Antimycotics for systemic use, triazole derivatives, ATC code:
Pharmacology: Pharmacodynamics: Mechanism of Action:
Isavuconazole is the active moiety formed after oral or intravenous administration of isavuconazonium sulfate (see Pharmacology: Pharmacokinetics in the following text).
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.
Clinical efficacy and safety:
Treatment of invasive aspergillosis: The safety and efficacy of isavuconazole for the treatment of patients with invasive aspergillosis was evaluated in a double-blind, active-controlled clinical study in 516 patients with invasive fungal disease caused by Aspergillus
species or other filamentous fungi. In the intent-to-treat (ITT) population, 258 patients received isavuconazole and 258 patients received voriconazole. CRESEMBA was administered intravenously (equivalent to 200 mg isavuconazole) every 8 hours for the first 48 hours, followed by once-daily intravenous or oral treatment (equivalent to 200 mg isavuconazole). The protocol-defined maximum treatment duration was 84 days. Median treatment duration was 45 days.
The overall response at end-of-treatment (EOT) in the myITT population (patients with proven and probable invasive aspergillosis based on cytology, histology, culture or galactomannan testing) was assessed by an independent blinded Data Review Committee. The myITT population comprised 123 patients receiving isavuconazole and 108 patients receiving voriconazole. The overall response in this population was n=43 (35%) for isavuconazole and n=42 (38.9%) for voriconazole. The adjusted treatment difference (voriconazole-isavuconazole) was 4.0 (95% confidence interval: -7.9; 15.9).
The all-cause mortality at Day 42 in this population was 18.7% for isavuconazole and 22.2% for voriconazole. The adjusted treatment difference (isavuconazole-voriconazole) was -2.7% (95% confidence interval: -12.9; 7.5).
Treatment of mucormycosis: In an open-label non-controlled study, 37 patients with proven or probable mucormycosis received isavuconazole at the same dose regimen as that used to treat invasive aspergillosis. Median treatment duration was 84 days for the overall mucormycosis patient population, and 102 days for the 21 patients not previously treated for mucormycosis. For patients with probable or proven mucormycosis as defined by the independent Data Review Committee (DRC), all-cause mortality at Day 84 was 43.2% (16/37) for the overall patient population, 42.9% (9/21) for mucormycosis patients receiving isavuconazole as primary treatment, and 43.8% (7/16) for mucormycosis patients receiving isavuconazole who were refractory to, or intolerant of, prior antifungal therapy (mainly amphotericin B-based treatments). The DRC-assessed overall success rate at EOT was 11/35 (31.4%), with 5 patients considered completely cured and 6 patients partially cured. A stable response was observed in an additional 10/35 patients (28.6%). In 9 patients with mucormycosis due to Rhizopus
spp., 4 patients showed a favourable response to isavuconazole. In 5 patients with mucormycosis due to Rhizomucor
spp., no favourable responses were observed. The clinical experience in other species is very limited (Lichtheimia
spp. n=2, Cunninghamella
spp. n=1, Actinomucor elegans
Isavuconazonium sulfate is a water-soluble prodrug that can be administered as an intravenous infusion or orally as hard capsules. Following administration, isavuconanium 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 CRESEMBA 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).
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As shown in Table 2 below, the absolute bioavailability of isavuconazole following oral administration of a single dose of CRESEMBA is 98%. Based on these findings, intravenous and oral dosing can be used interchangeably. (See Table 2.)
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Effect of food on absorption: Oral administration of CRESEMBA equivalent to 400 mg isavuconazole with a high-fat meal reduced isavuconazole Cmax
by 9% and increased AUC by 9%. CRESEMBA 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.
Biotransformation: In vitro/in vivo
studies indicate that CYP3A4, CYP3A5, and subsequently uridine diphosphateglucuronosyltransferases (UGT), are involved in the metabolism of isavuconazole.
Following single doses of [cyano-14
C] isavuconazonium and [pyridinylmethyl-14
C] 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/day.
Pharmacokinetics in special populations:
Paediatric patients: The pharmacokinetics in paediatric patients (<18 years) have not yet been evaluated. No data are available.
Renal impairment: 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 CRESEMBA 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 (see Dosage & Administration).
Hepatic impairment: 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.
CRESEMBA 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. See Dosage & Administration and Precautions.
Toxicology: Preclinical safety data:
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 (see Use in Pregnancy & Lactation).
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 14
C-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
Environmental risk assessment has shown that CRESEMBA may pose a risk for the aquatic environment.
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
) 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
Clinical efficacy has been demonstrated for the following Aspergillus
species: Aspergillus fumigatus
, A. flavus
, A. niger
, and A. terreus
(see further below).
Mechanism(s) of resistance:
Reduced susceptibility to triazole antifungal agents has been associated with mutations in the fungal cyp
51A and cyp
51B 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.
Breakpoints: EUCAST MIC breakpoints are defined for the following species (susceptible S; resistant R): Aspergillus fumigatus:
S ≤1 mg/L, R >1 mg/L.
S ≤0.25 mg/L, R >0.25 mg/L.
S ≤1 mg/L, R >1 mg/L
There are currently insufficient data to set clinical breakpoints for other Aspergillus