Pharmacology Update
Caspofungin—A New Antifungal Agent
By William T. Elliott, MD, FACP and James Chan, PharmD, PhD
Earlier this year, the FDA approved the first in a new class of antifungal agents. Caspofungin represents the first of the echinocandine class, antifungal agents that inhibit fungal cell wall synthesis by inhibiting 1,3-beta-D-glucan synthase. Caspofungin exhibits in vitro antifungal activity against a wide range of fungi and yeast including Candida and Aspergillus spp, but is only currently approved for use against Aspergillus. The drug, which is given intravenously, is being marketed by Merck under the trade name Cancidas.
Indication
Caspofungin is indicated for the treatment of invasive aspergillosis in patients who are refractory to or intolerant of other antifungals.1
Dosage
The recommended dose is a single 70-mg loading dose on day 1 and 50 mg daily thereafter. The duration of therapy should be dictated by the severity of the patient’s underlying disease and clinical response.1
The drug should be given by intravenous infusion over about 1 hour. No dosage adjustment is needed in patients with mild hepatic impairment or renal impairment.1
Potential Advantages
Caspofungin provides a new antifungal with a different mechanism of action. About 50% of patients who had previously been refractory to, or intolerant of, other antifungals had a favorable response to caspofungin.1 Its long elimination half-life (9-11 hours) permits once daily dosing. Caspofungin is generally well tolerated and similar to intraconazole.2 It is better tolerated than amphotericin B. Caspofungin does not appear to interact with other drugs metabolized by the cytochrome P450 isoenzymes.
Potential Disadvantages
There are limited clinical data on caspofungin and no published clinical trials. Data to support FDA approval was a noncomparative open-label study involving 69 patients. The incidence of drug resistance is not known. The concomitant use of caspofungin and cyclosporine is not recommended as elevation of alanine transaminase 2 to 3 times the upper limits of normal has been reported.1
Comments
Caspofungin is a new class of antifungal agents that inhibits the formation of beta (1,3)-D-glucan by inhibiting glucan synthase. This mechanism differs from that of amphotericin B and azoles which affect ergosterol albeit in different ways. Beta (1,3)-D-glucan is found in the cell wall of many filamentous fungi (molds) but not in mammalian cells. Caspofungi is active in vitro against Aspergillus fumigatus, A flavus, A terreus, and many Candida species including both fluconazole susceptible and resistant species.2-4 Candida species including C albicans, C galabrata, C tropicalis, C krusei, and C lusitaniae. It has limited activity against Cryptococcus neoformans.5 Standardized testing for susceptibility of caspofungin has not been established and results of such testing may not correlate with clinical effectiveness. Caspofungin has been studied in various animal infection models, but data in humans is limited. Some degree of efficacy has been reported in oropharyneal and esophageal candidiasis and invasive aspergillosis,6 however, it is only FDA approved for treating invasive aspergillosis refractory to or intolerant of other therapies.
Approval was based on an unpublished, open-label, noncomparative study in 69 patients. These patients had previously failed to improve or had disease progression despite at least 7 days of therapy with amphotericin B including lipid formulations, itraconazole, or an investigational azole with reported activity to Aspergillus. Some were also intolerant to previous therapy defined as doubling of serum creatinine or other side effects which may or may not be infusion-related.1 About 50% of patients who received more than 7 days of therapy with caspofungin showed a favorable response.1 This was defined as complete or partial response of all signs and symptoms and radiographic findings.1
The cost of caspofungin for a 14-day treatment course is about $4000 which is similar to intraconazole and less costly than lipid formulations of amphotericin ($7000 to $15,000).
Clinical Implications
Current antifungal therapies for aspergillosis include amphotericin B, azoles such as intraconazole, and lipid formulations of amphotericin (Abelcet, Ambisone). Renal toxicity has been associated with amphotericin B and some fungi have developed resistance to the azoles. Caspofungin provides another option if the patient is refractory to or intolerant of these standard therapies. Broader clinical experience will ultimately define the role of caspofungin.
William Elliott is Chair of the Formulary Committee at Northern California Kaiser Permamente and Assistant Clinical Professor of Medicine at the University of California-San Francisco. James Chan is Pharmacy Quality and Outcomes Manager at Kaiser Permanente in Oakland California. Both are associate editors of Internal Medicine Alert.
References
1. Cancidas Product Information. Merck & Co., Inc. January 2001.
2. Arikan S. et al. Antimicrob Agents Chemother. 2001; 45:327-330.
3. Barchiesi F, et al. Eur J Clin Microbiol Infect Dis. 1999;18:302-304.
4. Pfaller MA, et al. Diagn Microbiol Infect Dis. 1999;35: 19-25.
5. Ernst EJ, et al. Antimicrob Agents Chemother. 2000; 44:1108-1111.
6. Keating GM, Jarvis B. Drugs. 2001;61:1121-1129.
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