Discovered in 2009 as MK-3118 or SCY-078 enfumafungin derivatives. Approved for use in the United States in 2021 for treatment of vulvovaginal candidiasis.
|Structure and mechanism|
Ibrexafungerp is the first of a new class of oral glucan synthase inhibitors. While the mode of action and spectrum of activity is similar to the echinocandins, this treatment is notable for its high oral bioavailability.
Ibrexafungerp is a non-competitive inhibitor of β-(1,3) D-glucan with different binding sites than the echinocandins.
|Formulations and dosage|
Oral tablets of 150 mg.
There is also an IV version in clinical development examining the efficacy in treating invasive aspergillosis in combination therapy with azoles.
ACTIVE – most Candida spp., including azole resistant strains and C. auris.
Fungistatic for Aspergillus spp.
Good activity was also shown against Penicillium spp., most dermatophytes, Paecilomyces variotii, Scytalidium dimidiatum as well as Alternaria spp. and Cladosporium spp.
Some activity against the multi-resistant Lomentospora prolificans was demonstrated.
Activity against C. lusitaniae and C. krusei is lower than other Candida spp.
Cross-resistance between echinocandin- and ibrexafungerp-resistant strains is rare.
Ibrexafungerp has potent activity against most, but not all, echinocandin-resistant C. glabrata.
Certain amino acid mutations in either of the glucan synthase copies in Candida spp. lead to ibrexafungerp resistance.
INACTIVE – Cryptococcus, Mucorales, Trichosporon and other fungi.
For vulvovaginal candidiasis, the dose of ibrexafungerp is 300 mg twice a day, for a single day.
Ibrexafungerp is ~50% bioavailable after oral administration, with some inter-patient variability.
Peak concentrations occur after 6-9 hours and the half-life is 16-24 hours. It is extensively distributed to most tissues in much greater concentrations than in plasma (4- to 50-fold), but not to the brain.
Metabolism is via cytochrome P450 CYP3A4, so that >90% is excreted via the liver and bile and <2% in urine.
Exposure to ibrexafungerp may increase if given in combination with strong CYP3A4 inhibitors such as diltiazem, and the dose should be reduced by 50%. Lower concentrations of ibreaxungerp are likely if given concomitantly with rifampin, carbamazepine, phenytoin, St. John’s wort, bosentan, efavirenz, or etravirine.
|Side effects and toxicity|
Ibrexafungerp is teratogenic in some experimental animals and contraindicated in pregnancy.
The most common adverse events during therapy are diarrhoea, nausea, abdominal discomfort, vomiting and light-headedness. Unusual or rare side effects include dysmenorrhea, flatulence, back pain, elevated transaminases, vaginal bleeding or skin rash.