Isavuconazole

Isavuconazole Uses, Dosage, Side Effects, Food Interaction and all others data.

Isavuconazole is an triazole antifungal with broad spectrum of activity and good safety profile . It is approved by the FDA and EMA for the treatment of invasive aspergillosis and mucormycosis. It works by inhibiting fungal cell membrane synthesis. Invasive fungal infections pose significant clinical challenges for patients, especially those who are immunocompromised. In vitro, most of the Candida species, most Aspergillus species, Mucorales, Cryptococcus spp., Fusarium species, dermatophytes and dimorphic fungi displayed susceptibility to isavuconzaole . Resistance to isavuconazole has been associated with the mutation in the target gene CYP51 . Cross-resistance between isavuconazole and other azoles was also proposed although the clinical relevance is unclear .

As isavuconazole displays low water solubility, it is found as an active ingredient of its prodrug, Isavuconazonium. The prodrug formulation of isavuconazole is FDA- and EMA-approved and is marketed under the trade name Cresemba for the treatment of invasive aspergillosis and mucormycosis as oral or intravenous administration. The intravenous formulation is cyclodextrin-free which gives isavuconazole an advantage over other azole antifungals that requires cyclodextrin for facilitating drug solubility; this is because cyclodextrin has a potential for nephrotoxicity . It is proposed that the intravenous and oral dosing can be used interchangeably , without the need for a repeat loading dose when transitioning from an IV to an oral formulation . Isavuconazonium displays excellent water solubility for intravenous formulations, good absorption, and enhanced oral bioavailability . Following administration, isavuconazonium undergoes biotransformation to form the active moiety, isavuconazole, for the antifungal actions.

Isavucoanzole exhibits antifungal activity against most strains of Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, and Mucorales such as Rhizopus oryzae and Mucormycetes species in vivo and in vitro . In a cardiac electrophysiology study involving healthy subjects, isavuconazole induced dose-related shortening of the QTc interval but the additive effect of isavuconazole with other QTc-prolonging drug is unknown .

Isavuconazole
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Isavuconazole
Generic	Isavuconazole
Isavuconazole Other Names	isavuconazol, Isavuconazole, isavuconazolum
Type
Formula	C₂₂H₁₇F₂N₅OS
Weight	Average: 437.47 Monoisotopic: 437.112187687
Protein binding	Isavuconazole is highly protein bound (greater than 99%), predominantly to albumin .
Groups	Approved, Investigational
Therapeutic Class
Manufacturer
Available Country
Last Updated:	September 19, 2023 at 7:00 am

Uses

Indicated for patients 18 years of age and older for the treatment of invasive aspergillosis .
Indicated for patients 18 years of age and older for the treatment of invasive mucormycosis , including patients where treatment amphotericin B is inappropriate .

How Isavuconazole works

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 . This explains the wide antifungal spectrum of isavuconazole and possible cross-resistance to other triazoles . 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 . 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 , and ultimately cell death. Mammalian cell demethylation is less sensitive to isavuconazole inhibition .

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 . Other multiple mechanisms leading to resistance, including changes in sterol profile and elevated efflux pump activity of fungal species, cannot be excluded .

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 .

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 . 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 . 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 . 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 . In rats, a dose-related increase in the incidence of zygomatic arch fusion was also noted in offspring .

Food Interaction

Avoid St. John's Wort.
Exercise caution with grapefruit products.

Volume of Distribution

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

Elimination Route

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 . It is proposed that the Cmax at steady state is reached approximately 2–3 hours after single and multiple dosing of isavuconazole . Administration of 400 mg of oral and intravenous isavuconazole resulted in mean AUC of 189462.8 hng/mL and 193906.8 hng/mL, respectively . 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% . The absolute bioavailability of isavuconazole following oral administration of a single dose of isavuconazole is 98% .

Half Life

Based on a population pharmacokinetics analysis of healthy subjects and patients, the mean plasma half-life of isavuconazole was 130 hours . The mean half life following oral and intravenous administration of 400 mg isavuconazole was 110 and 115 hours, respectively .

Clearance

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

Elimination Route

Following oral administration, 46.1% of total radiolabelled isavuconzaole was detected in the feces, and about 45.5% was recovered in urine . Unchanged isavuconazole in the urine was less than 1% of the total dose administered .