Chemical formula: C₂₂H₁₇F₂N₅OS Molecular mass: 437.47 g/mol
Isavuconazole is the active moiety formed after oral or intravenous administration of isavuconazonium sulfate. Isavuconazole demonstrates a fungicidal effect by blocking the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450-dependent enzyme lanosterol 14-alpha-demethylase, responsible for the conversion of lanosterol to ergosterol. This results in an accumulation of methylated sterol precursors and a depletion of ergosterol within the cell membrane, thus weakening the structure and function of the fungal cell membrane.
In animal models of disseminated and pulmonary aspergillosis, the pharmacodynamic (PD) index important in efficacy is exposure divided by minimum inhibitory concentration (MIC) (AUC/MIC). No clear correlation between in vitro MIC and clinical response for the different species (Aspergillus and Mucorales) could be established.
Concentrations of isavuconazole required to inhibit Aspergillus species and genera/species of the order Mucorales in vitro have been very variable. Generally, concentrations of isavuconazole required to inhibit Mucorales are higher than those required to inhibit the majority of Aspergillus species.
Clinical efficacy has been demonstrated for the following Aspergillus species: Aspergillus fumigatus, A. flavus, A. niger, and A. terreus (see further below).
Reduced susceptibility to triazole antifungal agents has been associated with mutations in the fungal cyp51A and cyp51B genes coding for the target protein lanosterol 14-alpha-demethylase involved in ergosterol biosynthesis. Fungal strains with reduced in vitro susceptibility to isavuconazole have been reported, and cross-resistance with voriconazole and other triazole antifungal agents cannot be excluded.
EUCAST MIC breakpoints are defined for the following species (susceptible S; resistant R):
There are currently insufficient data to set clinical breakpoints for other Aspergillus species.
Isavuconazonium sulfate is a water-soluble prodrug that can be administered as an intravenous infusion or orally as hard capsules. Following administration, isavuconazonium sulfate is rapidly hydrolysed by plasma esterases to the active moiety isavuconazole; plasma concentrations of the prodrug are very low, and detectable only for a short time after intravenous dosing.
Following oral administration of isavuconazole in healthy subjects, the active moiety isavuconazole is absorbed and reaches maximum plasma concentrations (Cmax) approximately 2–3 hours after single and multiple dosing (see Table 1).
Table 1. Steady state pharmacokinetic parameters of isavuconazole following oral administration of isavuconazole:
| Parameter Statistic | Isavuconazole 200 mg (n=37) | Isavuconazole 600 mg (n=32) |
|---|---|---|
| Cmax (ng/mL) | ||
| Mean | 7499 | 20028 |
| SD | 1893.3 | 3584.3 |
| CV % | 25.2 | 17.9 |
| tmax (h) | ||
| Median | 3.0 | 4.0 |
| Range | 2.0-4.0 | 2.0-4.0 |
| AUC (h•ng/mL) | ||
| Mean | 121402 | 352805 |
| SD | 35768.8 | 72018.5 |
| CV % | 29.5 | 20.4 |
As shown in table 2 below, the absolute bioavailability of isavuconazole following oral administration of a single dose of isavuconazole is 98%. Based on these findings, intravenous and oral dosing can be used interchangeably.
Table 2. Pharmacokinetic comparison for oral and intravenous dose (Mean):
| ISA 400 mg oral | ISA 400 mg i.v. | |
|---|---|---|
| AUC (h•ng/mL) | 189462.8 | 193906.8 |
| CV % | 36.5 | 37.2 |
| Half-life (h) | 110 | 115 |
Oral administration of isavuconazole equivalent to 400 mg isavuconazole with a high-fat meal reduced isavuconazole Cmax by 9% and increased AUC by 9%. Isavuconazole can be taken with or without food.
Isavuconazole is extensively distributed, with a mean steady state volume of distribution (Vss) of approximately 450 L. Isavuconazole is highly bound (>99%) to human plasma proteins, predominantly to albumin.
In vitro/in vivo studies indicate that CYP3A4, CYP3A5, and subsequently uridine diphosphate- glucuronosyltransferases (UGT), are involved in the metabolism of isavuconazole.
Following single doses of [cyano-14C] isavuconazonium and [pyridinylmethyl-14C] isavuconazonium sulfate in humans, in addition to the active moiety (isavuconazole) and the inactive cleavage product, a number of minor metabolites were identified. Except for the active moiety isavuconazole, no individual metabolite was observed with an AUC >10% of total radio-labelled material.
Following oral administration of radio-labelled isavuconazonium sulfate to healthy subjects, a mean of 46.1% of the radioactive dose was recovered in faeces, and 45.5% was recovered in urine.
Renal excretion of intact isavuconazole was less than 1% of the dose administered.
The inactive cleavage product is primarily eliminated by metabolism and subsequent renal excretion of the metabolites.
Studies in healthy subjects have demonstrated that the pharmacokinetics of isavuconazole are proportional up to 600 mg per day.
The pharmacokinetics in paediatric patients (<18 years) have not yet been evaluated. No data are available.
No clinically relevant changes were observed in the total Cmax and AUC of isavuconazole in subjects with mild, moderate or severe renal impairment compared to subjects with normal renal function. Of the 403 patients who received isavuconazole in the Phase 3 studies, 79 (20%) of patients had an estimated glomerular filtration rate (GFR) less than 60 mL/min/1.73 m². No dose adjustment is required in patients with renal impairment, including those patients with end-stage renal disease. Isavuconazole is not readily dialysable.
After a single 100 mg dose of isavuconazole was administered to 32 patients with mild (Child-Pugh Class A) hepatic insufficiency and 32 patients with moderate (Child-Pugh Class B) hepatic insufficiency (16 intravenous and 16 oral patients per Child-Pugh class), the least square mean systemic exposure (AUC) increased 64% in the Child-Pugh Class A group, and 84% in the Child-Pugh Class B group, relative to 32 age- and weight-matched healthy subjects with normal hepatic function. Mean plasma concentrations (Cmax) were 2% lower in the Child-Pugh Class A group and 30% lower in the Child-Pugh Class B group. The population pharmacokinetic evaluation of isavuconazole in healthy subjects and patients with mild or moderate hepatic dysfunction demonstrated that the mild and moderate hepatic impairment populations had 40% and 48% lower isavuconazole clearance (CL) values, respectively, than the healthy population.
No dose adjustment is required in patients with mild to moderate hepatic impairment.
Isavuconazole has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Use in these patients is not recommended unless the potential benefit is considered to outweigh the risks.
In rats and rabbits, isavuconazole at systemic exposures below the therapeutic level were associated with dose-related increases in the incidence of skeletal anomalies (rudimentary supernumerary ribs) in offspring. In rats, a dose-related increase in the incidence of zygomatic arch fusion was also noted in offspring.
Administration of isavuconazonium sulfate to rats at a dose of 90 mg/kg/day (2.3-fold the human maintenance dose [200 mg] based on mg/m²/day) during pregnancy through the weaning period showed an increased perinatal mortality of the pups. In utero exposure to the active moiety isavuconazole had no effect on the fertility of the surviving pups.
Intravenous administration of 14C-labelled isavuconazonium sulfate to lactating rats resulted in the recovery of radiolabel in the milk.
Isavuconazole did not affect the fertility of male or female rats treated with oral doses up to 90 mg/kg/day (2.3-fold the clinical maintenance dose based on mg/m²/day comparisons).
Isavuconazole has no discernible mutagenic or genotoxic potential. Isavuconazole was negative in a bacterial reverse mutation assay, was weakly clastogenic at cytotoxic concentrations in the L5178Y tk+/- mouse lymphoma chromosome aberration assay, and showed no biologically relevant or statistically significant increase in the frequency of micronuclei in an in vivo rat micronucleus test.
No carcinogenicity studies have been performed.
Isavuconazole inhibited the hERG potassium channel and the L-type calcium channel with an IC50 of 5.82 μM and 6.57 μM respectively (34- and 38-fold the human non-protein bound Cmax at maximum recommended human dose [MRHD], respectively). The in vivo 39-week repeated-dose toxicology studies in monkeys did not show QTcF prolongation at doses up to 40 mg/kg/day (2.1-fold the recommended clinical maintenance dose, based on mg/m²/day comparisons).
Environmental risk assessment has shown that isavuconazole may pose a risk for the aquatic environment.
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