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 names	Eraxis, 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.com	Monograph
License data	EU EMA: by INN US FDA: Anidulafungin
Routes of administration	Intravenous
ATC code	J02AX06 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	100% (intravenous use only)
Protein binding	Extensive (>99%)
Metabolism	Hepatic metabolism not observed, CYP system not involved
Elimination half-life	27 hours; 40–50 hours (terminal)
Excretion	Feces (~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	166663-25-8 Y
PubChem CID	166548
DrugBank	DB00362 Y
ChemSpider	21106258 Y
UNII	9HLM53094I
KEGG	D03211 N
ChEBI	CHEBI:55346 N
ChEMBL	ChEMBL1630215 N
CompTox Dashboard (EPA)	DTXSID50873201
ECHA InfoCard	100.184.856
Chemical and physical data
Formula	C58H73N7O17
Molar mass	1140.254 g·mol−1
3D model (JSmol)	Interactive image
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

• Candidemia and other forms of invasive Candida infections (intra-abdominal abscess and peritonitis)
• Esophageal candidiasis

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]

Pharmacology

Pharmacodynamics

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]

Parameter	Value
Volume of distribution (L)	30–50 L.[10]
Plasma protein binding (%)	99%[10]
Elimination half-life [h]	24 hours[10]

Pharmacokinetics

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.^[11][12][13]

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.^[14]

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;^[15] in three subsequent synthetic steps, including a chemical reacylation, the antifungal drug anidulafungin^[14][16] 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.^[17] Pfizer acquired the drug upon its acquisition of Vicuron in the fall of 2005.^[18] Pfizer gained approval by the Food and Drug Administration (FDA) on February 21, 2006.^[19]

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, et al. (June 2004). "Phase 2, randomized, dose-ranging study evaluating the safety and efficacy of anidulafungin in invasive candidiasis and candidemia". Antimicrobial Agents and Chemotherapy. 48 (6): 2021–2024. 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 (November 2005). "In vitro activities of anidulafungin against more than 2,500 clinical isolates of Candida spp., including 315 isolates resistant to fluconazole". Journal of Clinical Microbiology. 43 (11): 5425–5427. 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, et al. (November 2005). "Effectiveness of anidulafungin in eradicating Candida species in invasive candidiasis". Antimicrobial Agents and Chemotherapy. 49 (11): 4795–4797. doi:10.1128/AAC.49.11.4795-4797.2005. PMC 1280139. PMID 16251335.
6. Grau S, Azanza JR, Ruiz I, Vallejo C, Mensa J, Maertens J, et al. (January 2017). "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 RT (March 2017). "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. 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". RxList. 24 June 2009. Retrieved 1 August 2009.
10. Kofla G, Ruhnke M (April 2011). "Pharmacology and metabolism of anidulafungin, caspofungin and micafungin in the treatment of invasive candidosis: review of the literature". European Journal of Medical Research. 16 (4): 159–166. doi:10.1186/2047-783x-16-4-159. PMC 3352072. PMID 21486730.
11. Trissel LA, Ogundele AB (April 2005). "Compatibility of anidulafungin with other drugs during simulated Y-site administration". American Journal of Health-System Pharmacy. 62 (8): 834–837. doi:10.1093/ajhp/62.8.834. PMID 15821277.
12. Vazquez JA (June 2005). "Anidulafungin: a new echinocandin with a novel profile". Clinical Therapeutics. 27 (6): 657–673. doi:10.1016/j.clinthera.2005.06.010. PMID 16117974.
13. Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA, et al. (February 2008). "Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America" (PDF). Clinical Infectious Diseases. 46 (3): 327–360. doi:10.1086/525258. PMID 18177225. S2CID 8789905.
14. Denning DW (November 1997). "Echinocandins and pneumocandins--a new antifungal class with a novel mode of action". The Journal of Antimicrobial Chemotherapy. 40 (5): 611–614. doi:10.1093/jac/dkf045. PMID 9421307.
15. Shao L, Li J, Liu A, Chang Q, Lin H, Chen D (February 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.
16. "Anidulafungin" (PDF). EMA Europa. 2007.
17. "Vicuron Pharmaceuticals Files New Drug Application (NDA) for Anidulafungin for Treatment of Invasive Candidiasis/Candidemia". PRNewswire. 18 August 2005. Archived from the original on 16 May 2012.
18. "Vicuron Pharmaceuticals Stockholders Approve Merger With Pfizer". PRNewswire. 15 August 2005. Archived from the original on 16 May 2012.
19. "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 1 August 2009.