Caspofungin

{{Infobox drug

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| verifiedrevid =

| image = Caspofungin.svg

| image_class = skin-invert-image

| width = 275

| alt =

| pronounce = {{IPAc-en|ˌ|k|æ|s|p|oʊ|ˈ|f|ʌ|n|dʒ|ɪ|n}} {{respell|KAS|poh|FUN|jin}}

| tradename = Cancidas

| Drugs.com = {{drugs.com|monograph|caspofungin-acetate}}

| MedlinePlus = a615001

| DailyMedID = Caspofungin

| pregnancy_AU = B3

| pregnancy_AU_comment =

| pregnancy_category =

| routes_of_administration = Intravenous

| class =

| ATC_prefix = J02

| ATC_suffix = AX04

| ATC_supplemental =

| legal_AU = S4

| legal_AU_comment = {{cite web | title=Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/publication/publications/prescription-medicines-registration-new-generic-medicines-and-biosimilar-medicines-2017 | access-date=30 March 2024}}

| legal_BR =

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| legal_CA =

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| legal_DE =

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| legal_NZ =

| legal_NZ_comment =

| legal_UK =

| legal_UK_comment =

| legal_US = Rx-only

| legal_US_comment = {{cite web | title=Cancidas- caspofungin acetate injection, powder, lyophilized, for solution | website=DailyMed | date=20 November 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3bad23a6-09a6-4194-9182-093ed61bc71c | access-date=20 March 2024}}

| legal_EU = Rx-only

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| legal_UN =

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| legal_status = Rx-only

| bioavailability = 100% (intravenous use only)

| protein_bound = ~97%

| metabolism = Liver

| metabolites =

| onset =

| elimination_half-life = 9–11 hours

| duration_of_action =

| excretion = Kidney (41%), feces (35%)

| index2_label = as acetate

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 162808-62-0

| CAS_number2 = 179463-17-3

| CAS_supplemental =

| PubChem = 16119814

| PubChem2 = 16119813

| IUPHAR_ligand =

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB00520

| DrugBank2 = DB00520

| ChemSpiderID = 17277006

| ChemSpiderID2 = 5254092

| UNII = F0XDI6ZL63

| UNII2_Ref = {{fdacite|correct|FDA}}

| UNII2 = VUW370O5QE

| KEGG_Ref = {{keggcite|changed|kegg}}

| KEGG = D07626

| KEGG2 = D02501

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEBI = 474180

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 499808

| ChEMBL2 = 4297142

| NIAID_ChemDB =

| PDB_ligand =

| synonyms = (4R,5S)-5-[(2-Aminoethyl)amino]-N²-(10,12-dimethyltetradecanoyl)-
4-hydroxy-L-ornithyl-L-threonyl-trans-4-hydroxy-L-prolyl-(S)-4-hydroxy-4-(p-hydroxyphenyl)-L-threonyl-threo-3-hydroxy-L-ornithyl-trans-3-hydroxy-L-proline cyclic (6→1)-peptide
{{cite web|title=International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary names (Rec.INN): List 42|url=https://www.who.int/medicines/publications/druginformation/innlists/RL42.pdf|publisher=World Health Organization|access-date=11 November 2016|date=1999}}{{rp|185}}

1-[(4R,5S)-5-[(2-Aminoethyl)amino]-N²-(10,12-dimethyl-1-oxotetradecyl)-4-hydroxy-L-ornithine]-5-[(3R)-3-hydroxy-L-ornithine] pneumocandin B₀

| IUPAC_name = (10R,12S)-N-{(2R,6S,9S,11R,12S,14aS,15S,20S,23S,25aS)-12-[(2-Aminoethyl)amino]-20-[(1R)-3-amino-1-hydroxypropyl]-23-[(1S,2S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-2,11,15-trihydroxy-6-[(1R)-1-hydroxyethyl]-5,8,14,19,22,25-hexaoxotetracosahydro-1H-dipyrrolo[2,1-c:2',1'-l] [1,4,7,10,13,16]hexaazacyclohenicosin-9-yl}-10,12-dimethyltetradecanamide

| C=52 | H=88 | N=10 | O=15

| SMILES = [C@@]12(N(C[C@@H](C1)O)C([C@H]([C@@H](C)O)NC(=O)[C@](C[C@H]([C@@H](NCCN)NC([C@@H]3[C@H](CCN3C([C@H]([C@@H](CCN)O)NC(=O)[C@H]([C@@H]([C@H](C4=CC=C(C=C4)O)O)O)NC2=O)=O)O)=O)O)(NC(CCCCCCCC[C@H](C[C@H](CC)C)C)=O)[H])=O)[H]

| SMILES2 = CC(O)=O.CC(O)=O.[H][C@@]12C[C@@H](O)CN1C(=O)[C@@H](NC(=O)[C@]([H])(C[C@@H](O)[C@@H](NCCN)NC(=O)[C@@H]1[C@@H](O)CCN1C(=O)[C@@H](NC(=O)[C@@H](NC2=O)[C@H](O)[C@@H](O)C1=CC=C(O)C=C1)[C@H](O)CCN)NC(=O)CCCCCCCC[C@@H](C)C[C@@H](C)CC)[C@@H](C)O

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C52H88N10O15/c1-5-28(2)24-29(3)12-10-8-6-7-9-11-13-39(69)56-34-26-38(68)46(55-22-21-54)60-50(75)43-37(67)19-23-61(43)52(77)41(36(66)18-20-53)58-49(74)42(45(71)44(70)31-14-16-32(64)17-15-31)59-48(73)35-25-33(65)27-62(35)51(76)40(30(4)63)57-47(34)72/h14-17,28-30,33-38,40-46,55,63-68,70-71H,5-13,18-27,53-54H2,1-4H3,(H,56,69)(H,57,72)(H,58,74)(H,59,73)(H,60,75)/t28-,29+,30+,33+,34-,35-,36+,37-,38+,40-,41-,42-,43-,44-,45-,46-/m0/s1

| StdInChI2 = 1S/C52H88N10O15.2C2H4O2/c1-5-28(2)24-29(3)12-10-8-6-7-9-11-13-39(69)56-34-26-38(68)46(55-22-21-54)60-50(75)43-37(67)19-23-61(43)52(77)41(36(66)18-20-53)58-49(74)42(45(71)44(70)31-14-16-32(64)17-15-31)59-48(73)35-25-33(65)27-62(35)51(76)40(30(4)63)57-47(34)72;2*1-2(3)4/h14-17,28-30,33-38,40-46,55,63-68,70-71H,5-13,18-27,53-54H2,1-4H3,(H,56,69)(H,57,72)(H,58,74)(H,59,73)(H,60,75);2*1H3,(H,3,4)/t28-,29+,30+,33+,34-,35-,36+,37-,38+,40-,41-,42-,43-,44-,45-,46-;;/m0../s1

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = JYIKNQVWKBUSNH-WVDDFWQHSA-N

| StdInChIKey2 = OGUJBRYAAJYXQP-IJFZAWIJSA-N

| density =

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}}

Caspofungin (INN;[http://www.emea.europa.eu/htms/human/epar/c.htm European Medicines Agency's list of authorised medicines for human use (C)] {{webarchive |url=https://web.archive.org/web/20071017030749/http://www.emea.europa.eu/htms/human/epar/c.htm |date=17 October 2007 }} brand name Cancidas) is a lipopeptide antifungal drug from Merck & Co., Inc..{{cite web |title=Patent Covering Caspofungin |url=https://patents.google.com/patent/US5378804?oq=5378804 | access-date=18 March 2015}} It is a member of a class of antifungals termed the echinocandins.{{medcn|date=March 2024}} It works by inhibiting the enzyme (1→3)-β-D-glucan synthase and thereby disturbing the integrity of the fungal cell wall.{{medcn|date=March 2024}}

Caspofungin was the first inhibitor of fungal (1→3)-β-D-glucan synthesis to be approved by the United States Food and Drug Administration.{{cite journal | vauthors = Deresinski SC, Stevens DA | title = Caspofungin | journal = Clinical Infectious Diseases | volume = 36 | issue = 11 | pages = 1445–57 | date = June 2003 | pmid = 12766841 | doi = 10.1086/375080 | doi-access = free }} Caspofungin is administered intravenously. It is on the World Health Organization's List of Essential Medicines.{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}

Medical uses

Caspofungin acetate for injection was initially approved by both the US Food and Drug Administration (FDA), and the European Medicines Agency (EMA) in 2001.{{cn|date=March 2024}}

Its approved therapeutic indications by both organizations include the empirical therapy of presumed fungal infections in febrile, neutropenic adults and for salvage therapy in people treatment of invasive aspergillosis in adults whose disease is refractory to, or who are intolerant of, other antifungal agents (i.e., conventional or lipid formulations of amphotericin B and/or itraconazole).{{medcn|date=March 2024}} Additionally, the FDA approval includes indication for the treatment of candidemia and some specific Candida infections (intra-abdominal abscesses, peritonitis, pleural cavity infections, and esophagitis) and the EMA approval includes indication for the treatment of general invasive candidiasis in adults.{{medcn|date=March 2024}}

The mean duration of therapy in previous studies was 34 days.{{medcn|date=March 2024}} Some people were even healed by a one-day treatment. However, a few people were treated for as long as 162 days and tolerated the drug well, indicating that longtime use may be indicated and tolerated favourably in complicated cases of aspergillosis. Generally, the duration of treatment is dictated by the severity of the disease, the clinical response, and the improvement of immunocompetence in immunocompromised people.{{medcn|date=March 2024}}

About 36% of patients refractory to other therapies responded well to caspofungin therapy, while even 70% of patients intolerant to other therapies were classified as responders. Direct comparative studies to other drugs in the treatment of invasive aspergillosis have so far not been undertaken.{{medcn|date=March 2024}}

= Spectrum of activity =

Caspofungin has been effective in treating fungal infections caused by Aspergillus and Candida species. It is a member of the echinocandin family, a new class of antifungal agents with broad spectrum of activity against all Candida species. In comparison to treatment with either fluconazole or amphotericin B, all three drugs in this class have been demonstrated to be highly effective or superior in well-defined clinical settings including invasive Candida infections, Candida oesophagitis and candidaemia. Higher minimum inhibitory concentration (MIC) of these agents has been observed against C. parapsilosis and C. guilliermondii.{{cite journal |vauthors=Kofla G, Ruhnke M |date=April 2011 |title=Pharmacology and metabolism of anidulafungin, caspofungin and micafungin in the treatment of invasive candidosis: review of the literature |journal=European Journal of Medical Research |volume=16 |issue=4 |pages=159–66 |doi=10.1186/2047-783X-16-4-159 |pmc=3352072 |pmid=21486730 |doi-access=free}}

In a few patients with infections caused by Candida albicans, mutants with reduced sensitivity to caspofungin have been noticed, but is currently still rare. The mechanism is probably a point mutation in the (1→3)-β-D-glucan synthase gene.{{cite journal |vauthors=Baixench MT, Aoun N, Desnos-Ollivier M, Garcia-Hermoso D, Bretagne S, Ramires S, Piketty C, Dannaoui E |date=June 2007 |title=Acquired resistance to echinocandins in Candida albicans: case report and review |journal=The Journal of Antimicrobial Chemotherapy |volume=59 |issue=6 |pages=1076–83 |doi=10.1093/jac/dkm095 |pmid=17468115 |doi-access=}} There are no data regarding development of resistance in other fungi than C. albicans.{{medcn|date=March 2024}}

The following summarizes MIC susceptibility for a few medically significant organisms.{{Cite web |title=Archived copy |url=http://www.toku-e.com/Assets/MIC/Caspofungin%20acetate.pdf |url-status=dead |archive-url=https://web.archive.org/web/20160304002425/http://www.toku-e.com/Assets/MIC/Caspofungin%20acetate.pdf |archive-date=4 March 2016 |access-date=13 August 2013}}

Candida albicans 0.015 — 16 μg/mL
Candida krusei 0.03 — 8 μg/mL
Cryptococcus neoformans — 16 μg/mL

= Specific populations =

Caspofungin has been shown in animal studies to have embryotoxic properties.{{medcn|date=March 2024}} The drug is found in the milk of lactating rats, but it is not known whether this is seen in humans.{{medcn|date=March 2024}}

Caspofungin is FDA approved for people aged three months and older. Dosing is based on body surface area (BSA) as calculated by the Mosteller formula.{{cite journal |vauthors=Mosteller RD |date=October 1987 |title=Simplified calculation of body-surface area |journal=The New England Journal of Medicine |volume=317 |issue=17 |pages=1098 |doi=10.1056/NEJM198710223171717 |pmid=3657876}}

Adverse effects

Compared to amphotericin B, caspofungin seems to have a relatively low incidence of side effects. In clinical studies and postmarketing reports, the side effects seen in 1% or more of the patients were as follows:{{medcn|date=March 2024}}

Gastrointestinal system: nausea, vomiting, abdominal pain, and diarrhea
Central nervous system: headache
Whole body: fever, phlebitis or thrombophlebitis, complications at the intravenous cannulation site (e.g. induration), unspecified pain, flu-like syndrome, myalgia, chills, and paresthesia
Respiratory: dyspnea
Renal: increased plasma creatinine
Hematological: anemia
Electrolytes: hypokalemia
Liver: increased liver enzymes (asymptomatic)
Hypersensitivity: rash, facial edema, pruritus
Other: tachycardia

Additionally, infrequent cases of symptomatic liver damage, peripheral edema and swelling, and hypercalcemia have been seen.{{medcn|date=March 2024}}

= Liver effects =

The concomitant use of caspofungin and ciclosporin in healthy volunteers led to a more frequent increase of liver enzymes (ALT=SGPT and AST=SGOT) than noted with cyclosporine alone.{{medcn|date=March 2024}}

= Sensitivity reactions =

Reactions due to histamine release (rash, facial swelling, pruritus, sensation of warmth) have been seen.{{medcn|date=March 2024}} Known hypersensitivity to caspofungin acetate or any other ingredient contained in the formulation contraindicate its use.{{medcn|date=March 2024}}

Pharmacology

Caspofungin is semisynthesized from pneumocandin B0, a fermentation product of Glarea lozoyensis.

= Pharmacokinetics =

Caspofungin is slowly metabolized by peptide hydrolysis and N-acetylation in liver. Therefore, in case of liver impairment the dose needs to be reduced. Caspofungin also undergoes spontaneous chemical degradation to an open-ring peptide compound, L-747969. Additional metabolism involves hydrolysis into constitutive amino acids and their derivatives, including dihydroxyhomotyrosine and N-acetyl-dihydroxyhomotyrosine.

Interactions

Cyclosporin: see under liver effects
Tacrolimus: potential pharmacokinetic interactions
Other systemic antimycotic agents: with amphotericin B, itraconazole and mycophenolate, no interactions have been seen
Inducers of drug clearance (e.g. carbamazepine, phenytoin, rifampin, dexamethasone): consider 70 mg intravenous as maintenance dose instead of 50 mg

References

Category:Antifungals

Category:Echinocandins

Category:Drugs developed by Merck & Co.

Category:World Health Organization essential medicines

Category:Aminoethyl compounds