Population pharmacokinetics and pharmacodynamics of caspofungin in pediatric patients.

We describe the pharmacokinetics (PKs) of caspofungin, an echinocandin antifungal, administered once daily as a 1-hour intravenous infusion in children and adolescents (ages, 3 months to 17 years), based on pooled data from four prospective pediatric studies. Caspofungin dosing was body-surface-area (BSA) based (50 mg/m2 daily after 70 mg/m2 on day 1). The area under the concentration-time curve from time zero to 24 h (AUC0-24), the concentration at the end of infusion (1 h after the start of infusion; C1), and the trough concentration (24 h after the start of infusion; C24) were obtained for 32 pediatric patients with invasive candidiasis, 10 with invasive aspergillosis, and 82 in the setting of empirical therapy with fever and neutropenia. Exposures were modestly higher (93 to 134% for C1, 45 to 78% for C24, ∼40% for AUC0-24) in pediatric patients than in adults receiving the standard 50-mg daily dose. The potential for covariates (age, gender, weight, race, renal status, serum albumin level, and disease state) to alter PKs was evaluated with a multiple-linear-regression model. Weight and disease state had statistically significant (P<0.05) yet small effects on caspofungin PKs in pediatric patients. Concomitant use of dexamethasone (a cytochrome p450 inducer) was associated with a statistically significant reduction (44%) in C24 in a limited number of patients (n=4). Odds ratios were estimated for the association between log-transformed PKs and treatment outcome or adverse events. No PK parameter or hybrid parameter (AUC/MIC, C1/MIC, and C24/MIC) was significantly correlated with treatment outcome or adverse events in the setting of similar response levels as adults, which suggests that the concentrations examined fall within the therapeutic window for caspofungin in pediatric patients. These results support a 50-mg/m2 daily dosing regimen (after a 70-mg/m2 loading dose) in children ages 3 months to 17 years.

Caspofungin use in patients with invasive candidiasis caused by common non-albicans Candida species: review of the caspofungin database.

Increasing rates of invasive candidiasis caused by non-albicans Candida species have been reported worldwide. Particular concerns have been raised for C. parapsilosis because of reduced in vitro susceptibility to echinocandins. We identified 212 patients with invasive candidiasis due to non-albicans Candida species (>or=5 cases per species) in 5 clinical trials of caspofungin monotherapy from the pharmaceutical sponsor's (Merck and Co., Inc.) database: 71 cases were caused by C. parapsilosis, 65 by C. tropicalis, 54 by C. glabrata, 10 by C. krusei, 9 by C. guilliermondii, and 5 by C. lusitaniae. One hundred sixty-seven cases caused by C. albicans were also identified. Efficacy was assessed at the end of caspofungin therapy. Success (favorable overall response) required favorable clinical and microbiological responses. The mean APACHE II scores were 16.5 in the non-albicans group and 15.7 in the C. albicans group. Neutropenia at study entry was more common in the non-albicans group (12%) than in the C. albicans group (5%). The median duration of caspofungin therapy was 14 days in both groups. The success rates were 77% in both groups and at least 70% for each non-albicans species: 74% for C. parapsilosis, 71% for C. tropicalis, 85% for C. glabrata, 70% for C. krusei, 89% for C. guilliermondii, and 100% for C. lusitaniae. The times to negative blood culture were similar for the various species. The overall mortality rates were 26% in the non-albicans group and 29% in the C. albicans group. Drug-related serious adverse events and discontinuations due to caspofungin toxicity were uncommon. Although the sample sizes were limited, caspofungin demonstrated favorable efficacy and safety profiles in the treatment of invasive candidiasis caused by the following non-albicans Candida species: C. parapsilosis, C. tropicalis, C. glabrata, C. krusei, C. guilliermondii, and C. lusitaniae.

Immunogenicity, Safety, and Tolerability of a Hexavalent Vaccine in Infants.

BACKGROUND: DTaP5-IPV-Hib-HepB is a fully liquid investigational hexavalent vaccine directed against 6 diseases. METHODS: This multicenter, open-label, comparator-controlled, phase III study randomly assigned healthy infants 2-to-1 as follows: group 1 received DTaP5-IPV-Hib-HepB, PCV13, and RV5 at 2, 4, and 6 months of age followed by DTaP5, Hib-OMP, and PCV13 at 15 months of age; group 2 received DTaP5-IPV/Hib, PCV13, and RV5 at 2, 4, and 6 months of age, with HepB at 2 and 6 months of age, followed by DTaP5, Hib-TT, and PCV13 at 15 months of age. RESULTS: Overall, 981 participants were vaccinated in group 1 and 484 in group 2. Immune responses in group 1 to all antigens contained in DTaP5-IPV-Hib-HepB 1 month after dose 3 and for concomitant rotavirus vaccine were noninferior to those in group 2, with the exception of antipertussis filamentous hemagglutinin (FHA) geometric mean concentrations (GMCs). Vaccine response rates for FHA were noninferior to control. After the toddler dose, group 1 immune responses were noninferior to group 2 for all pertussis antigens. Solicited adverse event rates after any dose were similar in both groups, with the exceptions of increased injection-site erythema, increased fever, and decreased appetite in group 1. Fever was not associated with hospitalization or seizures. CONCLUSIONS: The safety and immunogenicity of DTaP5-IPV-Hib-HepB are comparable with the analogous licensed component vaccines. Decreased FHA GMCs and increased injection-site reactions and fever are unlikely to be clinically significant. DTaP5-IPV-Hib-HepB provides a new combination vaccine option aligned with the recommended US infant immunization schedule.

Overview of safety experience with caspofungin in clinical trials conducted over the first 15 years: a brief report.

Safety experience is available from 32 completed clinical studies (17 Phase I and 15 Phase II-III) of caspofungin (CAS) conducted between 1995 and 2010 in adult and paediatric patients. Clinical and laboratory adverse events (AEs) were collected from all enrolled subjects and patients. Investigators identified the seriousness, causality and result of all AEs noted during study therapy and for up to 28 days post therapy. Up to 31 December 2010, full safety data are available from 1951 individuals who have received at least one dose of CAS in Phase I-III clinical studies, including 171 paediatric patients, 394 volunteer adult subjects and 1386 adult patients (276 with oropharyngeal/oesophageal candidiasis, 366 with invasive candidiasis, 180 with invasive aspergillosis and 564 with persistent fever and neutropenia). CAS was administered for up to 196 days at daily doses ranging from 5mg to 210 mg. Overall, 41.8% of CAS recipients had an AE that was classified as drug-related. The most frequently reported drug-related AEs were fever (9.3%), chills (5.2%), increased alanine aminotransferase (6.5%), increased aspartate aminotransferase (6.0%) and increased alkaline phosphatase (5.2%). Serious AEs were reported in 27.3% of CAS recipients overall but were attributed to CAS in only 0.8%, and discontinuation of CAS due to a drug-related AE was infrequent (2.7%). Dose-related CAS toxicity was not observed. In conclusion, CAS has demonstrated a favourable safety profile in 1951 adult and paediatric patients enrolled in clinical trials.

Safety experience with caspofungin in pediatric patients.

We analyzed the caspofungin safety experience in 5 clinical registration studies in 171 pediatric patients, 1 week to 17 years of age. Caspofungin was administered for 1 to 87 (mean 12.1) days. The most common drug-related adverse events were fever, increased AST, increased ALT, and rash; few events were serious or required treatment discontinuation. Caspofungin was well tolerated in this pediatric population.

A prospective, multicenter study of caspofungin for the treatment of documented Candida or Aspergillus infections in pediatric patients.

OBJECTIVE: We evaluated the safety, tolerability, and efficacy of caspofungin in pediatric patients with invasive aspergillosis, invasive candidiasis, or esophageal candidiasis. METHODS: This was a multicenter, prospective, open-label study in children 3 months to 17 years of age with proven or probable invasive aspergillosis, proven invasive candidiasis, or proven esophageal candidiasis. All of the patients received caspofungin 70 mg/m(2) on day 1, followed by 50 mg/m(2) per day (maximum: 70 mg/day), as primary or salvage monotherapy. Favorable response was defined as complete resolution of clinical findings and microbiologic (or radiographic/endoscopic) eradication (complete response) or significant improvement in these parameters (partial response). Efficacy was assessed at the end of caspofungin therapy in patients with a confirmed diagnosis who received >/=1 dose of caspofungin. The primary safety evaluation was the proportion of patients with clinical or laboratory drug-related adverse events. RESULTS: Of the 49 patients enrolled, 3 were <2 years of age, 30 were 2 to 11 years of age, and 16 were 12 to 17 years of age. Forty-eight patients had confirmed disease: invasive aspergillosis (10), invasive candidiasis (37), and esophageal candidiasis (1). Eight of 10 patients with invasive aspergillosis had pulmonary involvement; 34 of 37 patients with invasive candidiasis had candidemia. Caspofungin was given for 2 to 87 days. Success at end of therapy was achieved in 5 of 10 patients with invasive aspergillosis, 30 of 37 with invasive candidiasis, and 1 of 1 with esophageal candidiasis. One patient (invasive candidiasis) relapsed during the 28-day follow-up period. Drug-related clinical or laboratory adverse events occurred in 27% and 35% of patients, respectively. There were no serious drug-related adverse events or discontinuations of caspofungin because of toxicity. CONCLUSIONS: Caspofungin was generally well tolerated in pediatric patients aged 6 months through 17 years. Efficacy outcomes in patients with invasive aspergillosis or invasive candidiasis were consistent with previous adult studies in these indications.