Ibrexafungerp

Ibrexafungerp (BREXAFEMME) – Description

• Ibrexafungerp is an oral triterpenoid antifungal agent indicated for the treatment of vulvovaginal candidiasis (VVC) and to reduce the incidence of recurrent vulvovaginal candidiasis (RVVC) in post-menarchal persons.
• Based on animal studies, ibrexafungerp may cause fetal harm; therefore, ibrexafungerp use is contraindicated during pregnancy.
• The most frequent adverse reactions reported with ibrexafungerp in clinical trials were abdominal pain, diarrhea, dizziness, fatigue, headache, nausea, urinary tract infection, and vomiting.⁶⁶⁷⁰⁵

Indications & Dosage

•  Candida albicans
•  Candida glabrata
•  Candida guilliermondii
•  Candida kefyr
•  Candida krusei
•  Candida lusitaniae
•  Candida parapsilosis
•  Candida sp.
•  Candida tropicalis
•  vulvovaginal candidiasis
•  vulvovaginal candidiasis prophylaxis

Contraindications

•  pregnancy

Precautions

•  breast-feeding
•  contraception requirements
•  embryo-fetal toxicity
•  pregnancy testing
•  reproductive risk

Drug Interactions of Ibrexafungerp

•  Adagrasib
•  Amobarbital
•  Amoxicillin; Clarithromycin; Omeprazole
•  Apalutamide
•  Aspirin, ASA; Butalbital; Caffeine
•  Atazanavir
•  Atazanavir; Cobicistat
•  Barbiturates
•  Bexarotene
•  Bosentan
•  Butalbital; Acetaminophen
•  Butalbital; Acetaminophen; Caffeine
•  Butalbital; Acetaminophen; Caffeine; Codeine
•  Butalbital; Aspirin; Caffeine; Codeine
•  Carbamazepine
•  Cenobamate
•  Ceritinib
•  Chloramphenicol
•  Clarithromycin
•  Cobicistat
•  Dabrafenib
•  Darunavir
•  Darunavir; Cobicistat
•  Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide
•  Efavirenz
•  Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate
•  Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate
•  Elagolix
•  Elagolix; Estradiol; Norethindrone acetate
•  Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide
•  Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate
•  Encorafenib
•  Enzalutamide
•  Eslicarbazepine
•  Etravirine
•  Fexinidazole
•  Fosphenytoin
•  grapefruit juice
•  Idelalisib
•  Itraconazole
•  Ketoconazole
•  Lansoprazole; Amoxicillin; Clarithromycin
•  Levoketoconazole
•  Lonafarnib
•  Lopinavir; Ritonavir
•  Lorlatinib
•  Lumacaftor; Ivacaftor
•  Lumacaftor; Ivacaftor
•  Methohexital
•  Mifepristone
•  Mitotane
•  Nafcillin
•  Nefazodone
•  Nelfinavir
•  Nirmatrelvir; Ritonavir
•  Omeprazole; Amoxicillin; Rifabutin
•  Pacritinib
•  Pentobarbital
•  Pexidartinib
•  Phenobarbital
•  Phenobarbital; Hyoscyamine; Atropine; Scopolamine
•  Phenytoin
•  Posaconazole
•  Primidone
•  Repotrectinib
•  Ribociclib
•  Ribociclib; Letrozole
•  Rifabutin
•  Rifampin
•  Rifapentine
•  Ritonavir
•  Saccharomyces boulardii
•  Saquinavir
•  Secobarbital
•  Sotorasib
•  St. John’s Wort, Hypericum perforatum
•  Tipranavir
•  Tucatinib
•  Vonoprazan; Amoxicillin; Clarithromycin
•  Voriconazole

Adverse Reactions

•  abdominal pain
•  back pain
•  diarrhea
•  dizziness
•  dysmenorrhea
•  elevated hepatic enzymes
•  fatigue
•  flatulence
•  headache
•  infection
•  nausea
•  rash
•  vaginal bleeding
•  vomiting

Mechanism of Action

Ibrexafungerp is a triterpenoid antifungal agent and acts by inhibiting glucan synthase, an enzyme involved in the formation of beta (1,3)-D-glucan. Beta (1,3)-D-glucan is a major fungal cell wall component, and by disrupting its biosynthesis, ibrexafungerp compromises the integrity of the fungal cell wall resulting in cell lysis. Ibrexafungerp has concentration-dependent fungicidal activity against Candida sp. and fungistatic activity against Aspergillus sp. Ibrexafungerp retains in vitro antifungal activity when tested at pH 4.5 (the normal vaginal pH).^6670566707

The potential for resistance to ibrexafungerp has been evaluated in vitro and is associated with mutations of the fks-2 gene; the clinical relevance of these findings is unknown. Ibrexafungerp retains activity against most fluconazole-resistant Candida sp. No resistance development has been observed after monthly dosing in persons with recurrent vulvovaginal candidiasis. The mechanism of action of ibrexafungerp is similar to the echinocandin antifungals; however, the binding sites on the glucan synthase enzyme are different, but partly overlap resulting in very limited cross-resistance between ibrexafungerp- and echinocandin-resistant strains. In vitro studies have not demonstrated antagonism between ibrexafungerp and azoles or echinocandins.^6670566707

Pharmacokinetics

Ibrexafungerp is administered orally. The mean steady-state Vd of ibrexafungerp is approximately 600 L. Ibrexafungerp is highly protein bound (more than 99%), predominately to albumin. Animal studies demonstrate a 9-fold higher exposure in vaginal tissue than in blood. Ibrexafungerp is eliminated mainly by metabolism and biliary excretion. Metabolism occurs via hydroxylation by CYP3A4, followed by glucuronidation and sulfation of a hydroxylated inactive metabolite. After oral administration of radiolabeled ibrexafungerp to healthy volunteers, a mean of 90% of the radioactive dose (51% as unchanged ibrexafungerp) was recovered in feces and 1% was recovered in urine. The elimination half-life of ibrexafungerp is approximately 20 hours.⁶⁶⁷⁰⁵

Affected cytochrome P450 isoenzymes and drug transporters: CYP2C8, CYP3A4, OATP1B3, P-gp

Ibrexafungerp is a substrate of CYP3A4 and P-gp. Concurrent administration with CYP3A4 inducers or inhibitors may alter ibrexafungerp plasma concentrations. Ibrexafungerp is also an inhibitor of CYP2C8, CYP3A4, OATP1B3, or P-gp; however, due to the short treatment duration, ibrexafungerp is not expected to significantly alter the pharmacokinetics of CYP2C8, CYP3A4, OATP1B3, or P-gp substrates.⁶⁶⁷⁰⁵

•Route-Specific Pharmacokinetics

Oral Route

After oral administration, ibrexafungerp generally reaches maximum plasma concentrations at 4 to 6 hours after single and multiple dosing. In a study of healthy volunteers, ibrexafungerp AUC and C_max increased approximately dose-proportionally after single-dose administration of 10 to 1,600 mg and multiple-dose administration of 300 to 800 mg. Based on a population pharmacokinetic analysis in patients with vulvovaginal candidiasis, the model predicts that 300 mg twice daily for 2 doses achieves a mean AUC_0-24 exposure of 6,832 ng x hour/mL and Cmax of 435 ng/mL under fasted conditions and a mean AUC_0-24 exposure of 9,867 ng x hour/mL and Cmax of 629 ng/mL under fed conditions. Administration with a high fat meal (800 to 1,000 calories; 50% fat) increased the C_max and AUC by 32% and 38%, respectively, as compared to fasting conditions; these changes are not considered clinically significant.⁶⁶⁷⁰⁵

•Special Populations

Hepatic Impairment

The pharmacokinetics of ibrexafungerp were not altered in subjects with mild or moderate hepatic impairment (Child-Pugh Class A or B) when the total AUC estimates were compared to healthy subjects. The impact of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of ibrexafungerp is unknown.⁶⁶⁷⁰⁵

Pediatrics

The pharmacokinetics of ibrexafungerp are not altered in post-menarchal adolescents (ages 13 to 17 years).⁶⁶⁷⁰⁵

Geriatric

A study in geriatric patients (ages 65 to 76 years) found no clinically meaningful differences in the pharmacokinetics of ibrexafungerp when compared to younger adults.⁶⁶⁷⁰⁵

Monitoring Parameters

Monitoring Parameters

•  pregnancy testing

Classifications

• General Anti-infectives Systemic
  • Systemic Antifungals
    •  Triterpenoid Antifungals

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