Retrospective study of the safety of caspofungin in immunocompromised pediatric patients

Caspofungin is an antifungal medication proved efficacious and well-tolerated in adults. Twenty-five pediatric patients at St. Jude Children’s Research Hospital who had received at least one dose of caspofungin were identified, and their records were reviewed retrospectively. Caspofungin was well-tolerated; only three patients experienced any adverse event judged possibly related to drug. Caspofungin appears to be safe in immunocompromised pediatric patients. Serious invasive mycoses are increasingly prevalent causes of significant morbidity and mortality in immunocompromised and debilitated patient populations. 1, 2 In addition to the increased number of cases of invasive mycoses, there has been an epidemiologic shift in the pathogenic fungi toward more resistant organisms such as drug-resistant strains of Candida, Aspergillus spp., Fusarium spp., Scedosporium spp., other dematiaceous fungi and Zygomycetes. 2, 3–6 For the last two decades, antifungal treatment, including amphotericin B and the azoles, has been aimed at disruption of the cell wall of the fungi by targeting ergosterol. 7 Amphotericin B is fungicidal but has many toxicities. The azoles are only fungistatic, and an increasing number of fungi are cross-resistant to all azoles. Despite aggressive therapy with amphotericin B and the azoles, the morbidity and mortality rates remain high in immunocompromised patients with invasive fungal disease. 8 Increased prevalence of disease, high morbidity and mortality rates, emergence of resistant organisms and toxicities related to the therapeutic regimens themselves all point to the need for continued efforts in the development of new antifungal agents. Several new agents have either recently been released for use or are in the final stages of testing. One of the promising agents recently made available is caspofungin. Caspofungin belongs to the group of novel antimycotic agents known as echinocandins, which are potent, highly selective, irreversible inhibitors of 1,3-beta-d-glucan synthase. 9–14 This novel mechanism of action provides an additional target for antimycotic therapy and an inherent selectivity for the pathogenic organism, improving the toxicity profile of the medication. Caspofungin is a fungicidal antimycotic 1, 7, 12, 13, 15 and is efficacious against a broad spectrum of fungi, including many strains that are resistant to amphotericin B and the azoles. 16 Caspofungin does not require dosage adjustment for renal dysfunction or mild hepatic dysfunction 14 and has a good safety profile and good toleration in adult patients. 13–15, 17 Caspofungin, however, should be avoided when possible in patients currently receiving cyclosporine, because concomitant use has been associated with transient elevations of alanine aminotransferase and aspartate aminotransferase. 14 To our knowledge this study represents the first published data regarding the safety of this important novel medication in the immunocompromised pediatric population. Subjects and methods. The pharmacy records at St. Jude Children’s Research Hospital (SJCRH) were reviewed to identify all patients who had received at least one dose of caspofungin between February 2001 and December 2001. A retrospective chart review was performed. Clinical and demographic data were obtained. Data regarding antecedent use (defined as use within the 14 days before initiation of caspofungin) or concurrent use of other antifungals, aminoglycosides, chemotherapeutic agents and systemic steroids were also obtained. The variables chosen for evaluation were based on the most common objective adverse drug-related events seen in adult studies evaluating the safety of caspofungin. The variables that were chosen for study included temperature curve, absolute neutrophil count, hemoglobin, platelet count, serum creatinine, alanine aminotransferase, aspartate aminotransferase, total bilirubin and potassium. The indication for caspofungin was assessed, including prophylaxis, treatment of suspected fungal infection or treatment of documented fungal infection. Further, in patients receiving caspofungin for a suspected or documented fungal infection, we assessed whether caspofungin was used for synergy or because of failure of previous therapy or toxicity of previous therapy. Toxicities were graded by the standardized National Cancer Institute Common Toxicity Criteria. 18 The aforementioned variables were evaluated from 1 week before initiation of caspofungin through 1 week after discontinuation of caspofungin or until the time of the patient’s death. For each patient weekly toxicity ratings were assigned for each variable. The toxicity rating for each variable was always assigned based on the weekly value for that particular variable that would produce the highest toxicity rating. This strategy was adopted to maximally identify potential adverse drug-related events. The clinical investigators (JAF and PMF) determined relatedness of the medication to each toxicity studied. Relatedness of the toxicity to the medication was described as (1) unrelated, (2) possibly related, (3) probably related, (4) definitely related or (5) undeterminable. Decisions regarding relatedness of observed toxicities to the medication were based on temporal relationships between the toxicity and medication administration, possible relationships resulting from concurrent medications and secondary diagnoses and physician clinical judgment. This study protocol was reviewed and approved by the Institutional Review Board at St. Jude Children’s Research Hospital. Results. Patient characteristics. Twenty-seven patients were initially identified as having received at least 1 dose of caspofungin between February 2001 and December 2001 by review of the SJCRH pharmacy records. However, after review of the patient chart, 2 patients were eliminated from evaluation because neither had actually received a dose of caspofungin. Therefore 25 patients were identified for this study. The median patient age was 9.8 years (range, 0.3 to 26.2 years). Nineteen of the patients were male. Nineteen of the patients were Caucasian, 4 were African-American and 2 were classified as other. Fourteen of the patients had undergone allogeneic bone marrow transplantation. Thirteen patients had a documented fungal infection, 8 patients had suspected fungal infection and 4 patients received caspofungin as prophylaxis for fungal infection. In no patient with documented or suspected fungal infection was caspofungin used as monotherapy; all 21 patients also received liposomal amphotericin B. Other concurrent systemic antifungals in patients with documented or suspected fungal infections included itraconazole (n = 3) and voriconazole (n = 3). Thirteen patients were neutropenic at the time caspofungin therapy was started with an absolute neutrophil count of <500 for a median of 19 days (range, 1 to 44 days). Drug administration. Recommendations for dosing of caspofungin at SJCRH had been established by the Department of Infectious Diseases. Patients in this study weighing ≥50 kg received 50 to 75 mg daily. Dosing for patients in this study weighing < 50 kg ranged from 0.8 to 1.6 mg/kg daily. The median duration of caspofungin therapy was 32 days (range, 1 to 116 days). No pharmacokinetic data were obtained to adjust dosing. The median cumulative doses received were 33.2 mg/kg (range, 0.84 to 167 mg/kg) and 747 mg/m2 (range, 29.3 to 3577 mg/m2 iv). Toxicity. Only three patients (12%) experienced any adverse event that was judged possibly related to caspofungin. The most commonly encountered adverse drug-related event was hypokalemia, which was seen in all three patients. Two of the three patients had elevations of the total serum bilirubin. One of the three patients had decreased hemoglobin. One of the three patients had an elevated alanine aminotransferase. No patient experienced an adverse event that was probably or definitely related to caspofungin. No serious adverse drug-related events were noted in patients receiving caspofungin. No patient had caspofungin therapy discontinued as a result of an adverse drug-related event. Three deaths occurred in patients receiving caspofungin, none attributable to caspofungin. Efficacy. The patients in this study had variable indications for the use of caspofungin and received multiple other antifungal agents concurrent with caspofungin; therefore no assessment of efficacy was performed. Discussion. Invasive mycoses represent a significant source of morbidity and mortality in immunocompromised patient populations. 2 Traditional antifungal agents such as amphotericin B and the azole compounds have various shortcomings that necessitate further research and development of new antifungal agents. Caspofungin is a novel antimycotic agent that was approved by the Food and Drug Administration in January 2001. 14 Several studies have shown caspofungin to have a broad antifungal spectrum 17 and to be well-tolerated in the adult population. 9, 13, 17 No prior studies have reported safety data for the immunocompromised pediatric population. Our study represents the first published safety data addressing this population. Our data support the safety and tolerability of caspofungin in the immunocompromised pediatric population. In our study no patient experienced a severe adverse drug-related event, and no patient had caspofungin therapy discontinued as a result of an adverse drug-related event. A limitation in this study is the small sample size available for evaluation (n = 25). A small study population does not lend itself to the detection of adverse drug-related events that occur infrequently. Second, because of the retrospective nature of this study, only data that could be reliable, complete and objective in a retrospective manner were evaluated. Therefore we were unable to assess for the occurrence of adverse drug-related events that would be subjective (such as nausea) or that would rely on specific documentation in the chart (such as thrombophlebitis). A third weakness in this study is the lack of pharmacokinetic data. Without pharmacokinetic data it is impossible to accurately comment on the issue of dose-related toxicities. Preliminary data suggest doses in the higher range used in this study (1.5 mg/kg/day) are necessary in children to achieve targeted serum concentrations. 19 Further investigation of the pharmacokinetics of caspofungin in children is currently under way. Acknowledgments. This work was supported in part by Cancer Center Support CORE Grant P30 CA 21765 and the American Lebanese Syrian Associated Charities.