Caspofungin—A Novel Antifungal Agent
Special feature
Caspofungin (cancidas), the first of a new class of antifun-gal agents, received approval by the FDA on January 26, 2001. Caspofungin is an echinocandin, a semisynthetic derivative of pneumocandin B0, which is a fermentation product of Glarea lozoyensis. It is a large (MW 1213 daltons), water soluble lipopeptide that, like other echinocandins, competitively inhibits the synthesis of b-(1,3)-D-glucan, a critical structural component of most fungal cell walls.1
Among fungi frequently encountered in the clinic, caspofungin has in vitro and in vivo activity against Aspergillus and Candida species and is also active in animal models of Pneumocystis carinii infection. Since its mechanism of action differs from those of the polyenes and the azoles, caspofungin retains activity against many fungal organisms resistant to these 2 classes of agents. It has activity against all Candida spp., including C krusei, is fungicidal against Candida spp. in a concentration-dependent manner, and has sterilizing abilities in a murine model of pyelonephritis. When combined in vitro with amphotericin B against either C albicans, A fumigatus, Fusarium spp., or Cryptococcus neoformans, either synergy or indifference is observed; antagonism has not been described. Antagonism was also not observed in experimental infection models of candidiasis (caspofungin plus either amphotericin B or fluconazole) or aspergillosis (caspofungin plus amphotericin B).
The in vitro activity of caspofungin against the endemic fungi, Coccidioides immitis, Histoplasma capsulatum, and Blastomyces dermatiditis is less than that against Candida and Aspergillus. One study reported limited activity in a murine model of histoplasmosis.2
Candida
The IC50 of caspofungin against C albicans glucan synthase is 0.6 nM and in vitro MICs are < 2.0 mg/mL. It is fungicidal against Candida in vitro, albeit more slowly so than is amphotericin B. C albicans resistance to caspofungin in vitro is rare, with selection on agar plates occurring at a frequency of 10-8. Four-fold resistance derived in vitro has been associated with mutation of the FKS1 gene; this resistance was not associated with loss of virulence. Because it does not require entry into the fungal cell (the enzyme target is embedded in the fungal cell membrane), caspofungin is not affected by the efflux pumps that constitute the major mechanism of resistance of Candida to the azole antifungals.
Caspofungin is at least as effective as both conventional amphotericin B and amphotericin B lipid complex in murine models of disseminated candidiasis. In addition, it is effective in the treatment of Candida esophagitis in humans. One hundred twenty-eight patients with Candida esophagitis, 78% of whom were HIV-infected, were randomized to intravenous therapy with either echinocandin MK-991 or (50 mg or 70 mg daily) or amphotericin B (0.5 mg/kg/d). The echinocandin was better tolerated than was amphotericin B and was associated with a response rate of 85.1% compared to 66.7% in the latter group.3
Aspergillus
Caspofungin has in vitro activity against A fumigatus, A niger, A nidulans, and A terreus with geometric mean MICs that range from 0.4 to 0.7 mg/mL and A flavus at 2.7 mg/mL. Whether it is classically fungicidal against Aspergillus appears uncertain at this time. It is active against Aspergillus spp. in a variety of murine models, and its ED50 in experimental disseminated infection in cytoxan-treated mice was virtually identical to that of amphotericin B.
In Protocol 019, patients with documented invasive aspergillosis who were either refractory to at least 7 days of therapy with an appropriate antifungal agent or who were intolerant to such therapy were eligible to receive caspofungin. Of the patients studied, 84% had failed therapy. Two-thirds had a hematologic malignancy and/or had undergone bone marrow transplantation and 13% had undergone solid organ transplantation; 22% were neutropenic (ANC, < 500/mm3) and 37% were receiving the equivalent of 20 mg or more of prednisone. Approximately 70.7% had pulmonary infection, 21% had disseminated infection, and 6.2% had paranasal sinus infection. The drug was administered for a mean of 33.7 days (range, 1-162 days).
Favorable outcomes were achieved in 40.7% (95% CI, 27.6-55.0%) of the entire cohort of 54 patients and in 48.9% of the 45 patients who received caspofungin for at least 7 days. The response rate was 70% in the intolerant group and 38.5% in the refractory group. A total of 296 patients were chosen to comprise a group of historical matched controls; a favorable outcome was achieved in only 17% (95% CI, 12.1-22.8%). A total of 54.5% of patients died.
Clinical drug-related adverse events occurred in 8 (11.6%) patients. Most frequently seen were fever, flushing, nausea, vomiting, headache, and infusion-related phelbitis; each occurred in less than 3%. Symptoms consistent with histamine release were seen in 5 patients (1.8%), and 1 case of anaphylaxis has been reported. Eosinophilia occurred in 3.1%. There was no significant nephrotoxicity.
Pharmacology (See Table)
| Table-Pharmacology of Caspofungin | |
| Recommended Dose | |
| Usual | 70 mg, then 50 mg q 24 h* |
| Renal insufficiency | 70 mg, then 50 mg q 24 h |
| Hemodialysis | 70 mg, then 50 mg q 24 h |
| Hepatic insufficiency—mild** | 70 mg, then 50 mg q 24 h |
| Hepatic insufficiency—moderate*** | 70 mg, then 35 mg q 24 h |
| Hepatic insufficiency—severe | No data |
| Pharmacokinetic Parameters**** | |
| Peak serum concentration | 12.1 mg/mL |
| Trough serum concentration | 1.3 mg/mL |
| Vd | 9.7 L |
| AUC (0-24 h) | 93.5 mg h/mL |
| α T 1/2 | 1-2 h |
| β T 1/2 | 9-11 h |
| δ T 1/2 | 40-50 h |
| Protein binding | 96.5% |
| *70 mg qd, based on limited data, also appears to be safe and may be considered in appropriate circumstances |
|
| **Child-Pugh score 5-6 | |
| ***Child-Pugh score 7-9 | |
| ****PAfter single 70 mg IV dose | |
Caspofungin is only available for intravenous administration. The recommended initial dose of 70 mg followed by 50 mg every 24 hours results in mean trough concentrations above 1.0 mg/mL. The mean peak serum concentration on day 1 is 12.1 mg/mL while the trough is 1.3 mg/mL.
The decline in serum caspofungin concentration after a single dose is triphasic. The initial a-phase lasts approximately 1-2 hours and is associated with distribution of the drug from plasma to the extracellular fluid space. The volume of distribution is 9.7 L. The b-phase, which has a mean half-life of 9-11 hours, exhibiting log-linear behavior from approximately 6 hours to approximately 48 hours after infusion, appears to represent a period of binding to and distribution into tissues, especially hepatocytes. No metabolism or excretion of the drug occurs during this phase. The b-phase accounts for most of the drug’s AUC. The g-phase has a half-life of 40-50 hours and appears to reflect slow drug release from tissues. Caspofungin clearance is approximately 12 mL/min (0.15 mL/kg/min) with approximately 1.4% of a dose appearing unchanged in the urine—renal clearance is only approximately 0.15 mL/min. Biliary excretion of unchanged drug is also minimal. The clearance of caspofungin is reduced approximately 25% in the elderly, but no dose alteration is required.
Renal insufficiency has little effect on drug kinetics and the drug is not removed during hemodialysis—no dosage modifications are required. There is a modest (1.76-fold) increase in AUC in the presence of moderate hepatic insufficiency (Child-Pugh score 7-9); as a consequence, dose alteration is recommended in this circumstance; after the initial 70 mg loading dose, a subsequent daily dose of 35 mg is suggested.
The drug undergoes spontaneous peptide hydrolysis and N-acetylation. Its major degradation product, a ring-opened peptide, lacks antifungal activity. Further metabolism of the hexapeptide structure is believed to involve hydrolysis into constituent amino acids. Metabolism is very slow and, as stated above, little biotransformation (or renal clearance) occurs during the first 48 hours after administration of a single dose.
Caspofungin is approximately 96.5% bound to plasma proteins. Despite this, its in vitro activity against A fumigatus is enhanced by the presence of human serum.4 In addition, irreversible covalent protein binding at a concentration of approximately 7 pmol/mg protein occurs, most likely the result of an interaction between plasma proteins and potentially reactive intermediates resulting from spontaneous degradation of caspofungin via either an imine or nucleophilic mechanism.
Caspofungin is neither a significant substrate nor a potent inhibitor of P-glycoprotein or of hepatic cytochrome enzymes. Nonetheless, potentially significant reductions (approximately 20%) in caspofungin AUC and clearance may be observed with coadministration of efavirenz, nevirapine, rifampin, dexamethasone, phenytoin, or carbamazepine, possibly as the result of induction of either a minor oxidative pathway or of a transport mechanism. As a consequence, the daily dose of caspofungin should be maintained at 70 mg in patients also receiving one of these agents.
There are no pharmacokinetic interactions with amphotericin B, itraconazole, or 2-hydroxy-itraconazole.
The 24-hour AUC of caspofungin is increased by approximately 35% when coadministered with cyclosporin; cyclosporin exposure is not affected. Studies in rats suggest that cyclosporin may inhibit the uptake of caspofungin into liver tissue. Modestly elevated (£ 3-fold of the upper limit of normal) serum transaminases were noted in some subjects who received caspofungin and cyclosporin together, an observation that has led to the recommendation that these 2 drugs not be coadministered in the absence of further data unless the potential benefit is estimated to outweigh the potential risk.
Coadministration of caspofungin with tacrolimus results in no effect on caspofungin exposure, but whole blood tacrolimus levels are reduced by approximately 20%. It has been suggested that this may result from decreased red blood cell binding by tacrolimus. There appears to be no pharmacokinetic interaction between caspofungin and mycophenolic acid or its pharmacologically active glucuronide.
Safety
The most commonly observed drug-related adverse effects have been pruritus at the drug injection site and other mild infusion-related complications, and headache. There were no caspofungin-related clinical or laboratory serious adverse events in the studies presented to the FDA and no drug-related nephrotoxicity observed. The incidence of transaminase elevations (all < 5-fold) was 14.1% in caspofungin recipients in studies comparing this drug to fluconazole, a frequency similar to that seen in the triazole recipients.
Caspofungin is a basic polypeptide, a class of drugs that may cause histamine release from mast cells when administered intravenously. Reactions consistent with histamine release were reported in 1.8% of recipients.
Caspofungin is embryotoxic in rats and rabbits and has been classified as Pregnancy Category C. Thus, it should only be used in pregnancy if the potential benefit outweighs the potential fetal risk.
Comment by Stan Deresinski, MD, FACP
At the time of this writing, caspofungin had received FDA approval only as a second-line agent in the treatment of invasive Aspergillus infections. It is likely, however, to receive approval in the treatment of invasive Candida infections as well. It has a number of favorable characteristics that make it a welcome contribution to our antifungal armamentarium. These include its activity against all clinically relevant species of Candida, its fungicidal activity against these organisms, as well as its high degree of tolerability and apparent absence of nephrotoxicity.
It is likely that caspofungin will find an immediate role for use in patients with nephrotoxicity or at risk of nephrotoxicity. It will also prove useful for empiric therapy (and, possibly, prophylactic therapy) of fungal infections in immunosuppressed patients, as well as preemptive treatment in intensive care patients with suspected invasive candidiasis or aspergillosis. The unavailability of an orally absorbable form of the drug will obviously limit its outpatient use.
In addition to further documentation of its effectiveness in Candida and Aspergillus infections, exploration of its role in additional fungal infections, such as those due to P carinii and C immitis, is warranted. Also worthy of further exploration is its use in combination with other antifungal agents, especially amphotericin B and itraconazole, as well as some drugs in development.
References
1. http://www.fda.gov/ohrms/dockets/ac/01/briefing/ 3676b1_01.pdf.
2. Kohler S, et al. Antimicrob Agents Chemother. 2000; 44:1850-1854.
3. 40th ICAAC 2000, LB-33.
4. Chiller T, et al. Antimicrob Agents Chemother. 2000; 44:3302-3305.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content