Caspofungin

Echinocandins are a new class of antifungal agents with a novel mechanism of action (interference with fungal cell wall synthesis). Caspofungin (Cancidas®, Caspofungin MSD®) is the first echinocandin to be approved and is administered intravenously.

Caspofungin 50 mg/day had similar efficacy to intravenous fluconazole 200 mg/day and was at least as effective as intravenous amphotericin B 0.5 mg/kg/day in patients with oesophageal candidiasis in two randomised, double-blind studies. A favourable combined clinical and endoscopic response occurred in 81% of caspofungin recipients versus 85% of fluconazole recipients and in 74% of caspofungin recipients versus 63% of amphotericin B recipients. A favourable combined response rate of ≈90% and ≈60% occurred in the stratum of patients with oesophageal candidiasis who received caspofungin or amphotericin B in a third randomised, double-blind study.

Caspofungin (70mg loading dose followed by 50 mg/day) had similar efficacy to intravenous amphotericin B (0.7–1.0 mg/kg/day in patients with neutropenia and 0.6–0.7 mg/kg/day in patients without neutropenia) in patients with invasive candidiasis in a double-blind, randomised trial. A favourable overall response occurred in 73.4% of caspofungin recipients and in 61.7% of amphotericin B recipients.

In a noncomparative study, salvage therapy with caspofungin (70mg loading dose followed by 50 mg/day) was effective in patients with invasive aspergillosis who were refractory to or did not tolerate standard antifungal therapy. A favourable response (complete plus partial response) occurred in 37 of 83 patients (45%).

Caspofungin was generally well tolerated in clinical trials; it had similar tolerability to intravenous fluconazole and was better tolerated than intravenous amphotericin B. Significantly fewer caspofungin than amphotericin B recipients reported chills, fever, nausea or infusion-related adverse events.

In conclusion, caspofungin is a valuable new antifungal agent with a novel mechanism of action. In comparative trials, caspofungin had similar efficacy to fluconazole and was at least as effective as amphotericin B in oesophageal candidiasis and had similar efficacy to amphotericin B in invasive candidiasis. In addition, caspofungin had similar tolerability to fluconazole and was better tolerated than amphotericin B in these indications. Caspofungin was also effective in patients with invasive aspergillosis who were refractory to or intolerant of standard antifungal agents. Thus, caspofungin provides an alternative to triazoles or amphotericin B in oesophageal candidiasis and an alternative to amphotericin B in invasive candidiasis, as well as being an effective salvage therapy in invasive aspergillosis.

Caspofungin inhibits the synthesis of β-(1,3)-D-glucan, an essential component of the cell wall of many fungi. Thus, by inhibiting β-(1,3)-D-glucan synthase, caspofungin interferes with fungal cell wall synthesis.

Caspofungin has fungicidal activity against Candida spp. in vitro. In one study, caspofungin demonstrated fungicidal activity against Candida albicans and C. tropicalis within 6–8 hours at concentrations that were 0.5–2 times the minimum inhibitory concentration (MIC); another study revealed that the activity of caspofungin was concentration dependent. Numerous studies demonstrated that caspofungin had in vitro activity against clinically significant Candida spp. (e.g. C. albicans, C. krusei, C. tropicalis, C. pseudotropicalis, C. glabrata, C. parapsilosis, C. lusitaniae, C. guilliermondii and C. dubliniensis), including both azole-sensitive and -resistant Candida spp. and amphotericin B-resistant Candida spp. Caspofungin was active against azole-resistant Candida spp. such as C. glabrata and C. krusei, but was less active against C. parapsilosis and C. guilliermondii. For various Candida spp. isolated from patients with invasive candidiasis, the caspofungin MIC ranged from 0.125 to >8 μg/mL. Caspofungin reduced the fungal tissue burden and prolonged survival in animal models of disseminated candidiasis (including immunocompetent and immunocompromised mice and rabbits).

Caspofungin showed in vitro activity against various Aspergillus spp., including Aspergillus flavus, A. fumigatus, A. niger and A. terreus. For Aspergillus isolates obtained from patients involved in clinical trials, 24-hour MIC values at which 80% growth inhibition occurred were <1 μg/mL for all isolates. Staining studies suggest that caspofungin causes lysis of actively growing A. fumigatus cells at the hyphal tips and branch points, although subapical cells with mature cell walls were less susceptible to lysis. Intraperitoneal caspofungin prolonged survival in immunocompromised mice and guinea pigs with disseminated aspergillosis. Results concerning the effect of caspofungin on residual fungal burden were mixed. Administering caspofungin to neutropenic rabbits for the prevention or treatment of pulmonary aspergillosis prolonged survival and reduced A. fumigatus-mediated pulmonary injury. However, the residual fungal burden in the lungs did not change and galactomannan antigenaemia increased.

Unless stated otherwise, pharmacokinetic studies were conducted in healthy volunteers. Administration of single doses of caspofungin 5–100mg resulted in dose-proportional increases in the area under the plasma concentration-time curve from time zero to infinity (AUC_0-∞) and in the plasma concentration 1 hour (C_1h) and 24 hours (C_24h; trough concentration) post-dose. Repeat administration of caspofungin suggested modest pharmacokinetic nonlinearity. Moderate accumulation of caspofungin occurred with repeat administration. Steady state was reached at about week 3. Administration of caspofungin 50 mg/day resulted in C_24h values of <1 μg/mL on day 1 and >1 μg/mL (proposed target concentration in invasive infections; derived from in vitro susceptibility testing of Candida spp.) on day 14. Administration of a 70mg loading dose of caspofungin followed by 50 mg/day resulted in a C_24h value of >1 μg/mL on both days 1 and 14. Caspofungin plasma concentrations decline in a polyphasic manner. It has a short α-phase of 1–2 hours (volume of distribution of 9.7L) and a β-phase half-life (t1/2) of ≈9–11 hours. The clearance of caspofungin from plasma is primarily influenced by distribution.

The AUC_0-∞ of caspofungin was increased by ≈76% in patients with moderate hepatic impairment (Child-Pugh score 7–9) compared with healthy controls following administration of a single 70mg dose of the drug. Administration of a 70mg loading dose of caspofungin followed by 35 mg/day to patients with moderate hepatic impairment only increased the AUC_24h on day 14 by 7% compared with healthy controls.

At clinically relevant concentrations, caspofungin does not inhibit any enzyme in the cytochrome P450 (CYP) system or induce the metabolism of other drugs via CYP3A4. Caspofungin does not act as a substrate for P-glycoprotein and is a poor substrate for CYP enzymes. Caspofungin pharmacokinetics were altered by the coadministration of cyclosporin or rifampicin (rifampin) [≈35% increase in AUC and 30% reduction in trough concentration, respectively]. Coadministration of caspofungin and efavirenz, nevirapine, phenytoin, dexamethasone or carbamazepine (inducers of drug clearance) may result in clinically significant reductions in caspofungin concentrations. The whole blood AUC_12h of tacrolimus was reduced by ≈20% with concomitant administration of caspofungin, although caspofungin pharmacokinetics were not altered by tacrolimus.

Studies have evaluated the efficacy of caspofungin in oesophageal candidiasis, invasive candidiasis and invasive aspergillosis. Study drugs in these trials were administered intravenously.

In two randomised, double-blind studies, caspofungin 50 mg/day had similar efficacy to fluconazole 200 mg/day and was at least as effective as amphotericin B 0.5 mg/kg/day in patients with oesophageal candidiasis. A favourable combined clinical and endoscopic response occurred in 81% of caspofungin recipients and 85% of fluconazole recipients 5–7 days after the end of treatment; caspofungin was shown to be noninferior to fluconazole. Four weeks after stopping treatment, the relapse rate was 28% in caspofungin recipients and 17% in fluconazole recipients. In the other study, a favourable combined clinical and endoscopic response occurred in 74% of caspofungin recipients and 63% of amphotericin B recipients 14 days after the completion of treatment; a favourable microbiological response occurred in 76% and 61% of patients. A favourable combined response rate of ≈90% and ≈60% occurred in the stratum of patients with oesophageal candidiasis who received caspofungin or amphotericin B in a third randomised, double-blind study (including patients with oropharyngeal or oesophageal candidiasis).

Retrospective analyses of oesophageal candidiasis trial data revealed that caspofungin 50 mg/day is effective in patients with oesophageal candidiasis who are refractory to fluconazole or are infected with Candida isolates that have reduced in vitro susceptibility to fluconazole, and is effective in eradicating the symptoms of oesophageal candidiasis in patients with HIV infection.

Caspofungin (70mg loading dose followed by 50 mg/day) had similar efficacy to amphotericin B (0.7–1.0 mg/kg/day in patients with neutropenia and 0.6–0.7 mg/kg/day in patients without neutropenia) in patients with invasive candidiasis. At the end of intravenous treatment, a favourable overall response occurred in 73.4% of caspofungin recipients and in 61.7% of amphotericin B recipients; caspofungin was shown to be noninferior to amphotericin B. Treatment failure occurred in 26.6% of caspofungin recipients and 38.3% of amphotericin B recipients. Similar proportions of caspofungin and amphotericin B recipients experienced relapse 6–8 weeks after the end of therapy (6.4% vs 7%) or died (34.2% vs 30.4%).

In a noncomparative study, salvage therapy with caspofungin (70mg loading dose followed by 50 mg/day) was effective in patients with invasive aspergillosis who were refractory to or did not tolerate standard antifungal therapy. A favourable response (complete plus partial response) occurred in 37 of 83 patients (45%). Analysis by the site of infection revealed a favourable response in 50%, 23% and 33% of patients with pulmonary aspergillosis, disseminated aspergillosis and single organ aspergillosis, respectively.

Caspofungin was generally well tolerated in clinical trials. In caspofungin recipients, the most commonly reported drug-related clinical adverse events included chills, fever, phlebitis/thrombophlebitis, tachycardia, nausea, vomiting, rash, abdominal pain, headache and diarrhoea (incidence ≤16%).

In comparative clinical trials, caspofungin had similar tolerability to fluconazole but was better tolerated than amphotericin B in patients with oesophageal or invasive candidiasis. Significantly fewer caspofungin than amphotericin B recipients reported drug-related clinical adverse events, specifically chills, fever, nausea or infusion-related adverse events. Caspofungin recipients were significantly less likely than amphotericin B recipients to discontinue therapy because of an adverse event. In addition, caspofungin recipients were significantly less likely than amphotericin B recipients to develop laboratory abnormalities or to discontinue treatment because of laboratory abnormalities. Significantly fewer caspofungin than amphotericin B recipients developed elevated blood urea nitrogen levels, decreased serum potassium levels/hypokalaemia, hypokalaemia requiring supplementation within 72 hours of onset, a nephrotoxic effect, decreased haemoglobin levels or increased serum creatinine levels.

With regards to potential drug interactions, coadministration of caspofungin and cyclosporin in healthy volunteers resulted in transient increases in alanine aminotransferase and aspartate aminotransferase levels. Patients receiving cyclosporin were generally excluded from clinical trials.

No dosage adjustment is needed in the elderly, in patients with renal dysfunction or in patients with mild hepatic impairment (Child-Pugh score 5–6), although in patients with moderate hepatic impairment (Child-Pugh score 7–9), the maintenance dosage of caspofungin should be reduced from 50 to 35 mg/day. No dose administration recommendations have been established for patients with severe hepatic impairment or in paediatric patients aged <18 years.

Concomitant administration of caspofungin and cyclosporin should be reserved for patients for whom the potential benefit outweighs the potential risk. When caspofungin is coadministered with tacrolimus, concentrations of the latter drug should be monitored and dosage adjustments made as necessary. An increased caspofungin dosage (70 mg/day) is recommended in patients receiving concomitant rifampicin and should be considered in patients concomitantly receiving inducers of drug clearance such as efavirenz, nevirapine, phenytoin, dexamethasone or carbamazepine.

Caspofungin should only be administered to pregnant women if the potential benefit justifies the potential risk to the fetus. US prescribing information recommends caution when administering caspofungin to breast-feeding women and EU prescribing information states that women receiving caspofungin should not breast feed.