Caspofungin Explained

Verifiedfields:changed
Watchedfields:changed
Width:275
Tradename:Cancidas
Dailymedid:Caspofungin
Pregnancy Au:B3
Routes Of Administration:Intravenous
Atc Prefix:J02
Atc Suffix:AX04
Legal Au:S4
Legal Au Comment:[1]
Legal Us:Rx-only
Legal Us Comment:[2]
Legal Eu:Rx-only
Legal Status:Rx-only
Bioavailability:100% (intravenous use only)
Protein Bound:~97%
Metabolism:Liver
Elimination Half-Life:9–11 hours
Excretion:Kidney (41%), feces (35%)
Index2 Label:as acetate
Cas Number:162808-62-0
Cas Number2:179463-17-3
Pubchem:16119814
Pubchem2:16119813
Drugbank:DB00520
Drugbank2:DB00520
Chemspiderid:17277006
Chemspiderid2:5254092
Unii:F0XDI6ZL63
Unii2:VUW370O5QE
Kegg:D07626
Kegg2:D02501
Chebi:474180
Chembl:499808
Chembl2:4297142
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
[3] 1-[(4''R'',5''S'')-5-[(2-Aminoethyl)amino]-N2-(10,12-dimethyl-1-oxotetradecyl)-4-hydroxy-L-ornithine]-5-[(3''R'')-3-hydroxy-L-ornithine] pneumocandin B0
Iupac Name:(10R,12S)-N--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: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:JYIKNQVWKBUSNH-WVDDFWQHSA-N
Stdinchikey2:OGUJBRYAAJYXQP-IJFZAWIJSA-N

Caspofungin (INN;[3] [4] brand name Cancidas) is a lipopeptide antifungal drug from Merck & Co., Inc..[5] It is a member of a class of antifungals termed the echinocandins. It works by inhibiting the enzyme (1→3)-β-D-glucan synthase and thereby disturbing the integrity of the fungal cell wall.

Caspofungin was the first inhibitor of fungal (1→3)-β-D-glucan synthesis to be approved by the United States Food and Drug Administration.[6] Caspofungin is administered intravenously. It is on the World Health Organization's List of Essential Medicines.[7]

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.

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). 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.

The mean duration of therapy in previous studies was 34 days. 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 peopls.

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.

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.[8]

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.[9] There are no data regarding development of resistance in other fungi than C. albicans.

The following summarizes MIC susceptibility for a few medically significant organisms.[10]

Specific populations

Caspofungin has been shown in animal studies to have embryotoxic properties. The drug is found in the milk of lactating rats, but it is not known whether this is seen in humans.

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.[11]

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:

Additionally, infrequent cases of symptomatic liver damage, peripheral edema and swelling, and hypercalcemia have been seen.

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.

Sensitivity reactions

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

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

Notes and References

  1. Web site: Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017 . Therapeutic Goods Administration (TGA) . 21 June 2022 . 30 March 2024.
  2. Web site: Cancidas- caspofungin acetate injection, powder, lyophilized, for solution . DailyMed . 20 November 2023 . 20 March 2024.
  3. Web site: International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary names (Rec.INN): List 42. World Health Organization. 11 November 2016. 1999.
  4. http://www.emea.europa.eu/htms/human/epar/c.htm European Medicines Agency's list of authorised medicines for human use (C)
  5. Web site: Patent Covering Caspofungin . 18 March 2015.
  6. Deresinski SC, Stevens DA . Caspofungin . Clinical Infectious Diseases . 36 . 11 . 1445–57 . June 2003 . 12766841 . 10.1086/375080 . free .
  7. Book: ((World Health Organization)) . The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) . 2023 . 10665/371090 . World Health Organization . World Health Organization . Geneva . WHO/MHP/HPS/EML/2023.02 . free .
  8. 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 . 159–66 . 10.1186/2047-783X-16-4-159 . 3352072 . 21486730 . free.
  9. Baixench MT, Aoun N, Desnos-Ollivier M, Garcia-Hermoso D, Bretagne S, Ramires S, Piketty C, Dannaoui E . June 2007 . Acquired resistance to echinocandins in Candida albicans: case report and review . The Journal of Antimicrobial Chemotherapy . 59 . 6 . 1076–83 . 10.1093/jac/dkm095 . 17468115 .
  10. Web site: Archived copy . dead . https://web.archive.org/web/20160304002425/http://www.toku-e.com/Assets/MIC/Caspofungin%20acetate.pdf . 4 March 2016 . 13 August 2013.
  11. Mosteller RD . October 1987 . Simplified calculation of body-surface area . The New England Journal of Medicine . 317 . 17 . 1098 . 10.1056/NEJM198710223171717 . 3657876.