Anidulafungin

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 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:

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

Activity in vivo

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.

General pharmacokinetic characteristics

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).

Distribution

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.

Biotransformation

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 ringopened 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.

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 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.

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 1.1 mg/min, the steady state C_max and trough concentrations (C_min) could reach approximately 7 and 3 mg/l, respectively, with an average steady state AUC of approximately 110 mg·h/l.

Weight

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.

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 Caucasians, 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 dialysable and may be administered without regard to the timing of hemodialysis.

Paediatric

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.