Caspofungin: new treatment for invasive aspergillosis

June 2001

With increasing rates of invasive fungal infections, new treatment options for patients are needed. In January 2001, caspofungin (Cancidas, Merck) was approved by the FDA for the treatment of invasive aspergillosis. This unique medication differs from other available antifungals and offers additional treatment for patients unable to tolerate the available antifungals or who are refractory to conventional treatments.

Caspofungin is a semisynthetic lipopeptide (echinocandin) synthesized from a fermentation product of Glarea lozoyensis. Caspofungin inhibits the synthesis of B (1,3)-D-glucan, an integral component of fungal cell walls, but not present in mammalian cells. In vitro, caspofungin exhibits activity against Aspergillus fumigatus, Aspergillus flavus and Aspergillus terreus. In vivo, caspofungin has shown activity against Aspergillus fumigatus. Standardized susceptibility testing methods for B (1,3)-D-glucan synthesis inhibitors have not been established, and drug resistance has not been studied.

Pharmacokinetics

Unlike other antifungals, caspofungin undergoes spontaneous chemical degradation and is slowly metabolized by hydrolysis and N-acetylation. After a single intravenous dose, 35% of caspofungin and its metabolites are eliminated in the feces and 41% is excreted in the urine. Caspofungin is extensively bound to albumin (approximately 97%) and distribution, not excretion or biotransformation, is the central mechanism affecting plasma clearance.

Pharmacokinetic data in special populations (geriatric, renal insufficiency and hepatic insufficiency) indicate dose adjustments must be made only in moderate hepatic insufficiency. Plasma concentrations after single-dose administration were only slightly increased in moderate (creatinine clearance [CrCL] 31-49 ml/min), advanced (CrCL 5-30 ml/min) and end-stage (CrCL <10 ml/min and dialysis dependent) renal insufficiency. In mild renal insufficiency (CrCL 50 to 80 ml/min), pharmacokinetics were similar to control patients. No dose adjustments are necessary in these patient populations, as no significant effects were seen with mild to advanced renal impairment on caspofungin trough concentrations in patients receiving 50 mg multiple daily doses.

In mild hepatic insufficiency (Child-Pugh score 5-6), the area under the curve (AUC) after a single 70-mg dose of caspofungin was increased by approximately 55% compared with healthy controls. Multiple dosing demonstrated only modest increases (19-25% in AUC) compared with controls; therefore, no dosing adjustment is recommended.

A decrease in the maintenance dose of caspofungin from 50 mg/day to 35 mg/day is recommended in patients with moderate hepatic impairment (Child-Pugh score 7-9). The average increase in AUC is 76% in this patient group compared with controls after a single 70-mg dose of caspofungin. There are no data in patients with severe hepatic insufficiency (Child-Pugh score >9).

Clinical trials

Caspofungin is approved for the treatment of invasive aspergillosis infections in patients refractory to or intolerant of other therapies (amphotericin B, amphotericin B lipid formulations, itraconazole [Sporanox, Janssen], or an investigational azole with reported activity against Aspergillus). Caspofungin has not been studied as initial therapy for invasive aspergillosis.

The FDA approval is based on an unpublished, open-label, noncomparative clinical trial in 69 patients who had failed other antifungal therapies due to disease progression, failure to improve despite antifungal therapy for at least seven days, doubling of creatinine (or creatinine 2.5 mg/dl while on therapy), other acute reactions, or infusion-related toxicity.

Inclusion criteria were at least one of the following: positive tissue histopathology, positive culture from tissue obtained by an invasive procedure, or positive radiographic or computed tomography evidence with supporting culture from bronchoalveolar lavage or sputum, galactomannan enzyme-linked immunosorbent assay, and/or polymerase chain reaction. Patients with extra-pulmonary disease had to have definite invasive aspergillosis, meeting the definitions of the Mycoses Study Group. Each patient received a single 70-mg loading dose on day 1, with a maintenance dose of 50 mg/day. The mean duration of therapy was 33.7 days, with a range of 1 to 12 days.

Of the 69 patients enrolled, 63 met entry diagnostic criteria and had outcome data for analysis. Fifty-three patients (84%) were refractory to previous antifungal therapy and 10 (16%) were intolerant; 45 patients (71%) had pulmonary disease and 18 (29%) had extrapulmonary disease. The overall favorable response rates (a complete resolution and/or clinically meaningful improvement) in patients receiving at least one dose and >7 days of therapy were 41% and 50%, respectively. These rates were 36% and 70% in patients refractory to or intolerant of previous therapies, respectively. Furthermore, 47% of those with pulmonary disease responded to caspofungin, while only 28% of the patients with extrapulmonary disease responded.

Caspofungin has also been studied in the treatment of oropharyngeal and esophageal candidiasis (unpublished data). However, it is not approved for this indication.

Adverse reactions experienced in clinical trials with caspofungin include fever, phlebitis, diarrhea, nausea, vomiting, flushing, headache, pain, flu-like illness, myalgia, paresthesia, rash, induration, increased serum alkaline phosphatase, decreased serum potassium, increased eosinophils and increased urine protein and red blood cells. No long-term studies in animals have been performed to evaluate the carcinogenic potential of caspofungin, but in vitro assays have shown evidence of mutagenic and genotoxic potential. Caspofungin is classified as pregnancy category C because of the embryotoxic effects seen in rats and rabbits. It is not known whether caspofungin is excreted in human milk. Finally, caspofungin has not been adequately studied in patients younger than 18 years of age.

Drug interactions

Caspofungin is a poor substrate of the cytochrome P450 enzyme system and lacks inhibitory or induction activity within this system. However, increases in maintenance dosing from 50 mg to 70 mg per day may be needed in patients concomitantly taking efavirenz (Sustiva, Dupont), nelfinavir (Viracept, Agouron), nevirapine (Viramune, Roxane), phenytoin (Dilantin, Parke-Davis), rifampin (Rifadin, Aventis), dexamethasone or carbamazepine.

Healthy volunteer studies show that the pharmacokinetics of caspofungin are not altered with simultaneous administration of itraconazole, amphotericin B, or mycophenolate. When administered with tacrolimus (Prograf, Fujisawa), caspofungin reduces the blood AUC, peak concentration, and 12-hour concentration of tacrolimus. In patients requiring both caspofungin and tacrolimus, monitoring of tacrolimus serum concentrations and dose adjustments may be necessary. Although cyclosporine pharmacokinetics are not altered by caspofungin administration, 2 clinical studies have demonstrated an increase in the AUC of caspofungin and transient increases in liver transaminases when these drugs are administered together.

The recommended dose of caspofungin is a 70 mg loading dose, followed by 50 mg daily thereafter. Caspofungin must be given intravenously over 1 hour. It should not be mixed or co-infused with other medications or dextrose solution. Duration of treatment is stipulated by the patient’s underlying disease, recovery from immunosuppression, and clinical response.

Summary

As a recent addition to the armamentarium of antifungals, caspofungin offers treatment for those with invasive aspergillosis refractory to or intolerant of conventional therapy. Moreover, caspofungin causes less adverse effects than amphotericin B and has less drug interactions than itraconazole. As more patients are treated with caspofungin, knowledge of this new class of antifungals will likely enhance patient care in this area.

For more information:

• Sunny Linnebur, PharmD, is a primary care resident at the University of Colorado Health Sciences Center, Denver.

• Merck and Co, Inc. Cancidas (caspofungin) package insert. Whitehouse Station, NJ; 2001.
• Micromedex Healthcare Series. Itraconazole, amphotericin B, amphotericin B lipid formulations: Drug Evaluation and Physicians Desk Reference. Micromedex, Inc. 2001.
• Denning DW, Lee JY, Hosteller JS, et al. NIAID Mycoses Study Group multicenter trial of oral itraconazole therapy for invasive aspergillosis. Am J Med. 1994;97:135-144.