Isavuconazole
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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.
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.
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 .
适用于治疗18岁和以上人群： ⑴侵袭性曲霉菌病[aspergillosis]。 ⑵侵袭性毛霉菌病[mucormycosis]。
每项发明一条，涵盖美国、欧洲、PCT 与中国的同族专利。
