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Cancidas

PubChem CID
2826718
Structure
Cancidas_small.png
Molecular Formula
Synonyms
  • Caspofungin
  • Cancidas
  • MK-991
  • Cancidas (TN)
  • 162808-62-0
Molecular Weight
1093.3 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2005-07-20
  • Modify:
    2025-01-18
Description
Caspofungin (brand name Cancidas worldwide) is an antifungal drug and the first member of a new drug class called the echinocandins, as coined by Merck & Co., Inc. It is typically administered intravenously. It shows activity against infections with Aspergillus and Candida, and works by inhibiting β(1,3)-D-Glucan of the fungal cell wall.
Caspofungin is an antimycotic echinocandin lipopeptide, semisynthetically derived from a fermentation product of the fungus Glarea lozoyensis. Caspofungin inhibits 1,3-beta-glucan synthase, resulting in decreased synthesis of beta(1,3)-D-glucan (an essential component of the fungal cell wall), weakening of the fungal cell wall, and fungal cell wall rupture. This agent is active against Aspergillus and Candida species.
A cyclic lipopeptide echinocandin and beta-(1,3)-D-glucan synthase inhibitor that is used to treat internal or systemic MYCOSES.
See also: Caspofungin (annotation moved to).

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Cancidas.png

1.2 3D Status

Conformer generation is disallowed since too many atoms, too flexible

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

N-[(3S,6S,9S,11R,15S,18S,20R,21S,24S,25S)-21-(2-aminoethylamino)-3-[(1R)-3-amino-1-hydroxypropyl]-6-[(1S,2S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-11,20,25-trihydroxy-15-[(1R)-1-hydroxyethyl]-2,5,8,14,17,23-hexaoxo-1,4,7,13,16,22-hexazatricyclo[22.3.0.09,13]heptacosan-18-yl]-10,12-dimethyltetradecanamide
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

InChI=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+/m1/s1
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

JYIKNQVWKBUSNH-OGZDCFRISA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

CCC(C)CC(C)CCCCCCCCC(=O)N[C@H]1C[C@H]([C@H](NC(=O)[C@@H]2[C@H](CCN2C(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@@H](NC1=O)[C@@H](C)O)O)[C@@H]([C@H](C4=CC=C(C=C4)O)O)O)[C@@H](CCN)O)O)NCCN)O
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C52H88N10O15
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

162808-62-0

2.3.2 ChEMBL ID

2.3.3 DrugBank ID

2.3.4 DSSTox Substance ID

2.3.5 KEGG ID

2.3.6 Metabolomics Workbench ID

2.3.7 NCI Thesaurus Code

2.3.8 PharmGKB ID

2.3.9 RXCUI

2.3.10 Wikidata

2.3.11 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • Cancidas
  • caspofungin
  • caspofungin acetate
  • Caspofungin MSD
  • L 743,872
  • L 743872
  • L-743,872
  • L-743872
  • L743,872
  • L743872
  • MK 0991
  • MK-0991
  • MK0991

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
1093.3 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3-AA
Property Value
0.3
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
16
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
18
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
23
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
1092.64306214 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
1092.64306214 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
412 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
77
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
1900
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
14
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
2
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Solubility

Mol wt, 1213.41. Hygroscopic white to off-white powder. Freely sol in water, methanol; slightly sol in ethanol /Acetate/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 320
Slightly soluble in ethanol, and soluble in phosphate buffer (pH 3.2)
Physicians Desk Reference 60th ed, Thomson PDR, Montvale, NJ 2006., p. 3139

3.2.2 LogP

0

3.3 Chemical Classes

3.3.1 Drugs

3.3.1.1 Human Drugs
Breast Feeding; Lactation; Milk, Human; Antifungal Agents; Echinocandins
Human drug -> Prescription
Human drugs -> Antimycotics for systemic use -> Human pharmacotherapeutic group -> EMA Drug Category
Antifungal medicines

5 Chemical Vendors

6 Drug and Medication Information

6.1 Drug Indication

For the treatment of esophageal candidiasis and invasive aspergillosis in patients who are refractory to or intolerant of other therapies.
Treatment of invasive candidiasis in adult or paediatric patients; treatment of invasive aspergillosis in adult or paediatric patients who are refractory to or intolerant of amphotericin B, lipid formulations of amphotericin B and / or itraconazole. Refractoriness is defined as progression of infection or failure to improve after a minimum of seven days of prior therapeutic doses of effective antifungal therapy; empirical therapy for presumed fungal infections (such as Candida or Aspergillus) in febrile, neutropaenic adult or paediatric patients.

6.2 Drug Classes

Breast Feeding; Lactation; Milk, Human; Antifungal Agents; Echinocandins

6.3 WHO Essential Medicines

Drug
Drug Classes
Antifungal medicines
Formulation
Indication
Systemic or invasive candidosis

6.4 Clinical Trials

6.4.1 ClinicalTrials.gov

6.4.2 EU Clinical Trials Register

6.5 EMA Drug Information

1 of 2
Category
Human drugs
Therapeutic area
Candidiasis; Aspergillosis
Active Substance
caspofungin (as acetate)
INN/Common name
caspofungin
Pharmacotherapeutic Classes
Antimycotics for systemic use
Status
This medicine is authorized for use in the European Union
Company
Merck Sharp & Dohme B.V.
Market Date
2001-10-23
2 of 2
Category
Human drugs
Therapeutic area
Candidiasis; Aspergillosis
Active Substance
caspofungin acetate
INN/Common name
caspofungin
Pharmacotherapeutic Classes
Antimycotics for systemic use
Status
Withdrawn
Company
Accord Healthcare S.L.U.
Market Date
2016-02-11

6.6 Therapeutic Uses

Caspofungin is indicated for the empirical therapy for presumed fungal infections in febrile, neutropenic patients. /Included in US product labeling/
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 744
Caspofungin is indicated for the treatment of candidemia and the following Candidiasis infections: esophageal, intra-abdominal and abscesses, peritonitis, and plural space infections. /Included in US product labeling/
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 744
Caspofungin is indicated in the tretment of invasive aspergillosis in patients who are refractory t or intolerant of other therapies, including amphotericin B (lipid and non-lipid formulations) and/or itraconazole. /Included in US product labeling/
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 744
/Expl Ther/ ... Azole-resistant isolates of Candida albicans remain susceptible to caspofungin ... /Caspofungin acetate/ is active in experimental animal infection with C. albicans, Aspergillus fumigatus, Pneumocystis carinii, and Histoplasma capsulatum. Clinical trials are in progress with iv formulations of caspofungin ... in patients with deep candidiasis, and with neutropenia and fever not responding to antibacterial therapy. /Caspofungin acetate/
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 1305
For more Therapeutic Uses (Complete) data for CASPOFUNGIN (8 total), please visit the HSDB record page.

6.7 Drug Warnings

Adverse effects occurring in 2% or more of patients with invasive aspergillosis receiving caspofungin acetate in an open-label, noncomparative clinical study include fever, infused vein complications, nausea, vomiting, or flushing. Fever, phlebitis/thrombophlebitis, infused vein complication, headache, nausea, pain (unspecified), rash, anemia, abdominal pain, diarrhea, vomiting, facial edema, flu-like illness, myalgia, paresthesia, induration, chills, and pruritus reported in clinical studies for uses other than aspergillosis.
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 514
The following postmarketing adverse events have been reported: Hepatobiliary: rare cases of clinically significant hepatic dysfunction Cardiovascular: swelling and peripheral edema Metabolic: hypercalcemia
Prescribing Information for Cancidas (Caspofungin Acetate) for Injection; Merck & Co, Inc. USA; 2005. Available from, as of January 22, 2007: https://www.merck.com/product/usa/pi_circulars/c/cancidas/cancidas_pi.pdf
Possible histamine-mediated symptoms have been reported including reports of rash, facial swelling, pruritus, sensation of warmth, or bronchospasm. Anaphylaxis has been reported during administration of CANCIDAS.
Prescribing Information for Cancidas (Caspofungin Acetate) for Injection; Merck & Co, Inc. USA; 2005. Available from, as of January 22, 2007: https://www.merck.com/product/usa/pi_circulars/c/cancidas/cancidas_pi.pdf
Caspofungin is distributed into milk in rats; not known whether caspofungin is distributed into milk in humans. Caution should be exercised if caspofungin is used in nursing women.
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 514
For more Drug Warnings (Complete) data for CASPOFUNGIN (6 total), please visit the HSDB record page.

6.8 Drug Tolerance

Mutants of Candida with reduced susceptibility to caspofungin have been identified in some patients during treatment. Similar observations were made in a study in mice infected with C. albicans and treated with orally administered doses of caspofungin. MIC values for caspofungin should not be used to predict clinical outcome, since a correlation between MIC values and clinical outcome has not been established. The incidence of drug resistance by various clinical isolates of Candida and Aspergillus species is unknown.
Prescribing Information for Cancidas (Caspofungin Acetate) for Injection; Merck & Co, Inc. USA; 2005. Available from, as of January 22, 2007: https://www.merck.com/product/usa/pi_circulars/c/cancidas/cancidas_pi.pdf

7 Pharmacology and Biochemistry

7.1 Pharmacodynamics

Caspofungin is an antifungal drug, and belongs to a new class termed the echinocandins. It is used to treat Aspergillus and Candida infection, and works by inhibiting cell wall synthesis. Antifungals in the echinocandin class inhibit the synthesis of glucan in the cell wall, probably via the enzyme 1,3-beta glucan synthase. There is a potential for resistance development to occur, however in vitro resistance development to Caspofungin by Aspergillus species has not been studied.

7.2 MeSH Pharmacological Classification

Antifungal Agents
Substances that destroy fungi by suppressing their ability to grow or reproduce. They differ from FUNGICIDES, INDUSTRIAL because they defend against fungi present in human or animal tissues. (See all compounds classified as Antifungal Agents.)
Enzyme Inhibitors
Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. (See all compounds classified as Enzyme Inhibitors.)

7.3 ATC Code

J02AX04

J - Antiinfectives for systemic use

J02 - Antimycotics for systemic use

J02A - Antimycotics for systemic use

J02AX - Other antimycotics for systemic use

J02AX04 - Caspofungin

7.4 Absorption, Distribution and Excretion

Absorption
92% tissue distribution within 36-48 hours after intravenous infusion
Route of Elimination
After single intravenous administration of [3H] caspofungin acetate, excretion of caspofungin and its metabolites in humans was 35% of dose in feces and 41% of dose in urine.
Clearance
12 mL/min [After single IV administration]
Elimination: Fecal: 35% as drug or metabolites. Renal: 41% as drug (approximately 1.4% unchanged) or metabolites. In dialysis: Not removed by hemodialysis.
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 744
Following administration of a single 70 mg irradiated dose, approximately 92% of the administered radioactivity was distributed into tissues within 36 to 48 hours. Distribution into red blood cells in minimal.
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 744
Caspofungin crosses the placenta in rats and rabbits and was detected in the plasma of fetuses of pregnant animals who were dosed with caspofungin.
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 744
Caspofungin is distributed into milk in rats; not known whether caspofungin is distributed into milk in humans.
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 514
For more Absorption, Distribution and Excretion (Complete) data for CASPOFUNGIN (13 total), please visit the HSDB record page.

7.5 Metabolism / Metabolites

Metabolized slowly by hydrolysis and N-acetylation
Slowly metabolized by hydrolysis and N-acetylation; also undergoes spontaneous chemical degradation and further hydrolysis to constitutive amino acids and their degredates, including dihydroxyhomotyrosine and N-acetyl-dihydroxyhomotyrosine.
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 744
Caspofungin is slowly metabolized in the liver via hydrolysis and N-acetylation; 35 and 41% of the parent drug and metabolites were excreted in feces and urine, respectively, following a single IV radiolabeled dose.
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 514
The metabolism, excretion, and pharmacokinetics of caspofungin were investigated after administration of a single intravenous dose to mice, rats, rabbits, and monkeys. ... Excretion of radioactivity in all species studied was slow, and low levels of radioactivity were detected in daily urine and fecal samples throughout a prolonged collection period. Although urinary profiles indicated the presence of several metabolites (M0, M1, M2, M3, M4, M5, and M6), the majority of the total radioactivity was associated with the polar metabolites M1 [4(S)-hydroxy-4-(4-hydroxyphenyl)-L-threonine] and M2 (N-acetyl-4(S)-hydroxy-4-(4-hydroxyphenyl)-L-threonine). Caspofungin was thus primarily eliminated by metabolic transformation; however, the rate of metabolism was slow. ...
Sandhu P et al; Antimicrob Agents Chemother 48 (4): 1272-80 (2004)
Caspofungin is slowly metabolized by hydrolysis and N-acetylation. Caspofungin also undergoes spontaneous chemical degradation to an open-ring peptide compound, L-747969. At later time points (> or = 5 days postdose), there is a low level (< or = 7 picomoles/mg protein, or < or = 1.3% of administered dose) of covalent binding of radiolabel in plasma following single-dose administration of (3)H caspofungin acetate, which may be due to two reactive intermediates formed during the chemical degradation of caspofungin to L-747969. Additional metabolism involves hydrolysis into constitutive amino acids and their degradates, including dihydroxyhomotyrosine and N-acetyl-dihydroxyhomotyrosine. These two tyrosine derivatives are found only in urine, suggesting rapid clearance of these derivatives by the kidneys. /Caspofungin acetate/
Prescribing Information for Cancidas (Caspofungin Acetate) for Injection; Merck & Co, Inc. USA; 2005. Available from, as of January 22, 2007: https://www.merck.com/product/usa/pi_circulars/c/cancidas/cancidas_pi.pdf
... Following a 1 hr IV infusion of 70 mg of (3)HCaspofungin acetate to healthy subjects, excretion of drug-related material was very slow, such that 41 and 35% of the dosed radioactivity was recovered in urine and feces, respectively, over 27 days. Plasma and urine samples collected around 24 hr postdose contained predominantly unchanged caspofungin acetate, together with trace amounts of a peptide hydrolysis product, M0, a linear peptide. However, at later sampling times, M0 proved to be the major circulating component, whereas corresponding urine specimens contained mainly the hydrolytic metabolites M1 and M2, together with M0 and unchanged MK-0991, whose cumulative urinary excretion over the first 16 days postdose represented 13, 71, 1, and 9%, respectively, of the urinary radioactivity. The major metabolite, M2, was highly polar and extremely unstable under acidic conditions when it was converted to a less polar product identified as N-acetyl-4(S)-hydroxy-4-(4-hydroxyphenyl)-L-threonine gamma-lactone. Derivatization of M2 in aqueous media led to its identification as the corresponding gamma-hydroxy acid, N-acetyl-4(S)-hydroxy-4-(4-hydroxyphenyl)-L-threonine. Metabolite M1, which was extremely polar, eluting from HPLC column just after the void volume, was identified by chemical derivatization as des-acetyl-M2. Thus, the major urinary and plasma metabolites of MK-0991 resulted from peptide hydrolysis and/or N-acetylation. /Caspofungin acetate/
Balani SK et al; Drug Metab Dispos 28 (11): 1274-8 (2000)

7.6 Biological Half-Life

9-11 hours
Initial: 9 TO 11 hours (beta phase). Additional: 40 to 50 hours (gamma phase).
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 744
After administration of a single intravenous dose to mice, rats, rabbits, and monkeys, caspofungin had a ... long terminal elimination half-life (11.7 hr to 59.7 hr) in all preclinical species.
Sandhu P et al; Antimicrob Agents Chemother 48 (4): 1272-80 (2004)

7.7 Mechanism of Action

Caspofungin inhibits the synthesis of beta-(1,3)-D-glucan, an essential component of the cell wall of Aspergillus species and Candida species. beta-(1,3)-D-glucan is not present in mammalian cells. The primary target is beta-(1,3)-glucan synthase.
Caspofungin inhibits the synthesis of beta(1,3)-d-glucan, an integral component of the fungal cell wall that is not present in mammalian cells.
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 514
Caspofungin acetate ... /belongs to a class of drugs/ referred to as echinocandins, which inhibit the formation of beta(1,3)-D-glucans in the fungal cell wall. Resistance is conferred by mutations in the FKS1 gene, which codes for a large subunit of (1,3)beta-glucan synthase. /Caspofungin acetate/
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 1305
Caspofungin acetate, the active ingredient of cancidas, inhibits the synthesis of alpha(1,3)-D-glucan, an essential component of the cell wall of susceptible Aspergillus species and Candida species. (1,3)-D-glucan is not present in mammalian cells. Caspofungin has shown activity against Candida species and in regions of active cell growth of the hyphae of Aspergillus fumigatus. /Caspofungin acetate/
Prescribing Information for Cancidas (Caspofungin Acetate) for Injection; Merck & Co, Inc. USA; 2005. Available from, as of January 22, 2007: https://www.merck.com/product/usa/pi_circulars/c/cancidas/cancidas_pi.pdf

8 Use and Manufacturing

8.1 Uses

THERAP CAT: Antifungal
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 309

Use (kg) in USA (2002): 5

Consumption (g per capita) in the USA (2002): 1.78e-05

Calculated removal (%): 1.9

8.1.1 Use Classification

Human drugs -> Antimycotics for systemic use -> Human pharmacotherapeutic group -> EMA Drug Category

8.2 Methods of Manufacturing

Preparation: J.M. Balkovec et al., WO 9421677; eidem, US 5378804 (1994, 1995 both to Merck & Co.)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 308

8.3 Formulations / Preparations

Parenteral: For injection, for IV infusion: 50 mg Cancidas ( with sucrose 39 mg and mannitol 26 mg), (Merck); 70 mg Cancidas (with sucrose 54 mg and mannitol 36 mg), (Merck).
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 514
Trade name: CANCIDASE, MK-0991 /Caspofungin acetate/
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 1305

8.4 General Manufacturing Information

Caspofungin acetate ... is a water-soluble, semisynthetic lipopeptide derivative of pneumocandin B0. /Caspofungin acetate/
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 1305

9 Identification

9.1 Clinical Laboratory Methods

Analyte: caspofungin; matrix: plasma; procedure: high-performance liquid chromatography with fluorescence detection at 220 nm
Sandhu P et al; Antimicrob Agents Chemother 48(4): 1272-80 (2004)
Analyte: caspofungin; matrix: human plasma, urine; procedure: high-performance liquid chromatography with fluoresence detection
Schwartz M et al; Anal Chim Acta 352(1-3): 299-307 (1997)

10 Safety and Hazards

10.1 Accidental Release Measures

10.1.1 Disposal Methods

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

10.2 Handling and Storage

10.2.1 Storage Conditions

Store lyophilized cake/powder between 2 and 8 °C (36 and 46 °F). Store reconstituted concentrate and infusion solution at or below 25 °C (77 °F).
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 746

10.3 Other Safety Information

10.3.1 Special Reports

Hoang A; Caspofungin Acetate: An Antifungal Agent; Am J Health Syst Pharm 58 (13): 1206-14 (2001)
Keating G, Figgitt D; Caspofungin: A Review of its Use in Oesophageal Candidiasis, Invasive Candidiasis and Invasive Aspergillosis; Drugs 63 (20): 2235-63 (2003)
Groll AH, Walsh TJ; Caspofungin: Pharmacology, Safety and Therapeutic Potential in Superficial and Invasive Fungal Infections;.Expert Opin Investig Drugs 10 (8): 1545-58 (2001)
Wiederhold NP, Lewis RE; The Echinocandin Antifungals: An Overview of the Pharmacology, Spectrum and Clinical Efficacy; Expert Opin Investig Drugs 12 (8): 1313-33 (2003)
Kulemann V et al; Pharmacology 75 (4): 165-78 (2005). Due to their broad antimycotic spectrum and the relatively low rate of side effects, the two antifungals caspofungin and voriconazole are considered as attractive therapeutic alternatives to amphotericin B. However, treatment of severe mycotic infections in patients taking co-medication is associated with the risk of severe adverse drug interactions. The risk of such interactions is increased if voriconazole and, much less pronounced caspofungin, are co-administered with drugs which have an inducing or inhibiting effect on the CYP 450 system, primarily on the isoenzymes CYP2C19, CYP2C9 and CYP3A4. This review provides a comprehensive overview on the potential drug interactions of caspofungin and voriconazole in multimorbid patients.

11 Toxicity

11.1 Toxicological Information

11.1.1 Drug Induced Liver Injury

Compound
caspofungin
DILI Annotation
Ambiguous DILI-concern
Severity Grade
7
Label Section
Warnings and precautions
References

M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007

M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

11.1.2 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

No information is available on the use of caspofungin during breastfeeding. Because caspofungin is 97% bound to plasma proteins and has poor oral bioavailability, it is unlikely to reach the milk and be absorbed by the infant. Caspofungin can safely be given intravenously to infants of aged 3 months or older. Any amount absorbed from milk is likely to be far less than an infant dose. If caspofungin is required by the mother, it is not a reason to discontinue breastfeeding.

◉ Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

◉ Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

11.1.3 Interactions

... In this study the efficacies of caspofungin and meropenem - separately and together - in mice with disseminated candidiasis were studied. Immunocompetent mice were infected intravenously with 2x10(6) CFU of Candida albicans. At 24 hr postinfection, intraperitoneal therapy was initiated and was continued for 7 days. Therapy groups included those given caspofungin (0.5, 1.25, 5 mg/kg/day), meropenem (20 mg/kg/day), and a combination of the two drugs. ... Kidney CFU counts showed that mice that had received both drugs had lower residual burdens. Caspofungin was effective at doses of 0.5, 1.25, 5 mg/kg compared to infected untreated controls. In vitro, MICs of caspofungin and meropenem were <0.075 ug/mL and >64 ug/mL, respectively. Synergism was observed with the combination. Histopathology showed that the degree of inflammation was 25% less and tubular necrosis was more restricted in combined therapy than monotherapy. The results indicate that concurrent caspofungin and meropenem therapy may be beneficial.
Ozcan SK et al; APMIS 114 (12): 829-36 (2006)
Concomitant use /with tacrolimus/ may result in decreased tacrolimus blood concentrations; monitoring of tacrolimus concentrations is recommended, and dosage adjustments may be required.
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 744
Potential pharmacokinetic interaction (reduction in caspofungin plasma concentrations.). Coadministration of caspofungin with inducers or mixed inducer/inhibitors of drug clearance such as efavirenz, nelfinavir, nevirapine, phenytoin, rifampin, dexamethasone, or carbamazepine may result in clinically important reductions in plasma caspofungin concentrations. ...
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 514
The potential for interactions between caspofungin and nelfinavir or rifampin was evaluated in two parallel-panel studies. In study A, healthy subjects received a 14-day course of caspofungin alone (50 mg administered intravenously [IV] once daily) (n = 10) or with nelfinavir (1,250 mg administered orally twice daily) (n = 9) or rifampin (600 mg administered orally once daily) (n = 10). In study B, 14 subjects received a 28-day course of rifampin (600 mg administered orally once daily), with caspofungin (50 mg administered IV once daily) coadministered on the last 14 days, and 12 subjects received a 14-day course of caspofungin alone (50 mg administered IV once daily). The coadministration/administration alone geometric mean ratio for the caspofungin area under the time-concentration profile calculated for the 24-hr period following dosing [AUC(0-24)] was as follows (values in parentheses are 90% confidence intervals [CIs]): 1.08 (0.93-1.26) for nelfinavir, 1.12 (0.97-1.30) for rifampin (study A), and 1.01 (0.91-1.11) for rifampin (study B). The shape of the caspofungin plasma profile was altered by rifampin, resulting in a 14 to 31% reduction in the trough concentration at 24 hr after dosing (C(24h)), consistent with a net induction effect at steady state. Both the AUC and the C(24hr) were elevated in the initial days of rifampin coadministration in study A (61 and 170% elevations, respectively, on day 1) but not in study B, consistent with transient net inhibition prior to full induction. The coadministration/administration alone geometric mean ratio for the rifampin AUC(0-24) on day 14 was 1.07 (90% CI, 0.83-1.38). Nelfinavir does not meaningfully alter caspofungin pharmacokinetics. Rifampin both inhibits and induces caspofungin disposition, resulting in a reduced C(24hr) at steady state. An increase in the caspofungin dose to 70 mg, administered daily, should be considered when the drug is coadministered with rifampin.
Stone A et al; Antimicrob Agents Chemother 48 (11): 4306-14 (2004)
For more Interactions (Complete) data for CASPOFUNGIN (9 total), please visit the HSDB record page.

11.1.4 Antidote and Emergency Treatment

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160-1

11.1.5 Human Toxicity Excerpts

/ALTERNATIVE and IN VITRO TESTS/ ... the aim of this study was to assess toxic effects of caspofungin (CAS) on human renal proximal and distal tubular epithelial cells (PTC and DTC) in vitro, and to compare them to those of amphotericin B (AmB). Cells were isolated from human kidney tissue, and exposed to clinically relevant concentrations of CAS and AmB for 24 hr. ... DTC were more vulnerable towards the antifungal agents than PTC. In contrast to AmB, cell-damaging effects of CAS were less severe. DAPI staining revealed slight and dose-dependent antiproliferative effects of CAS at concentrations reflecting relevant plasma levels. At these concentrations, cell viability, determined by MTT assay, was not decreased in PTC and DTC. LDH release was marginally increased in a dose-dependent manner; apoptosis was not detected. Nevertheless, at CAS concentrations reflecting potential tissue concentrations, cell damaging effects were considerably more pronounced. ...
Wegner B et al; Nephrol Dial Transplant 20 (10): 2071-9 (2005)
/CASE REPORTS/ ... A 68-year-old man developed reversible severe thrombocytopenia, possibly due to caspofungin, after being successfully treated for Candida albicans endocarditis. Given the limited clinical experience with caspofungin, continued vigilance for unusual and serious adverse events associated with the drug is imperative.
Lynch J, Wong-Beringer A; Pharmacotherapy 24 (10): 1408-11 (2004)

11.1.6 Non-Human Toxicity Excerpts

/GENOTOXICITY/ Caspofungin was not genotoxic when assessed in the mouse bone marrow chromosomal test at doses up to 12.5 mg/kg of body weight (equivalent to a human dose of 1 mg/kg based on body surface area comparisons), administered intravenously.
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 744
/GENOTOXICITY/ caspofungin did not show mutagenic or genotoxic potential in the following in vitro assays: bacterial (Ames) and mammalian cell mutagenesis assays, the alkaline elution/rat hepatocyte DNA strand break test, and the chromosome aberration assay in Chinese hamster ovary cells.
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 744
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Caspofungin was shown to be embryotoxic in rats and rabbits. Findings in rats included incomplete ossification of the skull and torso and an increased incidence of cervical rib. Increased incidence of incomplete ossification of the talus and calcaneus was seen in rabbits. Increases in resorptions in rats and rabbits and periimplantation losses in rats were also seen. Theses findings were seen at doses which produced exposures similar to those in patients who were treated with a 70 mg dose.
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 744
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In one 5-week study in monkeys at doses which produced exposures approximately 4 to 6 times those seen in patients treated with a 70-mg dose, scattered small foci of subcapsular necrosis were observed microscopically in the livers of some animals (2/8 monkeys at 5 mg/kg and 4/8 monkeys at 8 mg/kg); however, this histopathological finding was not seen in another study of 27 weeks duration at similar doses.
Prescribing Information for Cancidas (Caspofungin Acetate) for Injection; Merck & Co, Inc. USA; 2005. Available from, as of January 22, 2007: https://www.merck.com/product/usa/pi_circulars/c/cancidas/cancidas_pi.pdf

11.1.7 Populations at Special Risk

Caution should be exercised in dosing adults with severe hepatic impairment (Child-Pugh score exceeding 9) because of a lack of clinical experience in this patient population.
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 514
Laboratory abnormalities in liver function tests have been seen in healthy volunteers and patients treated with cancidas. In some patients with serious underlying conditions who were receiving multiple concomitant medications along with cancidas, clinical hepatic abnormalities have also occurred. Isolated cases of significant hepatic dysfunction, hepatitis, or worsening hepatic failure have been reported in patients; a causal relationship to cancidas has not been established. Patients who develop abnormal liver function tests during cancidas therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing cancidas therapy.
Prescribing Information for Cancidas (Caspofungin Acetate) for Injection; Merck & Co, Inc. USA; 2005. Available from, as of January 22, 2007: https://www.merck.com/product/usa/pi_circulars/c/cancidas/cancidas_pi.pdf

11.1.8 Protein Binding

97%

11.2 Ecological Information

11.2.1 Milk Concentrations

/EXPL/ Caspofungin is distributed into milk in rats; not known whether caspofungin is distributed into milk in humans. Caution should be exercised if caspofungin is used in nursing women.
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 514

12 Associated Disorders and Diseases

13 Literature

13.1 Consolidated References

13.2 NLM Curated PubMed Citations

13.3 Chemical Co-Occurrences in Literature

13.4 Chemical-Gene Co-Occurrences in Literature

13.5 Chemical-Disease Co-Occurrences in Literature

14 Patents

14.1 Depositor-Supplied Patent Identifiers

14.2 WIPO PATENTSCOPE

14.3 Chemical Co-Occurrences in Patents

14.4 Chemical-Disease Co-Occurrences in Patents

14.5 Chemical-Gene Co-Occurrences in Patents

15 Interactions and Pathways

15.1 Chemical-Target Interactions

15.2 Drug-Drug Interactions

16 Biological Test Results

16.1 BioAssay Results

17 Taxonomy

18 Classification

18.1 MeSH Tree

18.2 KEGG: ATC

18.3 KEGG : Antimicrobials

18.4 WHO ATC Classification System

18.5 NORMAN Suspect List Exchange Classification

18.6 EPA DSSTox Classification

18.7 FDA Drug Type and Pharmacologic Classification

18.8 MolGenie Organic Chemistry Ontology

19 Information Sources

  1. ChEMBL
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    http://www.ebi.ac.uk/Information/termsofuse.html
  2. ClinicalTrials.gov
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    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  3. Drug Induced Liver Injury Rank (DILIrank) Dataset
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  4. DrugBank
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    https://www.drugbank.ca/legal/terms_of_use
  5. NCI Thesaurus (NCIt)
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    https://www.cancer.gov/policies/copyright-reuse
  6. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  7. Hazardous Substances Data Bank (HSDB)
  8. European Medicines Agency (EMA)
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    Information on the European Medicines Agency's (EMA) website is subject to a disclaimer and copyright and limited reproduction notices.
    https://www.ema.europa.eu/en/about-us/legal-notice
  9. Therapeutic Target Database (TTD)
  10. Drugs and Lactation Database (LactMed)
  11. Drugs@FDA
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  12. WHO Model Lists of Essential Medicines
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    https://www.who.int/about/policies/publishing/copyright
  13. EU Clinical Trials Register
  14. WHO Anatomical Therapeutic Chemical (ATC) Classification
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    Use of all or parts of the material requires reference to the WHO Collaborating Centre for Drug Statistics Methodology. Copying and distribution for commercial purposes is not allowed. Changing or manipulating the material is not allowed.
    https://www.whocc.no/copyright_disclaimer/
  15. NORMAN Suspect List Exchange
    LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    CASPOFUNGIN ACETATE
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  16. KEGG
    LICENSE
    Academic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial license
    https://www.kegg.jp/kegg/legal.html
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
  17. Metabolomics Workbench
  18. Natural Product Activity and Species Source (NPASS)
  19. NLM RxNorm Terminology
    LICENSE
    The RxNorm Terminology is created by the National Library of Medicine (NLM) and is in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from NLM. Credit to the U.S. National Library of Medicine as the source is appreciated but not required. The full RxNorm dataset requires a free license.
    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  20. PharmGKB
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    PharmGKB data are subject to the Creative Commons Attribution-ShareALike 4.0 license (https://creativecommons.org/licenses/by-sa/4.0/).
    https://www.pharmgkb.org/page/policies
  21. Wikidata
  22. Wikipedia
  23. Medical Subject Headings (MeSH)
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    https://www.nlm.nih.gov/copyright.html
  24. PubChem
  25. National Drug Code (NDC) Directory
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  26. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  27. PATENTSCOPE (WIPO)
  28. NCBI
CONTENTS