacokinetics were similar to those observed in subjects with normal renal function. Anidulafungin is not dialyzable and may be administered without regard to the timing of hemodialysis.
Pediatric: The pharmacokinetics of anidulafungin after daily doses were investigated in 24 immunocompromised paediatric (2 to 11 years old) and adolescent (12 to 17 years old) patients with neutropenia. The steady state was achieved on the first day after a loading dose (twice the maintenance dose), and the steady state Cmax and AUCss increase in a dose-proportional manner. The systemic exposures following the daily maintenance doses, 0.75 and 1.5 mg/kg/day in patients aged 2 to 17 years old were comparable to those observed in adults following 50 and 100 mg/day, respectively.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazards for humans based on conventional studies of safety pharmacology, acute toxicity, repeated dose toxicity, and toxicity to reproduction. In 3 months studies, evidence of liver toxicity, including elevated enzymes and morphologic alterations, was observed in both rats and monkeys at doses 4 to 6-fold higher than the anticipated clinical therapeutic exposure. In vitro and in vivo genotoxicity studies with anidulafungin provided no evidence of genotoxic potential. Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of anidulafungin.
Administration of anidulafungin to rats did not indicate any effects on reproduction, including male and female fertility.
Anidulafungin crossed the placental barrier in rats and was detected in fetal plasma. The potential risk to the human fetus is unknown.
Anidulafungin was found in the milk of lactating rats. It is not known whether anidulafungin is excreted in human milk.
Anidulafungin did not produce any drug-related development toxicity in rats at the highest dose of 20 mg/kg/day, a dose equivalent to 2 times the proposed therapeutic maintenance dose of 100 mg on the basis of relative body surface area. Developmental effects observed in rabbits (slightly reduced fetal weights) occurred in the high dose group, a dose that also produced maternal toxicity.