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Drug Criteria & Outcomes: Drug evaluation: Caspofungin for IV infusion
By Candace Hodges, PharmD candidate
Agents for systemic fungal infections
Caspofungin acetate is a sterile, lyophilized, semisynthetic product for IV infusion. It is available as a hygroscopic white to off-white powder and is freely soluble in water and methanol, and slightly soluble in ethanol.
Caspofungin is the first of a new class of antifungals, the echinocandins or glucan synthesis inhibitors, which have a mechanism of action different from all other antifungals. Specifically, the echinocandins disrupt glucan formation by noncompetitively inhibiting the enzyme complex 1,3-b-D-glucan synthase, which is present in most pathogenic fungi and is essential for fungal cell wall formation. This enzyme complex is not present in human cells, so the unique mode of action of caspofungin potentially eliminates toxicity to humans. Echinocandins are considered fungicidal and, based on in vitro studies, their effects appear to depend on fungal growth and metabolism.
Dosage and administration
A single 70 mg loading dose should be administered on day one, followed by 50 mg/day thereafter. Caspofungin should be administered by slow IV infusion over approximately one hour. Limited safety data suggest that an increase in dose to 70 mg/day for patients who do not clinically respond to 50 mg/day is well-tolerated. The highest dose in clinical trials was 100 mg as a single dose to five patients, which was generally well-tolerated. Duration of treatment should be based upon the severity of the patient’s underlying disease, recovery from immunosuppression, and clinical response. The mean duration of therapy in the study of the use of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of other therapies was 33.7 days, with a range of one to 162 days.
During the past year, caspofungin was in short supply due to an increase in demand and production problems at Merck. The manufacturer’s patient allocation program ended in June 2002 when the drug again became available without restriction.
Caspofungin is contraindicated in patients with hypersensitivity to any component of the product. Besides the active ingredient caspofungin, inactive ingredients in caspofungin include sucrose, mannitol, acetic acid, and sodium hydroxide.
Although caspofungin is not metabolized by the CYP450 enzyme system, results from regression analyses of patient pharmacokinetic data suggest that co-administration with inducers or mixed inducer/inhibitors of this system may decrease concentrations of caspofungin. These include drugs such as efavirenz (Sustiva), nelfinavir (Viracept), nevirapine (Viramune), phenytoin (Dilatin), rifampin (Rifadin, others), dexamethasone (Decadron, others) or carbamazepine (Tegretol, others). If patients are concurrently treated with any of these drugs and caspofungin and are not clinically responding to therapy, consider increasing the daily dose to 70 mg, following the usual 70 mg loading dose.
The Table, below provides drug-related adverse events and laboratory abnormalities occurring in > 5 % of patients. A direct comparison was made between caspofungin and conventional amphotericin B for investigational indications other than aspergillosis. Only data for caspofungin were given for the aspergillosis study. Data for amphotericin B Lipid Complex Injection and itraconazole were taken from their corresponding package inserts and are not necessarily comparable.
Caspofungin demonstrates fungicidal or fungistatic activity depending on the isolate tested. The drug exhibits a post-antifungal effect that lasts longer than 12 hours at concentrations above the minimum inhibitory concentrations (MIC), and up to two hours when the concentration is below the MIC, according to in vitro data. In vitro activity has been verified in animal infection models with Candida, Aspergillus, and Histoplasma.
Caspofungin demonstrates significant activity against most clinically important Candida species. In vitro, the drug is at least as potent as fluconazole, itraconazole, voriconazole, and amphotericin B against C. albicans, C. glabrata, and C. tropicalis, and is comparable in potency to amphotericin B against C. krusei. The drug is fungicidal against most Candida species, at concentrations of less than 1-2 mg/L.
Caspofungin’s in vitro activity against Aspergillus compares well with that of amphotericin B, itraconazole, and flucytosine; MIC90 values against both A. flavus and A. fumigatus have been reported as 0.12 mg/L. Against histoplasmosis in mice, caspofungin was less effective than amphotericin B, and possesses only limited activity against Cryptococcus neoformans, Fusarium spp., Rhizopus spp., and Scedosporium prolificans. Caspofungin demonstrates potency against Pneumocystis carinii in immunocompromised animal models, but benefits in acute infection are yet unknown.
There are no published reports of resistance development in the clinical setting with caspofungin. Research has shown synergistic action with caspofungin and amphotericin B against A. fumigatus, C. neoformans, and Fusarium.
Clinical data on the use of caspofungin in humans with invasive fungal infections is limited to three trials. One examined the use of caspofungin in invasive aspergillosis; the data were presented in a poster, and the study resulted in Food and Drug Administration (FDA) approval of the drug. The other two trials examined the use of caspofungin in oropharyngeal candidiasis (OPC) and/or esophageal candidiasis (EC) in patients who were mostly HIV patients. One of the two trials studied the use of caspofungin in EC, and the other studied its use in both EC and OPC; the unpublished data were presented to the FDA as abstracts. The Table, below provides results from the oropharyngeal and esophageal candidal trials.
Both studies in the Table, above were randomized, double-blind comparative trials. In the Arathoon et al. study, minimum therapy was seven days for OPC and 10 days for EC. Efficacy was assessed three to four days after the end of therapy and was defined as complete resolution of symptoms and a reduction in disease grade to 0 or ½. The authors concluded that caspofungin appears to be effective for treatment of OPC and EC, with high efficacy rates and generally few drug-related adverse events.
In the Sable et al. study, patients had endoscopically proven esophageal candidiasis and were randomized to receive one of the above-mentioned regimens for 14 days. Clinical response (efficacy) was defined as a resolution of symptoms and a significant reduction in endoscopic lesions 14 days after completing therapy.
The clinical study on the use of caspofungin in aspergillosis patients refractory to other antifungal therapy was important for the drug’s FDA approval. A review of this trial follows:
Maertens J, Raad I, Sable CA, et al. Multicenter, noncomparative study to evaluate safety and efficacy of caspofungin in adults with invasive aspergillosis refractory or intolerant to amphotericin B, amphotericin B lipid formulations or azoles [poster]. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto; Sept. 18, 2000.
Objective: To evaluate the safety, tolerability, and efficacy of caspofungin in patients with invasive aspergillosis refractory to or intolerant of other antifungal therapies (e.g., amphotericin B, lipid formulations of amphotericin B, and/or itraconazole).
Design: Open-label, multicenter, non-comparative study; four-week follow-up period after discontinuation of caspofungin for patients with favorable response.
Efficacy: Favorable response rate, evaluated by independent expert panel.
Safety/tolerability: Clinical adverse experiences, laboratory abnormalities.
Regimen: Caspofungin 70 mg loading dose, followed by 50 mg daily. Mean duration of therapy was 33.7 days (range: one to 162 days).
Baseline characteristics of patients:
— 10 to standard amphotericin B;
— 10 to lipid amphotericin B preps;
— 13 to itraconazole;
— 1 to voriconazole;
— 19 to more than one antifungal agent.
— hematologic malignancy (N=24, 38%);
— allogenic bone marrow/stem cell transplant (N=18, 28%);
— organ transplant (N=8, 13%);
— solid tumor (N=3, 5%);
— other conditions (N=10, 16%).
All participants received concomitant therapies for underlying conditions.
Efficacy (response rates):
Efficacy has been show by caspofungin acetate in a wide range of murine models for fungal infections, including Candida spp., Aspergillus spp., Histoplasma, and Pneumocystis carinii. In contrast, the drug did not protect immunodeficient mice against lethal challenge with Cryptococcus neoformans.
Potential for medication error(s):
Caspofungin should be administered over a one-hour infusion.
Caspofungin should not be used with diluents containing dextrose (b-D-glucose).
An example of patient selection criteria is presented in the Caspofungin Order Form HHS.
As additional studies are completed, caspofungin’s usage for different indications may expand.
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• Arathoon E, Gotuzzo E, Noriega L, et al. A randomized, double-blind, multicenter trial of MK-0991, an echinocandin antifungal agent vs. amphotericin B for the treatment of oropharyngeal and esophageal candidiasis in adults [abstract]. Clin Infect Dis 1998; 27:939.
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