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Cresemba: A novel, broad-spectrum triazole antifungal agent
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Invasive fungal infections are associated with significant morbidity and mortality, creating the need for effective antifungal treatments.
Cresemba (isavuconazonium sulfate, Astellas Pharma), a prodrug of the novel triazole antifungal agent isavuconazole, was approved in March for the treatment of invasive mucormycosis and aspergillosis. While not approved for Candida infections, isavuconazole has in vitro activity against most Candida species, comparable to Vfend (voriconazole, Pfizer) and Noxafil (posaconazole, Merck) and more potent than Diflucan (fluconazole, Pfizer) and Sporanox (itraconazole, Janssen Pharmaceuticals).
Pharmacology
After administration, isavuconazonium sulfate is rapidly split by plasma esterases into the active drug isavuconazole and an inactive metabolite. Like other triazole antifungals, isavuconazole inhibits the 14-alpha-demethylase enzyme needed to convert lanosterol to ergosterol during fungal cell wall formation. Additionally, isavuconazole has improved binding to the fungal CYP51 protein, which confers a broader spectrum of activity, even against those fungal species resistant to other triazoles.
Owing to its long half-life, a unique loading-dosing strategy is recommended to achieve therapeutic concentrations quicker. Isavuconazole should be given as a loading dose of 200 mg every 8 hours for 2 days (6 doses) follwed by the routine dose of 200 mg once daily. This dosing strategy is identical for both IV and oral routes of administration given its 98% oral bioavailability. Unlike several other triazole antifungals, oral isavuconazole may be administered without regard for concomitant food or pH-altering agents. Additionally, the minimal interpatient variability in drug exposure negates the need for routine therapeutic drug monitoring of serum concentrations at this time.
Similar to other agents in its class, drug-drug interactions related to the CYP450 enzymes must be considered. Isavuconazole is a sensitive CYP3A4 substrate and concomitant administration of potent CYP3A4 inhibitors like Norvir (ritonavir, AbbVie) and inducers like rifampin and carbamazepine are contraindicated. As a moderate inhibitor of CYP3A4 and p-glycoprotein, coadministration with substrates of these enzymes is permissible with caution and monitoring, in contrast to coadministration of the more potent CYP3A4 inhibitor voriconazole with the CYP3A4 substrate sirolimus, which is simply contraindicated. Unlike voriconazole, isavuconazole has no impact on the function of CYP2C9 and CYP2C19, nor is it metabolized by either of these enzymes.
Renal elimination of isavuconazole appears to be minimal, so while no dosage adjustments are needed in the setting of renal dysfunction, it likely has no role in the management of urinary tract infections unlike the other triazoles, which offer potent concentrations at these sites of infection. While no dosage adjustment is recommended for patients with mild or moderate hepatic dysfunction, isavuconazole has not been studied in people with severe impairment and should thus be used only when potential benefits of therapy exceed potential risks, and with close monitoring of liver function tests.
Clinical studies
The approval of isavuconazole for treatment of invasive aspergillosis was based on results from the SECURE study, in which patients were randomly assigned to receive either voriconazole (n = 108) or isavuconazole (n = 123). The study showed comparable success rates of 39% among patients treated with voriconazole and 35% with isavuconazole. While no differences were noted in terms of treatment efficacy, isavuconazole was better tolerated than voriconazole, with significantly fewer patients experiencing drug-related adverse events (39% for isavuconazole vs. 62% for voriconazole; P < .001).
Given the variability and rarity of invasive mucormycosis, comparative studies to support the approval of isavuconazole for these infections were unavailable, and the indication was instead based on the VITAL study, an open-label noncomparative study that treated 37 patients with a 65% survival rate at 42 days and a 53% survival rate at 180 days. This was comparable to historical cure rates with amphotericin B and posaconazole, generally ranging between 35% and 45%.
Practical considerations
The improved water solubility of isavuconazole compared with voriconazole and posaconazole allows for IV administration without the use of the cyclodextrin vehicle known to accumulate in the setting of renal dysfunction. However, IV isavuconazole has its own unique requirement of an in-line filter for administration, as particulate matter composed of active isavuconazole following separation from the prodrug has been observed and may contribute to infusion-related reactions. These include respiratory distress, chills and hypotension, warranting patient monitoring during infusion. As such, the drug should be infused over 1 hour and not given as a bolus injection. In addition, vigorous shaking of the reconstituted IV product should be avoided, and the drug should be hand-delivered within an institutional setting rather than transported via typical pneumatic tube systems.
Isavuconazole is supplied as its prodrug, isavuconazonium sulfate. One capsule for oral administration contains 186 mg of the prodrug and is labeled as such. Each 186-mg capsule is equivalent to 100 mg isavuconazole. Similarly, vials for IV administration are supplied and labeled based on the total isavuconazonium sulfate content of 372 mg per vial, equal to 200 mg isavuconazole. Care must be taken when ordering and dispensing doses to maintain consistency between prodrug and active compound dosages.
As with all triazole antifungals, elevated transaminases have been reported and liver function should be monitored during therapy, though specific dosage adjustments for varying degrees of liver dysfunction have not been established. Other reported adverse events among the comprehensive list found in the drug package insert include gastrointestinal distress, peripheral edema and hypokalemia. A unique effect of unclear clinical significance is a shortened QT interval on echocardiogram, warranting its contraindication for use among patients with the rare disorder of familial short QT syndrome.
Special populations
While human data are unavailable, increased perinatal mortality and breastmilk excretion of the drug was observed in animal models. As such, isavuconazole is pregnancy category C and should also be avoided in breast-feeding mothers. Patients aged older than 65 years were represented in clinical studies, and no special considerations or dosage adjustments appear to be needed. Both clinical data and approval for use are limited to patients aged 18 years and older as no pediatric data currently exist.
Role in therapy
Isavuconazole is anticipated to serve as an important alternative for patients unable to tolerate voriconazole or posaconazole for invasive aspergillosis or mucormycosis, respectively. While efficacy appears to be similar, isavuconazole has fewer adverse events, less potential for drug-drug and drug-food interactions, and a more convenient once-daily dosing regimen.
- References:
- Cresemba. Package insert. www.astellas.us/docs/cresemba.pdf. Accessed August 25, 2015.
- Kontoyiannis D, et al. Abstract 1211. Presented at: IDWeek 2014. Oct. 8-12; Philadelphia.
- Marty FM, et al. Abstract 824: Presented at: IDWeek 2014. Oct. 8-12; Philadelphia.
- Miceli MH, et al. Clin Infect Dis. 2015;doi:10.1093/cid/civ571.
- FDA. Isavuconazonium: Invasive Aspergillosis and Invasive Mucormycosis. Advisory Committee Briefing Document. www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/anti-infectivedrugsadvisorycommittee/ucm430748.pdf. Accessed August 19, 2015.
- For more information:
- Leah Molloy, PharmD, is a clinical pharmacist, specialist in infectious diseases, at Children’s Hospital of Michigan, Detroit. She can be reached at Children’s Hospital of Michigan, Department of Pharmacy Services, 3901 Beaubien St., Detroit, MI 48201; email: lmolloy@dmc.org.
Disclosure: Molloy reports no relevant financial disclosures.
Editor's Note: On Sept. 25, we corrected the article to clarify that isavuconazole should be given as a loading dose of 200 mg every 8 hours for 2 days (6 doses) followed by the routine dose of 200 mg once daily. The Editors regret this error.