Ibrexafungerp

Last updated

Ibrexafungerp
Ibrexafungerp.svg
Clinical data
Pronunciation /ˌbrɛksəˈfʌnɜːrp/
eye-BREKS-ə-FUN-jurp
Trade names Brexafemme
Other namesSCY-078
License data
Pregnancy
category
  • Contraindicated [1]
Routes of
administration
oral, intravenous
Drug class Antifungal
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding >99% [1]
Metabolism Hydroxylation (CYP3A4) then conjugation (glucuronidation, sulfation) [1]
Elimination half-life 20 hours [1]
Identifiers
  • (1R,5S,6R,7R,10R,11R,14R,15S,20R,21R)-21-[(2R)-2-amino-2,3,3-trimethylbutoxy]-5,7,10,15-tetramethyl-7-[(2R)-3-methylbutan-2-yl]-20-(5-pyridin-4-yl-1,2,4-triazol-1-yl)-17-oxapentacyclo[13.3.3.01,14.02,11.05,10]henicos-2-ene-6-carboxylic acid
CAS Number
PubChem CID
DrugBank
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C44H67N5O4
Molar mass 730.051 g·mol−1
3D model (JSmol)
  • CC(C)[C@@H](C)[C@@]1(C)CC[C@]2(C)[C@H]3CC[C@H]4[C@@]5(C)COC[C@@]4(C[C@@H](n4ncnc4-c4ccncc4)[C@@H]5OC[C@](C)(N)C(C)(C)C)C3=CC[C@@]2(C)[C@@H]1C(=O)O
  • InChI=1S/C44H67N5O4/c1-27(2)28(3)39(7)18-19-41(9)30-12-13-33-40(8)23-52-25-44(33,31(30)14-17-42(41,10)34(39)37(50)51)22-32(35(40)53-24-43(11,45)38(4,5)6)49-36(47-26-48-49)29-15-20-46-21-16-29/h14-16,20-21,26-28,30,32-35H,12-13,17-19,22-25,45H2,1-11H3,(H,50,51)/t28-,30+,32-,33+,34-,35+,39-,40-,41-,42+,43+,44+/m1/s1
  • Key:BODYFEUFKHPRCK-ZCZMVWJSSA-N

Ibrexafungerp, sold under the brand name Brexafemme, is an antifungal medication used to treat vulvovaginal candidiasis (VVC) (vaginal yeast infection). [1] It is taken orally (by mouth). [1] It is also currently undergoing clinical trials for other indications via an intravenous (IV) formulation. An estimated 75% of women will have at least one episode of VVC and 40 to 45% will have two or more episodes in their lifetime. [2]

Contents

Ibrexafungerp acts via inhibition of glucan synthase, which prevents formation of the fungal cell wall. [1]

Ibrexafungerp was approved for medical use in the United States in June 2021. [1] [3] It is the first non-azole oral antifungal drug to be approved by the U.S. Food and Drug Administration (FDA) for the treatment of vaginal yeast infections. [3] The FDA considers it to be a first-in-class medication. [4]

Medical uses

Ibrexafungerp is indicated for the treatment of adult and postmenarchal pediatric females with vulvovaginal candidiasis (VVC). [1] [3]

Ibrexafungerp is currently undergoing late-stage clinical trials for an intravenous formulation for the treatment of various fungal diseases, including life-threatening fungal infections caused primarily by Candida (including C. auris) and Aspergillus species. It has demonstrated broad-spectrum antifungal activity, in vitro and in vivo, against multidrug-resistant pathogens, including azole- and echinocandin-resistant strains. [5]

Pharmacology

Pharmacodynamics

Ibrexafungerp is a triterpenoid antifungal agent. [1] It acts via inhibition of the enzyme glucan synthase, which is involved in the formation of 1,3-β-D-glucan—an essential component of the fungal cell wall. [1] The compound has concentration-dependent fungicidal activity against Candida species. [1]

Pharmacokinetics

Ibrexafungerp has a time to maximal concentrations of 4 to 6 hours. [1] It is metabolized by hydroxylation via CYP3A4 and subsequently by glucuronidation and sulfation. [1] The medication has an elimination half-life of approximately 20 hours. [1]

Synthesis

Synthetic pathway of ibrexafungerp, adapted from Scheme 1 of McInturff et al. 2023. Ibrexafungerp synthesis.svg
Synthetic pathway of ibrexafungerp, adapted from Scheme 1 of McInturff et al. 2023.

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<span class="mw-page-title-main">Antifungal</span> Pharmaceutical fungicide or fungistatic used to treat and prevent mycosis

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<span class="mw-page-title-main">Nystatin</span> Pharmaceutical drug

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<span class="mw-page-title-main">Amphotericin B</span> Antifungal and antiparasitaric chemical compound

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<span class="mw-page-title-main">Miconazole</span> Chemical compound

Miconazole, sold under the brand name Monistat among others, is an antifungal medication used to treat ring worm, pityriasis versicolor, and yeast infections of the skin or vagina. It is used for ring worm of the body, groin, and feet. It is applied to the skin or vagina as a cream or ointment.

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Invasive candidiasis is an infection (candidiasis) that can be caused by various species of Candida yeast. Unlike Candida infections of the mouth and throat or vagina, invasive candidiasis is a serious, progressive, and potentially fatal infection that can affect the blood (fungemia), heart, brain, eyes, bones, and other parts of the body.

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TOL-463 is an anti-infective medication which is under development for the treatment of bacterial vaginosis (BV) and vulvovaginal candidiasis (VVC). It is a boric acid-based vaginal anti-infective enhanced with ethylenediaminetetraacetic acid (EDTA) which was designed to have improved activity against vaginal bacterial and fungal biofilms while sparing protective lactobacilli. EDTA enhances the antimicrobial activity of boric acid and improves its efficacy against relevant biofilms. In a small phase 2 randomized controlled trial, TOL-463 as an insert or gel achieved clinical cure rates of 50–59% against BV and 81–92% against VVC in women who had one or both conditions. It was effective and safe in the study, though it was without indication of superiority over other antifungal medications for VVC. The cure rates against BV with TOL-463 were said to be comparable to those with recently approved antibiotic treatments like single-dose oral secnidazole (58%) and single-dose metronidazole vaginal gel (41%). As of May 2019, TOL-463 is in phase 2 clinical trials for the treatment of BV and VVC. It was originated by Toltec Pharmaceuticals and is under development by Toltec Pharmaceuticals and the National Institute of Allergy and Infectious Diseases.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 "Brexafemme- ibrexafungerp tablet, film coated". DailyMed. Retrieved 12 September 2021.
  2. "Vulvovaginal Candidiasis - STI Treatment Guidelines". www.cdc.gov. 22 July 2021. Retrieved 6 April 2022.
  3. 1 2 3 "Scynexis Announces FDA Approval of Brexafemme (ibrexafungerp tablets) as the First and Only Oral Non-Azole Treatment for Vaginal Yeast Infections". Scynexis, Inc. (Press release). 2 June 2021. Archived from the original on 31 December 2021. Retrieved 2 June 2021.
  4. Advancing Health Through Innovation: New Drug Therapy Approvals 2021 (PDF). U.S. Food and Drug Administration (FDA) (Report). 13 May 2022. Archived from the original on 6 December 2022. Retrieved 22 January 2023.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  5. "SCYNEXIS Announces Successful Completion of Phase 1 Trial Evaluating Intravenous (IV) Formulation of Ibrexafungerp". www.scynexis.com. Scynexis inc. 9 November 2021. Archived from the original on 20 October 2022. Retrieved 20 October 2022.
  6. McInturff, Emma L.; France, Scott P.; Leverett, Carolyn A.; Flick, Andrew C.; Lindsey, Erick A.; Berritt, Simon; Carney, Daniel W.; DeForest, Jacob C.; Ding, Hong X.; Fink, Sarah J.; Gibson, Tony S.; Gray, Kaitlyn; Hubbell, Aran K.; Johnson, Amber M.; Liu, Yiyang; Mahapatra, Subham; McAlpine, Indrawan J.; Watson, Rebecca B.; O’Donnell, Christopher J. (1 August 2023). "Synthetic Approaches to the New Drugs Approved During 2021". Journal of Medicinal Chemistry. American Chemical Society (ACS). 66 (15): 10150–10201. doi:10.1021/acs.jmedchem.3c00501. ISSN   0022-2623.

Further reading