Singapore Drugs Database

Indication

- Indicated for patients 18 years of age and older for the treatment of invasive aspergillosis [FDA Label]. - Indicated for patients 18 years of age and older for the treatment of invasive mucormycosis [FDA Label], including patients where treatment amphotericin B is inappropriate [L1482].

Mechanism of Action

Isavuconazole displays fungicidal actions by disrupting the biosynthesis of ergosterol, which is a key component of fungal cell membrane. It inhibits cytochrome P-450 dependent enzyme lanosterol 14-alpha-demethylase that mediates the conversion of lanosterol to ergosterol. The side arm of of the active isavuconazole molecule allows for greater affinity for the binding pocket in the fungal CYP51 protein by orienting the triazole ring of the molecule to engage with the heme moiety at the bottom of the binding pocket [A32026, A32029]. This explains the wide antifungal spectrum of isavuconazole and possible cross-resistance to other triazoles [A32026, A32029]. As a result of lanosterol 14-alpha-demethylase inhibition, toxic methylated sterol precursors such as 14-α-methylated lanosterol, 4,14-dimethylzymosterol, and 24-methylenedihydrolanosterol alter the function of fungal membrane and accumulate within the fungal cytoplasm [A32029]. Depletion of ergosterol within the fungal cell membrane leads to decreased structural integrity and function of the cell membrane, inhibited fungal cell growth and replication [A32026], and ultimately cell death. Mammalian cell demethylation is less sensitive to isavuconazole inhibition [FDA Label]. Mechanism of resistance and reduced susceptibility to isavuconazole arises from mutations in the fungal cyp51A and cyp51B genes coding for the target protein lanosterol 14-alpha-demethylase [L1482]. Other multiple mechanisms leading to resistance, including changes in sterol profile and elevated efflux pump activity of fungal species, cannot be excluded [FDA Label].

Pharmacokinetics

Absorption

Following oral administration of 200 mg isavuconazole, the mean peak plasma concentration (Cmax) at steady state was 7499 ng/mL. Cmax following oral administration of 600 mg isavuconazole was 20028 ng/mL [FDA Label]. It is proposed that the Cmax at steady state is reached approximately 2–3 hours after single and multiple dosing of isavuconazole [FDA Label]. Administration of 400 mg of oral and intravenous isavuconazole resulted in mean AUC of 189462.8 h*ng/mL and 193906.8 h*ng/mL, respectively [L1482]. While isavuconazole can be administered with or without food, concurrent consumption of a high-fat meal reduced oral isavuconazole Cmax by 9% and increased AUC by 9% [FDA Label]. The absolute bioavailability of isavuconazole following oral administration of a single dose of isavuconazole is 98% [FDA Label].

Distribution

The mean steady state volume of distribution (Vss) was approximately 450 L following intravenous administration [FDA Label].

Metabolism

Following rapid conversion of the prodrug isavuconazonium to isavuconazole via esterase-mediated hydrolysis, a number of minor metabolites were identified in addition to the active moiety itself and the inactive cleavage product of isavuconazonium. However, no individual metabolite was observed with an AUC greater than 10% of total radio-labeled material [FDA label]. The main enzymes involved in the metabolism of isavuconazole are CYP3A4, CYP3A5, and subsequently uridine diphosphate- glucuronosyltransferases (UGT) according to the findings of _in vivo_ and _in vitro_ studies [FDA Label].

Elimination

Clearance

The clearance (CL) rate was 2.5 ± 1.6 L/h in patients receiving 200 mg isavuconazole orally or intravenously [A32028].

Toxicity

At three times the recommended maintenance dose of isavuconazole, treatment-emergent adverse reactions included headache, dizziness, paresthesia, somnolence, disturbance in attention, dysgeusia, dry mouth, diarrhea, oral hypoesthesia, vomiting, hot flush, anxiety, restlessness, palpitations, tachycardia, photophobia and arthralgia. As there is no specific antidote or effective method of hemodialysis for isavuconazole, supportive treatment with appropriate monitoring is recommended in case of overdose [FDA Label]. No mutagenic or clastogenic effects were detected in the in vitro bacterial reverse mutation assay and the in vivo bone marrow micronucleus assay in rats [FDA Label]. However, isavuconazole was weakly clastogenic at cytotoxic concentrations in the L5178Y tk+/- mouse lymphoma chromosome aberration assay without any significant evidence of increased frequency of micronuclei in an in vivo rat micronucleus test [L1482]. While carcinogenicity studies isavuconazole have not been performed, other drugs in the azole class at near human recommended doses were associated with the development of hepatocellular adenomas and carcinomas in mice and rat carcinogenicity studies [FDA Label]. At doses up to 90 mg/kg/day, oral isavuconazole did not affect the fertility in male or female rats. Isavuconazole at systemic exposures of subtherapeutic levels was associated with dose-related increases in the incidence of skeletal anomalies in rat and rabbit offsprings [L1482]. In rats, a dose-related increase in the incidence of zygomatic arch fusion was also noted in offspring [L1482].

Active Ingredient/Synonyms

isavuconazol | isavuconazole | isavuconazolum | Isavuconazole |