Pharmacokinetics, safety, and tolerability of caspofungin in children and adolescents

Abstract

Caspofungin is a parenteral antifungal that inhibits beta-1,3-D-glucan synthesis. Although licensed for adult use, the appropriate caspofungin dosing regimen in pediatric patients is not yet known. We therefore investigated the pharmacokinetics and safety of caspofungin in pediatric patients. Thirty-nine children (ages 2 to 11 years) and adolescents (ages 12 to 17 years) with neutropenia were administered caspofungin using either a weight-based regimen (1 mg/kg of body weight/day) or a body surface area regimen (50 mg/m2/day or 70 mg/m2/day). Plasma samples for caspofungin profiles were collected on days 1 and 4. These results were compared to those from adults treated with either 50 or 70 mg/day for mucosal candidiasis. In children receiving 1 mg/kg/day (maximum, 50 mg/day), the area under the concentration-time curve over 24 h (AUC(0-24)) was significantly smaller (46% after multiple doses) than that observed in adults receiving 50 mg/day (P < 0.001). In children and adolescents receiving 50 mg/m2/day (maximum, 70 mg/day), the AUC(0-24) following multiple doses was similar to that for the exposure in adults receiving 50 mg/day. The AUC(0-24) and concentration trough (at 24 h) in pediatric patients receiving the 50-mg/m2 daily regimen were consistent across the range of ages. Caspofungin was generally well tolerated in this study. None of the patients developed a serious drug-related adverse event or were discontinued for toxicity. These results demonstrate that caspofungin at 1 mg/kg/day in pediatric patients is suboptimal. Caspofungin administration at 50 mg/m2/day provides a comparable exposure to that of adult patients treated with 50 mg/day.

FIG. 1.

Mean caspofungin plasma concentration-time profiles in children and adolescents with neutropenia and adult patients with mucosal candidiasis. Profiles for pediatric patients are from day 4 of therapy, and profiles for adults are from day 9 of therapy.

FIG. 2.

Individual caspofungin pharmacokinetics following multiple doses in children and adolescents receiving caspofungin at 50 mg/m²/day, adults with mucosal candidiasis receiving caspofungin at 50 mg/day, and adults with persistent fever and neutropenia receiving caspofungin at 50 mg/day.

FIG. 3.

Caspofungin CL versus age in pediatric patients and adult patients with mucosal candidiasis. The slope of the CL linear regression line (top) is 0.0391, the slope of the weight-normalized CL linear regression line (middle) is −0.0152, and the slope of the BSA-normalized CL linear regression line (bottom) is 0.00056.

FIG. 4.

Effects of 1-mg/kg and 50-mg/m² dosages on the total dose administered to pediatric patients receiving caspofungin. The BSA was calculated from the 50th-percentile height and weight parameters of standard nomograms of normal males aged 2 through 17 years. The total dose of caspofungin was then calculated as a function of weight and BSA.