Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Basilea Pharmaceutica Deutschland GmbH, Marie-Curie-Strasse 8, 79539, Lörrach, Germany
Pharmacotherapeutic group: Antimycotics for systemic use, triazole- and tetrazole derivative
ATC code: J02AC05
Isavuconazole is the active moiety formed after oral or intravenous administration of isavuconazonium sulfate (see section 5.2).
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.
Table 5. EUCAST Breakpoints:
| Aspergillus species | Minimal Inhibitory Concentration (MIC) breakpoint (mg/L) | |
|---|---|---|
| ≤S (Susceptible) | >R (Resistant) | |
| Aspergillus flavus | 1 | 2 |
| Aspergillus fumigatus | 1 | 2 |
| Aspergillus nidulans | 0.25 | 0.25 |
| Aspergillus terreus | 1 | 1 |
There are currently insufficient data to set clinical breakpoints for other Aspergillus species.
The safety and efficacy of isavuconazole for the treatment of adult 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.
Isavuconazole 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).
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 n=1).
The clinical safety of isavuconazole was assessed in 77 paediatric patients who received at least one dose of intravenous or oral isavuconazole, including 31 paediatric patients who received isavuconazole in a clinical study for treating invasive aspergillosis or mucormycosis. Isavuconazole was safe and well tolerated in the treatment of invasive aspergillosis and mucormycosis at the intended treatment durations.
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 CRESEMBA in healthy adult subjects, the active moiety isavuconazole is absorbed and reaches maximum plasma concentrations (Cmax) approximately 2–3 hours after single and multiple dosing (see Table 6).
Table 6. Steady state pharmacokinetic parameters of isavuconazole following oral administration of CRESEMBA in healthy adults:
| Parameter Statistic | Isavuconazole 200 mg (n=37) | Isavuconazole 600 mg (n=32) |
|---|---|---|
| Cmax (mg/L) | ||
| Mean SD CV % | 7.5 1.9 25.2 | 20.0 3.6 17.9 |
| tmax (h) | ||
| Median Range | 3.0 2.0 – 4.0 | 4.0 2.0 – 4.0 |
| AUC (h•mg/L) | ||
| Mean SD CV % | 121.4 35.8 29.5 | 352.8 72.0 20.4 |
As shown in Table 7 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.
Table 7. Pharmacokinetic comparison for oral and intravenous dose (Mean) in adults:
| Isavuconazole 400 mg oral | Isavuconazole 400 mg i.v. | |
|---|---|---|
| AUC (h•ng/mL) | 189.5 | 194.0 |
| CV % | 36.5 | 37.2 |
| Half-life (h) | 110 | 115 |
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.
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 paediatric dosage regimens were confirmed using a population pharmacokinetic (popPK) model developed using data from three clinical studies (N=97); this included two clinical studies (N=73) conducted in paediatric patients aged 1 to <18 years, of whom 31 received isavuconazole for treating invasive aspergillosis or mucormycosis.
The predicted exposures to isavuconazole for paediatric patients at steady state based on different age groups, weight, route of administration, and dose are shown in Table 7.
Table 7. Isavuconazole AUC (h•mg/L) values at steady state by age group, weight, route of administration, and dose:
| Age group (years) | Route | Weight (kg) | Dose | AUCss (h•mg/L) |
|---|---|---|---|---|
| 1 – <3 | Intravenous | <37 | 5.4 mg/kg | 108 (29 – 469) |
| 3 – <6 | Intravenous | <37 | 5.4 mg/kg | 123 (27 – 513) |
| 6 – <18 | Intravenous | <37 | 5.4 mg/kg | 138 (31 – 602) |
| 6 – <18 | Oral | 16 – 17 | 80 mg | 116 (31 – 539) |
| 6 – <18 | Oral | 18 – 24 | 120 mg | 129 (33 – 474) |
| 6 – <18 | Oral | 25 – 31 | 160 mg | 140 (36 – 442) |
| 6 – <18 | Oral | 32 – 36 | 180 mg | 137 (27 – 677) |
| 6 – <18 | Intravenous and oral | ≥37 | 200 mg | 113 (27 – 488) |
| ≥18 | Intravenous and oral | ≥37 | 200 mg | 101 (10 – 343) |
The predicted exposures for paediatric patients, regardless of route of administration and age group, were comparable to exposures at steady state (AUCss) from a clinical study conducted in adult patients with infections caused by Aspergillus species and other filamentous fungi (mean AUCss = 101.2 h•mg/L with standard deviation (SD) = 55.9, see Table 7).
The predicted exposures under the paediatric dosing regimen were lower than the exposures of adults who received multiple daily supratherapeutic doses of 600 mg isavuconazole (Table 6), where there was a greater occurrence of adverse events (see section 4.9).
No clinically relevant changes were observed in the total Cmax and AUC of isavuconazole in adult 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 (see section 4.2).
No data are available in paediatric patients with renal impairment (see section 4.2).
After a single 100 mg dose of isavuconazole was administered to 32 adult 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 adult patients with mild to moderate hepatic impairment.
Isavuconazole has not been studied in adult 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 sections 4.2 and 4.4).
No data are available in paediatric patients with hepatic impairment (see section 4.2).
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 section 4.6).
Administration of isavuconazonium sulfate to rats at a dose of 90 mg/kg/day (approximately 1.0-fold the systemic exposure at the human clinical maintenance dose of 200 mg isavuconazole) 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 or the normal development 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 (approximately 1.0-fold the systemic exposure at the human clinical maintenance dose of 200 mg isavuconazole).
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.
Isavuconazole has demonstrated carcinogenic potential in 2-year rodent carcinogenicity studies. Liver and thyroid tumours are likely caused by a rodent-specific mechanism that is not relevant for humans. Skin fibromas and fibrosarcomas were seen in male rats. The mechanism underlying this effect is unknown. Endometrial adenomas and carcinomas of the uterus were seen in female rats, which is likely due to a hormonal disturbance. There is no safety margin for these effects. The relevance for humans of the skin and uterine tumours cannot be excluded.
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 (approximately 1.0-fold the systemic exposure at the human clinical maintenance dose of 200 mg isavuconazole).
Isavuconazonium sulfate, when administered to juvenile rats, demonstrated a similar toxicological profile to that observed in adult animals. In juvenile rats, treatment-related toxicity considered rodent specific was observed in the liver and thyroid. These changes are not considered clinically relevant. Based on the no-observed-adverse-effect level in juvenile rats, the safety margins for isavuconazonium sulfate were approximately 0.2- to 0.5-fold the systemic exposure at the clinical maintenance dose for paediatric patients, similar to those observed in adult rats.
Environmental risk assessment has shown that isavuconazole may pose a risk for the aquatic environment.
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