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 g/ml, respectively, on day 1, and 11.1 and 2.4 g/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.Candida infections are a major concern in neonatal intensive care units, especially for infants with very low birth weights (Ͻ1,500 g). Late-onset sepsis develops in approximately 20% of critically ill neonates and low-birth-weight infants, and Candida species account for at least 10% of these infections (16). Antifungal regimens currently used in neonates are associated with increasing fungal resistance, notable toxicity, drug-drug interactions, or a limited spectrum of activity (4). Hence, there is a medical need to pursue the use of newer antifungal agents for the neonatal population.Caspofungin is an echinocandin antifungal that is effective as primary therapy for esophageal candidiasis (1, 6, 19), candidemia (8), and other invasive Candida infections (5) in adults. In a pharmacokinetic study of 39 children and adolescents (2 to 17 years of age), a caspofungin dose of 50 mg/m 2 daily (based on body surface area [BSA] dosing) resulted in plasma concentrations commensurate with the 50-mg daily dose used in adults (20). Data for younger children (3 to 24 months of age) who received caspofungin at 50 mg/m 2 daily (11) show pharmacokinetic results similar to those seen for the 2-to 11-yearold cohort (20). Several reports suggest that caspofungin may be useful for the treatment of candidemia in neonates (10,12,15,21); however, the appropriate dosage for this population h...

Challenging issues in neonatal candidiasis

“…Regarding caspofungin dosing, neonatal clinical studies had used 1 to 2 mg/kg, but pharmacokinetic data indicate that 2.5 mg/kg should be used. For micafungin dosing, pharmacokinetic data suggest a dose of 10 mg/kg [21][22][23]29,30 . A micafungin RCT is currently suspended for further pharmacodynamic studies (www.Clinicaltrials.gov Identifier: NCT00815516).…”

“…Pharmacokinetic data have recently been published for fluconazole, micafungin, and caspofungin [14][15][16][17][18][19][20][21][22][23] . With studies examining pharmacokinetic data targeting comparable levels in adults, neonatal data are needed regarding safety.…”

Recent Developments and Current Issues in the Epidemiology, Diagnosis, and Management of Bacterial and Fungal Neonatal Sepsis

“…[82][83][84][85] Two of the most commonly used echinocandins, caspofungin and micafungin, have comparative susceptibility and safety profiles. There are ongoing pharmacokinetic trials of anidulafungin in neonates.…”

Candidiasis invasoras en recién nacidos: diagnóstico, tratamiento y prevención

“…En un estudio realizado por Sáez-Llorens y cols., se midió la concentración plasmática y perfil de seguridad de caspofungina en lactantes bajo 3 meses de edad. Los resultados establecieron que con una dosis de 25 mg/m 2 /día IV se alcanzan concentraciones plasmáticas equivalentes a la dosis usual de 50 mg/m 2 / día 42 . Caspofungina es bien tolerada, sin efectos adversos significativos, pero está contraindicado por ahora su uso cuando existe compromiso de SNC, debido a la ausencia de estudios concluyentes que evalúen la eficacia del tratamiento en este grupo etáreo.…”