Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050, Bruxelles, Belgium
Pharmacotherapeutic group: Antimycotics for systemic use, other antimycotics for systemic use
ATC code: JO2AX06
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.
Anidulafungin exhibited in-vitro activity against C. albicans, C. glabrata, C. parapsilosis, C. krusei and C. tropicalis. For the clinical relevance of these findings see "Clinical efficacy and safety."
Isolates with mutations in the hot spot regions of the target gene have been associated with clinical failures or breakthrough infections. Most clinical cases involve caspofungin treatment. However, in animal experiments these mutations confer cross resistance to all three echinocandins and therefore such isolates are classified as echinocandin resistant until further clinical experience are obtained concerning anidulafungin.
The in vitro activity of anidulafungin against Candida species is not uniform. Specifically, for C. parapsilosis, the MICs of anidulafungin are higher than are those of other Candida species. A standardized technique for testing the susceptibility of Candida species to anidulafungin as well as the respective interpretative breakpoints has been established by European Committee on Antimicrobial Susceptibility Testing (EUCAST).
Table 2. EUCAST Breakpoints:
| Candida Species | MIC breakpoint (mg/L) | |
|---|---|---|
| ≤S (Susceptible) | >R (Resistant) | |
| Candida albicans | 0,03 | 0,03 |
| Candida glabrata | 0,06 | 0,06 |
| Candida tropicalis | 0,06 | 0,06 |
| Candida krusei | 0,06 | 0,06 |
| Candida parapsilosis1 | 0,002 | 4 |
| Other Candida spp.2 | Insufficient evidence | |
1 C. parapsilosis harbours an intrinsic alteration in the target gene, which is the likely mechanism for the higher MICs than with other Candida species. In the clinical trials the outcome for anidulafungin with C. parapsilosis was not statistically different from other species however, the use of echinocandins in candidaemia due to C. parapsilosis may not be regarded as therapy of first choice
2 EUCAST has not determined non-species related breakpoints for anidulafungin
Parenterally administered anidulafungin was effective against Candida species in immunocompetent and immunocompromised mouse and rabbit models. Anidulafungin treatment prolonged survival and also reduced the organ burden of Candida species, when determined at intervals from 24 to 96 hours after the last treatment.
Experimental infections included disseminated C. albicans infection in neutropenic rabbits, oesophageal/oropharyngeal infection of neutropenic rabbits with fluconazole-resistant C. albicans and disseminated infection of neutropenic mice with fluconazole-resistant C. glabrata.
The safety and efficacy of anidulafungin were evaluated in a pivotal Phase 3, randomised, double-blind, multicentre, multinational study of primarily non-neutropenic patients with candidaemia and a limited number of patients with deep tissue Candida infections or with abscess-forming disease. Patients with Candida endocarditis, osteomyelitis or meningitis, or those with infection due to C. krusei, were specifically excluded from the study. Patients were randomised to receive either anidulafungin (200 mg intravenous loading dose followed by 100 mg intravenous daily) or fluconazole (800 mg intravenous loading dose followed by 400 mg intravenous daily), and were stratified by APACHE II score (≤20 and >20) and the presence or absence of neutropaenia. 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 medicinal products and were afebrile for at least 24 hours, and that the most recent blood cultures were negative for Candida species.
Patients who received at least one dose of study medicinal products and who had a positive culture for Candida species from a normally sterile site before study entry were included in the modified intent- to-treat (MITT) population. In the primary efficacy analysis, global response in the MITT populations at the end of intravenous therapy, anidulafungin was compared to fluconazole in a pre-specified two- step statistical comparison (non-inferiority followed by superiority). 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, ranging from 16 to 91 years in age, were randomised to treatment and received at least one dose of study medication. 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%) - with 20, 13 and 15 isolates of the last 3 species, respectively, in the anidulafungin group. The majority of patients had Apache II scores ≤ 20 and very few were neutropenic.
Efficacy data, both overall and by various subgroups, are presented below in Table 3.
Table 3. Global success in the MITT population: primary and secondary endpoints:
| Anidulafungin | Fluconazole | Between group differencea (95% CI) | |
|---|---|---|---|
| End of IV Therapy (1º endpoint) | 96/127 (75,6%) | 71/118 (60,2%) | 15,42 (3,9, 27,0) |
| Candidaemia only | 88/116 (75,9%) | 63/103 (61,2%) | 14,7 (2,5, 26,9) |
| Other sterile sitesb | 8/11 (72,7%) | 8/15 (53,3%) | - |
| Peritoneal fluid/IAc abscess | 6/8 | 5/8 | |
| Other | 2/3 | 3/7 | |
| C. albicansd | 60/74 (81,1%) | 38/61 (62,3%) | - |
| Non-albicans speciesd | 32/45 (71,1%) | 27/45 (60,0%) | - |
| Apache II score ≤20 | 82/101 (81,2%) | 60/98 (61,2%) | - |
| Apache II score >20 | 14/26 (53,8%) | 11/20 (55,0%) | - |
| Non-neutropenic (ANC, cells/mm³ >500) | 94/124 (75,8%) | 69/114 (60,5%) | - |
| Neutropenic (ANC, cells/mm³ ≤500) | 2/3 | 2/4 | - |
| At Other Endpoints | |||
| End of All Therapy | 94/127 (74,0%) | 67/118 (56,8%) | 17,24 (2,9, 31,6)ε |
| 2 Week Follow-up | 82/127 (64,6%) | 58/118 (49,2%) | 15,41 (0,4, 30,4)ε |
| 6 Week Follow-up | 71/127 (55,9%) | 52/118 (44,1%) | 11,84 (-3,4, 27,0)e |
a Calculated as anidulafungin minus fluconazole
b With or without concurrent candidaemia
c Intra-abdominal
d Data presented for patients with a single baseline pathogen.
e 98.3% confidence intervals, adjusted post hoc for multiple comparisons of secondary time points.
Mortality rates in both the anidulafungin and fluconazole arms are presented below in Table 4.
Table 4. Mortality:
| Anidulafungin | Fluconazole | |
|---|---|---|
| Overall study mortality | 29/127 (22.8%) | 37/118 (31.4%) |
| Mortality during study therapy | 10/127 (7.9%) | 17/118 (14.4%) |
| Mortality attributed to Candida infection | 2/127 (1.6%) | 5/118 (4.2%) |
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/mm 3 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 ⅔ (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, non- comparative 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.
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 5.
Table 5. Rate of Successful Global Response a and All-Cause Mortality in Patients with Deep Tissue Candidiasis – Pooled Analysis:
| MITT Population n/N (%) | |
|---|---|
| Global Response of Success at EOIVTb | |
| Overall | 102/129 (79,1) |
| Peritoneal cavity | 51/70 (72,9) |
| Hepatobiliary tract | 7/9 (77,8) |
| Pleural cavity | 6/7 (85,7) |
| Kidney | 3/4 (75,0) |
| Global Response of Success at EOTb | 94/129 (72,9) |
| All-Cause Mortality | 40/129 (31,0) |
a A successful global response was defined as both clinical and microbiologic success
b EOIVT, End of Intravenous Treatment; EOT, End of All Treatment
The pharmacokinetics of anidulafungin have been characterised in healthy subjects, special populations and patients. A low intersubject variability in systemic exposure (coefficient of variation ~25%) was observed. The steady state was achieved on the first day after a loading dose (twice the daily maintenance dose).
The pharmacokinetics of anidulafungin are characterised by a rapid distribution half-life (0.5-1 hour) and a volume of distribution, 30-50 l, which is similar to total body fluid volume. Anidulafungin is extensively bound (>99%) to human plasma proteins. No specific tissue distribution studies of anidulafungin have been done in humans. Therefore, no information is available about the penetration of anidulafungin into the cerebrospinal fluid (CSF) and/or across the blood-brain barrier.
Hepatic metabolism of anidulafungin has not been observed. Anidulafungin is not a 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 metabolised by cytochrome P450 isoenzymes.
Anidulafungin undergoes slow chemical degradation at physiologic temperature and pH to a ring-opened peptide that lacks antifungal activity. The in vitro 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.
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 characterises 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, indicating negligible renal clearance. 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.
Anidulafungin displays linear pharmacokinetics across a wide range of once daily doses (15-130 mg).
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 1.1 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.
Although 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.
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.
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.
Anidulafungin pharmacokinetics were similar among Caucasians, Blacks, Asians, and Hispanics.
Dosage adjustments are not required based on HIV positivity, irrespective of concomitant anti-retroviral therapy.
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.
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 dialysable and may be administered without regard to the timing of hemodialysis.
The pharmacokinetics of anidulafungin after at least 5 daily doses were investigated in 24 immunocompromised paediatric (2 to 11 years old) and adolescent (12 to 17 years old) patients with neutropenia. Steady state was achieved on the first day after a loading dose (twice the maintenance dose), and steady state C max and AUC ss increase in a dose-proportional manner. Systemic exposure following daily maintenance dose of 0.75 and 1.5 mg/kg/day in this population were comparable to those observed in adults following 50 and 100 mg/day, respectively. Both regimens were well- tolerated by these patients.
In 3 month 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 foetal plasma.
Embryo-foetal development studies were conducted with doses between 0.2- and 2-fold (rats) and between 1- and 4-fold (rabbits) the proposed therapeutic maintenance dose of 100 mg/day. Anidulafungin did not produce any drug-related developmental toxicity in rats at the highest dose tested. Developmental effects observed in rabbits (slightly reduced foetal weights) occurred only at the highest dose tested, a dose that also produced maternal toxicity.
The concentration of anidulafungin in the brain was low (brain to plasma ratio of approximately 0.2) in uninfected adult and neonatal rats after a single dose. However, brain concentrations increased in uninfected neonatal rats after five daily doses (brain to plasma ratio of approximately 0.7). In multiple dose studies in rabbits with disseminated candidiasis and in mice with CNS candida infection, anidulafungin has been shown to reduce fungal burden in the brain.
Rats were dosed with anidulafungin at three dose levels and anaesthetised within one hour using a combination of ketamine and xylazine. Rats in the high dose group experienced infusion-related reactions that were exacerbated by anaesthesia. Some rats in the mid dose group experienced similar reactions but only after administration of anaesthesia. There were no adverse reactions in the low-dose animals in the presence or absence of anaesthesia, and no infusion-related reactions in the mid-dose group in the absence of anaesthesia.
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