Caspofungin

Summary Abstract Caspofungin (Cancidas®) is the first of a new class of antifungal agents, the echinocandins, that inhibit the synthesis of the fungal cell wall component β-(l,3)-D-glucan. Caspofungin is administered once daily by slow intravenous infusion and is used to treat infections caused by Candida spp. and Aspergillus spp. Caspofungin is a valuable new antifungal agent with a novel mechanism of action. In comparative clinical trials, caspofungin was no less effective than liposomal amphotericin B in the empirical treatment of neutropenic patients with persistent fever, amphotericin B deoxycholate in the treatment of invasive candidiasis or fluconazole in the treatment of oesophageal candidiasis. Caspofungin also displayed broadly similar efficacy to amphotericin B deoxycholate in oesophageal or oropharyngeal candidiasis and was effective as salvage therapy in patients with invasive aspergillosis who were refractory to or intolerant of standard therapy. The tolerability profile of caspofungin was similar to that of fluconazole and superior to that of amphotericin B deoxycholate and liposomal amphotericin B. Therefore, in the appropriate indications, caspofungin is a viable alternative to amphotericin B deoxycholate, liposomal amphotericin B or fluconazole. Pharmacological Properties Caspofungin blocks the synthesis of β-(l,3)-D-glucan, an essential component of the cell wall of many fungi, resulting in osmotic disruption of the fungal cell. Caspofungin is most active in vitro against Candida spp., for which it is fungicidal, and Aspergillus spp., for which it is generally fungistatic. A target susceptibility breakpoint of 1 μg/mL for caspofungin against Candida spp. has been suggested based on in vitro susceptibility testing, although this has not been correlated with clinical outcome. Caspofungin was effective in a variety of animal models of disseminated candidiasis, including those caused by azole-resistant strains, and invasive aspergillosis. The in vitro development of resistance to caspofungin is rare. As the oral bioavailability of caspofungin is poor (<0.2%), the drug is administered by slow intravenous infusion over 1 hour. Single doses of 50 and 70mg produced mean peak (1 hour) plasma concentrations of 7.6 and 12.3 μg/mL and trough (24 hour) concentrations of 0.8 and 1.3 μg/mL. Steady state was reached after 14–21 days of multiple-dose administration. Plasma clearance of caspofungin is slow and is determined primarily by the distribution of drug into tissues, notably hepatocytes, rather than by the rate of metabolism or excretion. Caspofungin is slowly metabolised in the liver and dosage reduction is recommended in patients with moderate hepatic insufficiency. Excretion was minimal in the first 2 days following a single dose of radiolabelled caspofungin, and excretion in urine and faeces peaked at 6–7 days. Caspofungin does not readily interact with the cytochrome P450 system or P-glycoprotein. However, pharmacokinetic interactions between caspofungin and tacrolimus, ciclosporin (cyclosporin), rifampicin (rifampin) and other inducers of drug clearance have been reported. Therapeutic Efficacy In a head-to-head comparison, caspofungin 50 mg/day, following a 70mg loading dose on day 1, was no less effective than liposomal amphotericin B 3 mg/kg/day in the empirical treatment of presumed fungal infection in patients with neutropenia and persistent fever despite antibacterial therapy. Both treatments produced an overall favourable response in 34% of patients. Caspofungin 50 mg/day was no less effective than fluconazole 200 mg/day in the treatment of adult patients (mostly HIV-infected) with oesophageal candidiasis. The efficacy of caspofungin 50 mg/day was also broadly similar to that of amphotericin B deoxycholate 0.5 mg/kg/day in the treatment of oesophageal or oropharyngeal candidiasis in two phase II trials not powered to allow formal efficacy comparisons. Similarly, caspofungin 50 mg/day, following a loading dose of 70mg on day 1, was no less effective than amphotericin B deoxycholate 0.6–0.7 mg/kg/day in the treatment of patients with invasive candidiasis, mostly candidaemia. The respective favourable response rates were 73% and 62% of patients. In two noncomparative studies, salvage therapy with caspofungin 70mg on day 1 followed by 50 mg/day thereafter was effective in 44% and 45% of patients with invasive aspergillosis who were refractory to or intolerant of standard therapy (polyenes or triazoles). Analyses conducted in the US of drug acquisition costs and the costs of treating drug-induced nephrotoxicity predicted that caspofungin would have lower overall treatment costs than liposomal amphotericin B in febrile neutropenia and amphotericin B deoxycholate in invasive candidiasis. Tolerability Caspofungin was generally well tolerated in clinical trials. Serious adverse events were rare and only 11 of 979 caspofungin 50 mg/day recipients in prospective trials discontinued therapy as a result of probable drug-related adverse events. The tolerability of caspofungin was superior to that of liposomal amphotericin B in febrile neutropenic patients, particularly with respect to nephrotoxicity and infusion-related events. The tolerability profile of caspofungin was similar to that of fluconazole in patients with oesophageal candidiasis. Caspofungin was better tolerated than amphotericin B deoxycholate in patients with oesophageal, oropharyngeal or invasive candidiasis, particularly with respect to fever, chills, nausea, vomiting, infusion-related events, elevated serum creatinine, hypokalaemia, elevated blood urea nitrogen and decreased haemoglobin, each of which had a significantly higher incidence with amphotericin B deoxycholate.