Anidulafungin

Anidulafungin (INN)[1]: 42  (trade names Eraxis, Ecalta) is a semisynthetic echinocandin used as an antifungal drug. It was previously known as LY303366.[3][4][5] It may also have application in treating invasive Aspergillus infection when used in combination with voriconazole.[6] It is a member of the class of antifungal drugs known as the echinocandins; its mechanism of action is by inhibition of (1→3)-β-D-glucan synthase, an enzyme important to the synthesis of the fungal cell wall.[7]

Anidulafungin
Clinical data
Pronunciation/eɪˌnɪdjʊləˈfʌndʒɪn/ ay-NID-yuu-lə-FUN-jin
Trade namesEraxis, Ecalta
Other names(4R,5S)-4,5-Dihydroxy-N2-[[4''-(pentyloxy)-p-terphenyl-4-yl]carbonyl]-L-ornithyl-L-threonyl-trans-4-hydroxy-L-prolyl-(S)-4-hydroxy-4-(p-hydroxyphenyl)-L-threonyl-L-threonyl-(3S,4S)-3-hydroxy-4-methyl-L-proline cyclic (6→1)-peptide[1]
1-[(4R,5R)-4,5-Dihydroxy-N2-[[4''-(pentyloxy)[1',1':4',1''-terphenyl]-4-yl]carbonyl]-L-ornithine]echinocandin B[2]
AHFS/Drugs.comMonograph
License data
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability100% (intravenous use only)
Protein bindingExtensive (>99%)
MetabolismHepatic metabolism not observed, CYP system not involved
Elimination half-life27 hours; 40–50 hours (terminal)
ExcretionFeces (~30%), urine (<1%)
Identifiers
IUPAC name
  • N-[(3S,6S,9S,11R,15S,18S,20R,21R,24S,25S,26S)-6-[(1S,2R)-1,2-Dihydroxy-2-(4-hydroxyphenyl)ethyl]-11,20,21,25-tetrahydroxy-3,15-bis[(1R)-1-hydroxyethyl]-26-methyl-2,5,8,14,17,23-hexaoxo-1,4,7,13,16,22-hexaazatricyclo[22.3.0.09,13]heptacosan-18-yl]- 4-{4-[4-(pentyloxy)phenyl]phenyl}benzamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.184.856
Chemical and physical data
FormulaC58H73N7O17
Molar mass1140.254 g·mol−1
3D model (JSmol)
SMILES
  • CCCCCOc1ccc(cc1)c2ccc(cc2)c3ccc(cc3)C(=O)N[C@H]6C[C@@H](O)[C@@H](O)NC(=O)C4[C@@H](O)[C@@H](C)CN4C(=O)C(NC(=O)C(NC(=O)C5C[C@@H](O)CN5C(=O)C(NC6=O)[C@@H](C)O)[C@@H](O)[C@H](O)c7ccc(O)cc7)[C@@H](C)O
InChI
  • InChI=1S/C58H73N7O17/c1-5-6-7-24-82-40-22-18-35(19-23-40)33-10-8-32(9-11-33)34-12-14-37(15-13-34)51(74)59-41-26-43(70)54(77)63-56(79)47-48(71)29(2)27-65(47)58(81)45(31(4)67)61-55(78)46(50(73)49(72)36-16-20-38(68)21-17-36)62-53(76)42-25-39(69)28-64(42)57(80)44(30(3)66)60-52(41)75/h8-23,29-31,39,41-50,54,66-73,77H,5-7,24-28H2,1-4H3,(H,59,74)(H,60,75)(H,61,78)(H,62,76)(H,63,79)/t29-,30+,31+,39+,41-,42?,43+,44?,45?,46?,47?,48-,49+,50+,54+/m0/s1 Y
  • Key:JHVAMHSQVVQIOT-QZNDWXLFSA-N Y
 NY (what is this?)  (verify)

It is on the World Health Organization's List of Essential Medicines.[8]

Indications

Anidulafungin has not been studied in endocarditis, osteomyelitis, and meningitis due to Candida, and has not been studied in sufficient numbers of neutropenic patients to determine efficacy in this group.[2]

Pharmacodynamics and pharmacokinetics

Anidulafungin significantly differs from other antifungals in that it undergoes chemical degradation to inactive forms at body pH and temperature. Because it does not rely on enzymatic degradation or hepatic or renal excretion, the drug is safe to use in patients with any degree of hepatic or renal impairment.[9]

Volume of distribution: 30–50 L.

Anidulafungin is not evidently metabolized by the liver. This specific drug undergoes slow chemical hydrolysis to an open-ring peptide which lacks antifungal activity. The half-life of the drug is 27 hours. About 30% is excreted in the feces (10% as unchanged drug). Less than 1% is excreted in the urine.[10][11][12]

Mechanism of action

Anidulafungin inhibits glucan synthase, an enzyme important in the formation of (1→3)-β-D-glucan, a major fungal cell wall component. Glucan synthase is not present in mammalian cells, so it is an attractive target for antifungal activity.[13]

Semisynthesis

Anidulafungin is manufactured via semi-synthesis. The starting material is echinocandin B (a lipopeptide fermentation product of Aspergillus nidulans or the closely related species, A. rugulosus), which undergoes deacylation (cleavage of the linoleoyl side chain) by the action of a deacylase enzyme from the bacterium Actinoplanes utahensis;[14] in three subsequent synthetic steps, including a chemical reacylation, the antifungal drug anidulafungin[13][15] is synthesized.

History

Anidulafungin was originally discovered at Lilly laboratories by Turner and Debono and licensed to Vicuron Pharmaceuticals who submitted it to the FDA.[16] Pfizer acquired the drug upon its acquisition of Vicuron in the fall of 2005.[17] Pfizer gained approval by the Food and Drug Administration (FDA) on February 21, 2006.[18]

References
  1. "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary names: List 43" (PDF). World Health Organization. 2000. Retrieved 11 November 2016.
  2. "Eraxis (anidulafungin) for Injection, for Intravenous Use. Full Prescribing Information". Roerig (Division of Pfizer, Inc.), New York, NY 10017. Retrieved 11 November 2016.
  3. Krause DS, Reinhardt J, Vazquez JA, Reboli A, Goldstein BP, Wible M, Henkel T (2004). "Phase 2, randomized, dose-ranging study evaluating the safety and efficacy of anidulafungin in invasive candidiasis and candidemia". Antimicrob Agents Chemother. 48 (6): 2021–4. doi:10.1128/AAC.48.6.2021-2024.2004. PMC 415613. PMID 15155194.
  4. Pfaller MA, Boyken L, Hollis RJ, Messer SA, Tendolkar S, Diekema DJ (2005). "In Vitro Activities of Anidulafungin against More than 2,500 Clinical Isolates of Candida spp., Including 315 Isolates Resistant to Fluconazole". J Clin Microbiol. 43 (11): 5425–7. doi:10.1128/JCM.43.11.5425-5427.2005. PMC 1287823. PMID 16272464.
  5. Pfaller MA, Diekema DJ, Boyken L, Messer SA, Tendolkar S, Hollis RJ, Goldstein BP (2005). "Effectiveness of anidulafungin in eradicating Candida species in invasive candidiasis". Antimicrob Agents Chemother. 49 (11): 4795–7. doi:10.1128/AAC.49.11.4795-4797.2005. PMC 1280139. PMID 16251335.
  6. Grau, Santiago; Azanza, Jose Ramon; Ruiz, Isabel; Vallejo, Carlos; Mensa, Josep; Maertens, Johan; Heinz, Werner J.; Barrueta, Jon Andoni; Peral, Carmen (2017-01-01). "Cost-effectiveness analysis of combination antifungal therapy with voriconazole and anidulafungin versus voriconazole monotherapy for primary treatment of invasive aspergillosis in Spain". ClinicoEconomics and Outcomes Research. 9: 39–47. doi:10.2147/CEOR.S122177. PMC 5221484. PMID 28115858.
  7. Zida, A.; Bamba, S.; Yacouba, A.; Ouedraogo-Traore, R.; Guiguemdé, R. T. (2017-03-01). "Anti-Candida albicans natural products, sources of new antifungal drugs: A review". Journal de Mycologie Médicale. 27 (1): 1–19. doi:10.1016/j.mycmed.2016.10.002. ISSN 1773-0449. PMID 27842800.
  8. World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
  9. "Eraxis at RxList". 2009-06-24. Retrieved 2009-08-01.
  10. Trissel LA and Ogundele AB, "Compatibility of Anidulafungin With Other Drugs During Simulated Y-Site Administration,"Am J Health-Sys Pharm, 2005, 62:834-7.
  11. Vazquez JA, "Anidulafungin: A New Echinocandin With a Novel Profile," Clin Ther, 2005, 27(6):657-73.
  12. Walsh TJ, Anaissie EJ, Denning DW, et al., "Treatment of Aspergillosis: Clinical Practice Guidelines of the Infectious Diseases Society of America," Clin Infect Dis, 2008, 46(3):327-60
  13. Denning DW (1997). "Echinocandins and pneumocandins - a new antifungal class with a novel mode of action". J Antimicrob Chemother. 40 (5): 611–614. doi:10.1093/jac/dkf045. PMID 9421307.
  14. Lei Shao; Jian Li; Aijuan Liu; Qing Chang; Huimin Lin; Daijie Chen (2013). "Efficient Bioconversion of Echinocandin B to Its Nucleus by Overexpression of Deacylase Genes in Different Host Strains". Applied and Environmental Microbiology. 79 (4): 1126–1133. Bibcode:2013ApEnM..79.1126S. doi:10.1128/AEM.02792-12. PMC 3568618. PMID 23220968.
  15. "Anidulafungin EMA Europa" (PDF).
  16. PRNewswire. Vicuron Pharmaceuticals Files New Drug Application (NDA) for Anidulafungin for Treatment of Invasive Candidiasis/Candidemia Archived May 16, 2012, at the Wayback Machine 08-18-2005.
  17. PRNewswire. Vicuron Pharmaceuticals Stockholders Approve Merger With Pfizer Archived May 16, 2012, at the Wayback Machine 08-15-2005
  18. "FDA Approves New Treatment for Fungal Infections". FDA News Release. Food and Drug Administration. 2006-02-21. Archived from the original on 10 July 2009. Retrieved 2009-08-01.
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