Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Caspofungin
General information
Caspofungin is approved in patients over 18 years of age for second-line therapy of definite or probable invasive aspergillosis, for primary therapy in non-neutropenic patients with invasive Candida infections, and for empirical antifungal therapy in granulocytopenic patients with persistent fever.
Drug studies
Observational studies
Caspofungin has been investigated in a non-comparative phase II clinical study in 90 patients with invasive aspergillosis [ ]. Two patients withdrew because of drug-related adverse events; 84 developed at least one clinical adverse event. However, only 11 had an adverse event that was possibly, probably, or definitely related to caspofungin. Of the 90 patients 53 developed at least one laboratory adverse event, but only 12 were considered to have had a drug-related adverse event. Drug-related nephrotoxicity (1.1%) and hepatotoxicity (under 5%) occurred infrequently.
In 104 consecutive courses of caspofungin for invasive candidiasis cure rates were 83% (57/69) for bloodstream infections and 84% (22/26) for abdominal infections [ ], response rates similar to those obtained in controlled trials. There were no withdrawals because of adverse events.
In 48 patients with non-fungemic invasive candidiasis who received caspofungin 50 mg/day with the option of dosage escalation of up to 150 mg/day for endocarditis, osteomyelitis, or septic arthritis, the overall success rate was 81%. None of the patients had a serious drug-related adverse event or withdrew because of adverse effects [ ].
The efficacy and safety of caspofungin as salvage therapy for invasive aspergillosis has been studied in patients enrolled in the Caspofungin Compassionate Use Study [ ]. There was a favorable response in 20/45 patients, including nine and 11 with complete and partial responses respectively. One serious drug-related adverse event was reported in a patient with acute biphenotypic leukemia, who had an anaphylactic reaction to caspofungin, characterized by stridor/dyspnea, facial swelling, and accentuation of a pre-existing rash about 10 minutes into the infusion; all the symptoms resolved within 15 minutes of withdrawal of caspofungin and the administration of diphenhydramine and hydrocortisone.
Caspofungin 50 mg/day for a median duration of 20 (range 8–64) days has been used as first-line therapy for proven or probable pulmonary fungal infection in 32 immunocompromised patients with hematological malignancies (median age 52 years) [ ]. The overall response rate was 56% (18/32), with 12/18 complete responses and 6/18 partial responses. Granulocyte recovery and status of disease (remission/onset versus refractory/relapsed) were significantly associated with a favorable outcome. There were no clinical adverse events and only grades I and II transient increases in serum alkaline phosphatase and/or aminotransferase activities in 4/32 patients.
The effectiveness and tolerability of caspofungin 35–50 mg/day for up to 100 days as primary prophylaxis in 123 stem cell transplant recipients (117 allogeneic) has been assessed retrospectively [ ]. The median duration of caspofungin prophylaxis was 73 (range 10–100) days. Nine patients developed breakthrough invasive fungal infections; by day 100, there were five deaths, two of which were directly attributable to invasive fungal infections. There were no caspofungin-related adverse events.
Comparative studies
Caspofungin versus amphotericin
Caspofungin (n = 556) has been compared with liposomal amphotericin (n = 539) in a randomized, double-blind, multinational trial as empirical antifungal therapy [ ]. Patients were stratified according to risk and whether they had previously received antifungal prophylaxis. Premature withdrawal for any cause was less common with caspofungin than amphotericin (10% versus 15%). Fewer patients who received caspofungin sustained nephrotoxicity (2.6% versus 12%), an infusion-related event (35% versus 52%), or a systemic drug-related adverse event or discontinued therapy because of drug-related adverse events.
Caspofungin has also been compared with liposomal amphotericin in the management of febrile neutropenia or invasive fungal infections in an open study 73 episodes in patients with hematological malignancy [ ]. There were fewer episodes of drug toxicity with caspofungin than liposomal amphotericin (58% versus 84%). Response rate for episodes of febrile neutropenia were similar but there were more breakthrough fungal infections with caspofungin (33% versus 0%). None of four episodes of candidemia or hepatosplenic candidiasis responded to caspofungin compared with three of four episodes treated with liposomal amphotericin. Mortality was significantly higher with caspofungin than with liposomal amphotericin (6/24 versus 2/49), mainly because of an excess of fungal infections.
Caspofungin versus micafungin
The clinical usefulness of caspofungin for patients with invasive candidiasis has been further substantiated by the results of a randomized, double-blind, phase III comparison of micafungin 100 mg/day and micafungin 150 mg/day with a standard dosage of caspofungin in 595 adults. There were similar success rates. The types and frequencies of adverse events were similar, and less than 5% of patients withdrew prematurely because of drug-related adverse events [ ].
Combination studies
Caspofungin + amphotericin
The use of caspofungin in combination with other agents against certain types of invasive fungal infections is appealing, given the poor response rates to standard agents and its unique mechanism of action. Two retrospective analyses have explored the safety and potential benefits of a combination of caspofungin with liposomal amphotericin B (L-AmB).
In the first analysis the efficacy and safety of caspofungin in combination with L-AmB in 48 patients with hematological malignancies with definite or probable or possible invasive aspergillosis were evaluated [ ]. Caspofungin was given intravenously as a 70 mg loading dose on day 1, followed by a daily dose of 50 mg; L-AmB was started at an intravenous dose of 5 mg/day. The median duration of therapy with the combination was 20 (range 7–180) days. The combination of caspofungin and L-AmB was well tolerated: seven patients developed mild-to-moderate renal insufficiency that was attributed to the use of L-AmB and four required withdrawal. There was hypokalemia in three of the patients. One patient had a fever associated with caspofungin and another had hepatic dysfunction of multifactorial origin. In no patient was the combination withheld due to unanticipated adverse effects.
The second analysis included 30 patients with hematological malignancies and proven (n = 6), probable (n = 4), or possible (n = 20) invasive fungal lung infections refractory to L-AmB monotherapy 3–5 mg/kg/day [ ]. The dosage of caspofungin was 50 mg/day with a single loading dose of 70 mg on day 1. The median duration of combination therapy was 24 (range 3–74) days. In 18 patients there was a favorable antifungal response, defined as improvement in both clinical and radiographic signs of fungal pneumonia. There was mild to moderate nephrotoxicity in 15 patients, necessitating the substitution of liposomal amphotericin. There were mild rises in alkaline phosphatase activity in nine patients. Caspofungin was temporarily withheld from one patient who developed moderate but reversible biochemical hepatotoxicity.
In an open pilot study of a combination of liposomal amphotericin 3 mg/kg/day and caspofungin at the standard dose or monotherapy with high-dose amphotericin 10 mg/kg/day for proven or probable invasive aspergillosis in 30 patients, the median durations of treatment were 18 and 17 days respectively [ ]. There were significantly more favorable overall responses in the combination group (10 of 15 patients versus 4 of 15 patients). Survival rates at 12 weeks were similar. Infusion-related reactions occurred in three patients in the high-dose monotherapy group. There was a two-fold increase in serum creatinine in 4 of 17 patients who received high-dose monotherapy and 1 of 15 patients who received combination therapy; hypokalemia below 3 mmol/l occurred in three patients and two patients respectively.
These analyses suggest that caspofungin and L-AmB can be used safely together.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here