Pharmacokinetics and safety of caspofungin in neonates and infants less than 3 months of age

Abstract

Candida infections represent a major threat in neonatal intensive care units. This is the first prospective study to obtain caspofungin plasma levels and safety data for neonates and very young infants. Patients of <3 months of age receiving intravenous amphotericin B for documented or highly suspected candidiasis were enrolled in a single-dose (n = 6) or subsequent multiple-dose (n = 12) panel; all received caspofungin at 25 mg/m(2) once daily as a 1-hour infusion. Caspofungin plasma levels were measured by high-performance liquid chromatography and compared to historical data from adults. Patient chronological ages ranged from 1 to 11 weeks, and weights ranged from 0.68 to 3.8 kg. Gestational ages ranged from 24 to 41 weeks. Geometric mean (GM) peak (C(1 h)) and trough (C(24 h)) caspofungin levels were 8.2 and 1.8 microg/ml, respectively, on day 1, and 11.1 and 2.4 microg/ml, respectively, on day 4. GM ratios for C(1 h) and C(24 h) for neonates/infants relative to adults receiving caspofungin at 50 mg/day were 1.07 and 1.36, respectively, on day 1, and 1.18 and 1.21, respectively, on day 4. Clinical and laboratory adverse events occurred in 17 (94%) and 8 (44%) patients, respectively. Five patients (28%) had serious adverse events, none of which were considered drug related. Caspofungin at 25 mg/m(2) once daily was well tolerated in this group of neonates/infants of <3 months of age and appears to provide relatively similar plasma exposure to that obtained in adults receiving 50 mg/day. However, the small number of patients studied precludes any definitive recommendations about caspofungin dosing for this group comprising a broad range of ages and weights.

Trial registration: ClinicalTrials.gov NCT00330395.

Figures

FIG. 1.

Day 4 C1 h (peak) caspofungin levels in neonates and infants (< 3 months of age), young children (3 to 24 months), older children (2 to 11 years), adolescents (12 to 17 years), and adults. Geometric means and corresponding 95% CI for all groups were generated from an analysis of variance (ANOVA) model with the neonates/infants and each particular group. The geometric mean and corresponding 95% CI for the neonate/infant group were calculated from the ANOVA model addressing the primary comparison with adults. The first column of adult data (50 mg daily) is for patients with esophageal and/or oropharyngeal candidiasis, and the second column of adult data (50 mg daily following 70 mg on day 1) is for patients with invasive candidiasis.

FIG. 2.

Day 4 C24 h (trough) caspofungin levels in neonates and infants (<3 months of age), young children (3 to 24 months), older children (2 to 11 years), adolescents (12 to 17 years), and adults. Geometric means and corresponding 95% CI for all groups were generated from an ANOVA model with the neonates/infants and each particular group. The geometric mean and corresponding 95% CI for the neonate/infant group were calculated from the ANOVA model addressing the primary comparison with adults. The first column of adult data (50 mg daily) is for patients with esophageal and/or oropharyngeal candidiasis, and the second column of adult data (50 mg daily following 70 mg on day 1) is for patients with invasive candidiasis.

FIG. 3.

Comparison of mean caspofungin plasma concentrations in neonates and infants (25 mg/m2; n = 18 on day 1 and n = 11 or 12 on day 4) to mean caspofungin plasma concentrations in adults (50 mg/day; n = 6), young children (3 to 24 months) (50 mg/m2; n = 6 on day 1 and n = 7 on day 4), older children (2 to 11 years) (50 mg/m2; n = 8), and adolescents (12 to 17 years) (50 mg/m2; n = 10).