Caspofungin Cancidas

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Year of discovery: 1989 (Merck); Year of introduction: 2001; Drug category: Echinocan-din/lipopolypeptide antifungal agent/1,3-p-D-glucan synthesis inhibitor; Main uses: For the treatment of severe systemic fungal infections (e.g., invasive aspergillosis) especially in those who fail or cannot tolerate amphotericin B and/or itaconazole treatment; Related drugs: Micafungin (Mycamine), Anidulafungin (Eraxis).

Caspofungin, a semisynthetic cyclic lipid-bearing polypeptide, is an intravenously administered antifungal agent in the echinocandin class of natural products.

Echinocandins were first isolated in 1974 from the fermentation broth of Aspergillus rugulovavus and were found to have potent antifungal activity. The predominating compound, echinocandin B, was enzymatically degraded to a cyclic hexapeptide core (shown in red) and used to prepare a number of semisynthetic analogs. Caspofungin was the first echinocandin to gain FDA approval in 2001 for the treatment of systemic fungal infections. Invasive fungal infection is a growing problem in health care. It was the 10th leading cause of death in hospitals in 1980 and became the 7th most common cause by the late 1990s.1 Subsequently, micafungin sodium (Mycamine™, Astellas Pharma) and anidulafungin (Eraxis™, Pfizer) were introduced.2

Micafungin Sodium Anidulafungin

Because of the large size of these echinocandins (molecular weights >1200), and their low oral bioavailability, they are administered intravenously. The three echinocandins have half-lives of 8-13 h and are metabolized mainly in the liver by hydrolysis and N-acetylation to metabolites that do not have antifungal activity. Echinocandins are poor substrates for oxidation by . liver cytochrome P450 enzymes (unlike triazoles; see page 161), and so few interactions with other drugs have been observed.3

Echinocandins are potent inhibitors of the fungal enzyme 1,3-p-D-glucan synthase. Glucans are structurally diverse polymeric sugar molecules that form the rigid cell wall of fungi in combination with protein crosslinks. The function of the fungal cell wall is to protect the cell from changes in osmotic pressure and harmful environmental impacts, but also to allow the influx of nutrients. In contrast, mammalian cells do not have cell walls. Thus, termination of 1,3-P-D-glucan production leads to the disruption of fungal physiology and eventually results in fungal cell death.

Echinocandins are nontoxic at therapeutic doses and generally well-tolerated, but must be used with caution for those with liver abnormalities.

1. Am. J. Health. Syst. Pharm. 2006, 63. 1693-1703; 2. Lancet 2003 362, 1142-1151; 3 Eur. J Clin Microbiol. Infect. Dis. 2004. 23, 805-812; Refs. p. 178

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