Chemical formula: C₆₃H₈₅N₈O₁₇⁺ Molecular mass: 1,225.603 g/mol PubChem compound: 78318119
Rezafungin selectively inhibits fungal 1,3-β-D-glucan synthase. This results in inhibition of the formation of 1,3-β-D-glucan, an essential component of the fungal cell wall which is not present in mammalian cells. Inhibition of 1,3-β-D-glucan synthesis results in rapid and concentration-dependent fungicidal activity in Candida species (spp.).
Rezafungin MIC90 values (obtained using a modified EUCAST methodology) are generally ≤0.016 mg/L across non-parapsilosis Candida spp. (Candida parapsilosis MIC90 = 2 mg/L).
When tested against a collection of clinical isolates of Candida spp. enriched for echinocandin-resistant and/or azole-resistant strains, rezafungin activity was similar to that of anidulafungin.
Reduced susceptibility to echinocandins, including rezafungin, arises from mutations in glucan synthase catalytic subunit-encoding FKS genes (FKS1 for most Candida spp.; FKS1 and FKS2 for C. glabrata).
The pharmacokinetics of rezafungin have been characterised in healthy subjects, special populations and patients. Rezafungin has a long half-life, allowing for once-weekly dosing. Steady state is achieved with the first loading dose (twice the weekly maintenance dose).
Rezafungin is rapidly distributed with a volume of distribution approximately equal to body water (~40 L). Protein binding of rezafungin is high in humans (>97%).
In vitro, rezafungin was stable across species after incubation with liver and intestinal microsomes and with hepatocytes.
In a single-dose clinical trial, radiolabelled (14C) rezafungin (approximately 400 mg/200 µCi of radioactivity) was administered to healthy volunteers. The main circulating moiety was parent rezafungin; plasma AUC of rezafungin accounted for ~77% of total radiocarbon AUC, with individual metabolites accounting for less than 10% each.
Following single doses of rezafungin (intravenous infusion over 1 hr; 50, 100, 200, and 400 mg), mean total body clearance of rezafungin was low (approximately 0.2 L/h) throughout the dose levels with a mean terminal half-life of 127 to 146 hours. The fraction of dose excreted in urine as unchanged rezafungin was <1% at all dose levels, indicating minor contribution of renal clearance in rezafungin excretion.
In a single-dose clinical trial, radiolabelled (14C) rezafungin (approximately 400 mg/200 µCi of radioactivity) was administered to healthy volunteers. Estimated, mean total recovery of radioactivity was 88.3% at Day 60, based on interpolated data (from return visits to the clinical unit on Day 29 and Day 60). Approximately 74% of the recovered radioactive dose was in faeces (primarily as unchanged rezafungin) and 26% in urine (mainly as metabolites), indicating that elimination of rezafungin is primarily faecal excretion, as unchanged rezafungin.
Following single dose intravenous infusion, the pharmacokinetics of rezafungin are linear over a dose range of 50 to 1 400 mg. Time to reach maximum plasma concentration (Tmax) was observed at the end of infusion, as expected, for all doses and AUC increased in a dose proportional manner.
Rezafungin PK was examined in subjects with moderate (Child-Pugh B, n=8) and severe (Child-Pugh C, n=8) hepatic impairment. Mean rezafungin exposure was reduced by approximately 30% in subjects with moderate and severe hepatic impairment compared to matched subjects with normal hepatic function. Rezafungin PK was similar in subjects with moderate and severe hepatic impairment, and rezafungin exposure did not change with increasing degree of hepatic impairment. Hepatic impairment did not have a clinically meaningful effect on rezafungin PK.
A population PK analysis, including data from Phase 1, Phase 2 and Phase 3 studies, showed that creatinine clearance was not a significant covariate of rezafungin PK.
A population PK analysis, including data from Phase 1, Phase 2 and Phase 3 studies, showed that age was not a significant covariate of rezafungin PK.
A population PK analysis including data from Phase 1, Phase 2 and Phase 3 studies, showed that body surface area was a significant covariate of rezafungin PK. Simulation of exposure in clinically obese patients (body mass index (BMI) ≥30) showed that exposure was reduced in these subjects, but the reduction is not considered clinically meaningful.
A population PK analysis including data from Phase 1, Phase 2 and Phase 3 studies showed that gender and ethinicity were not significant covariates of rezafungin PK.
Rezafungin induced an acute histamine-release response in rats, but not in monkeys.
Rezafungin was negative for genotoxicity in the bacterial and mammalian cell in vitro studies, and in a rat micronucleus study.
During reproductive toxicology studies, rezafungin did not affect mating or fertility in male and female rats following intravenous (short bolus) administration once every 3 days at doses up to 45 mg/kg (6 times the clinical exposure, based on AUC determined in a separate rat study). During the male fertility study, decreased sperm motility was noted at ≥30 mg/kg and most males at 45 mg/kg showed mild/moderate hypospermia and had no detectable motile sperm. At rezafungin doses ≥ 30 mg/kg there was an increased incidence of sperm with abnormal morphology as well as mild to moderate degeneration of the seminiferous tubules.
In a 3-month toxicology study in rats, rezafungin was intravenously (short bolus) dosed once every 3 days. Males dosed at 45 mg/kg showed minimal tubular degeneration/atrophy in the testes and cellular debris in the epididymides at the end of 3 months. The incidence of this finding reduced by the end of a 4-week reversibility period.
By contrast, there were no testicular, epidydimal or spermatogenesis effects at 45 mg/kg (about 4.7 times the clinical dose based on AUC comparisons) in rats dosed intravenously (short bolus) once weekly for 6 months or after a 6-month recovery period.
Sperm concentration, production rate, morphology and motility were unaffected in adult monkeys dosed once weekly with rezafungin, up to 30 mg/kg (about 6 times the clinical dose based on AUC comparisons) for 11 or 22 weeks or after a 52-week recovery period.
No reproductive or developmental toxicity was observed with rezafungin following intravenous administration to pregnant rats and rabbits at ≥3.0-fold the predicted human AUC plasma concentration at steady state.
In a pre- and post-natal development study in rats administered up to 45 mg/kg rezafungin intravenously, there were no adverse effects on offspring growth, maturation, or measures of neurobehavioral or reproductive function. Rezafungin was measurable at low concentrations in the plasma of the foetuses of dosed animals (with concentrations in foetal plasma 2.0-3.6% of those found in maternal plasma) and was excreted in maternal milk (with concentrations in milk 22-26 % of those found in maternal plasma).
Reversible intention tremors (defined as a tremor that is more pronounced when movements are initiated) were observed in one 3-month monkey study with administration once every 3 days and had higher incidence at ≥30 mg/kg. The no observed effect level (NOEL) for intention tremors is considered to be 10 mg/kg in this study (about 2.5 times the clinical dose based on AUC comparisons). Intention tremors were not observed in the 6-month monkey study, in which animals were dosed intravenously once a week with up to 30 mg/kg (about 5.8 times the clinical dose based on AUC comparisons) or in any rat studies.
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