Methicillin-resistant Staphylococcus aureus remains an important cause of pediatric infections, and the incidence of Methicillin-resistant Staphylococcus aureus infections in hospitalized children has increased steadily in recent years.1 It is crucial that the currently available treatment options be dosed in a manner to achieve and maintain adequate systemic concentrations.
Data regarding the biodisposition of daptomycin in children are limited to case reports and a singular study evaluating children 2 to 17 years of age.2–4 These reports demonstrated that the pharmacokinetics of daptomycin are age dependent, with fixed weight-adjusted doses resulting in significantly lower systemic exposure in young children than in adolescents or adults. Consequently, this study was undertaken to explore the dose-exposure relationship of daptomycin at doses predicted to achieve the therapeutically relevant exposure targets observed in adults.
Children aged 2 to 6 years with suspected or proven Gram-positive infections were eligible for enrollment. Inclusion criteria included the following: a body mass index within the fifth to 95th percentile for age, no evidence of hemodynamic instability within 72 hours before enrollment, no evidence of renal or hepatic compromise, and normal serum creatine phosphokinase (CPK). Children with pneumonia as the sole Gram-positive infection; those receiving rifampin within 7 days or any intramuscular drug within 24 hours of study drug administration; those with a history and/or physical examination consistent with muscular disease, nervous system, or seizure disorder; and those anticipated to undergo a surgical procedure within 24 hours of study drug administration, were excluded from participation. The study was approved by the Institutional Review Board at each site. Written parental permission was obtained for each subject before enrollment.
This phase 1, multicenter, open-label, noncomparative study (DAP-PEDS-07–02) was registered with ClinicalTrials.gov (NCT00679835). Participants were stratified based on dose into 2 cohorts. Cohorts enrolled sequentially after a preliminary assessment of pharmacokinetics, and tolerability was made in the lower dosing arm. Group 1 received a single 8 mg/kg dose of daptomycin as a 1-hour infusion, whereas participants in group 2 were administered 10 mg/kg as a 1-hour infusion. The 1-hour infusion was chosen to minimize possible unknown effects of higher maximum plasma concentration (Cmax) values in these young children. Each dose was administered in 25 mL of normal saline and infused at a rate of 0.42 mL/min.
Pharmacokinetic Sampling and Analysis.
Venous blood samples (0.5 mL each) for determination of daptomycin concentrations were obtained from a contralateral extremity immediately before the infusion and at 0.5, 1, 2, 4, 7, 12, and 24 hours relative to the start of the infusion. Sample collection and analysis were identical to that of a previous report.4 Noncompartmental methods were used to perform analyses using WinNonlin version 5.2 (Pharsight Corporation, Mountain View, CA). Cmax and time of maximum plasma concentration (Tmax) were directly observed. Calculated indices included the following: area under the curve (AUC) from 0 to the last observable concentration (AUC0–last), AUC from 0 to infinity (AUC0–∞), plasma clearance (CL), terminal elimination rate constant, terminal half-life (t ½), and steady-state volume of distribution (Vss). Standard descriptive statistics were used to summarize the data (SAS v9.1.3, SAS Institute, Cary, NC). Missing data were considered to be missing at random and were not imputed.
Clinical laboratory testing and physical examination were performed at baseline and at 24 hours after administration of study drug. CPK values were measured at baseline, immediately prior to study drug infusion, and at 24 hours postinfusion. An adverse event was defined as any untoward medical occurrence, regardless of a causal relationship with study-drug administration. From the time of daptomycin administration through 7 days postdosing, all adverse events that were new in onset or preexisting conditions that were aggravated in severity or frequency were recorded as treatment-emergent. Investigators assessed the severity and relationship of each adverse event to study drug.
Subject Enrollment and Demographics.
A total of 12 participants were enrolled, 6 at each dose. A description of demographic and other baseline characteristics can be found in Table, Supplemental Digital Content 1, http://links.lww.com/INF/A752. All subjects were healthy, with no comorbidities that would interfere with drug distribution or elimination. Subjects were undergoing treatment for underlying infections that included cellulitis (n = 4), abscess (n = 4), pharyngitis (n = 2), and lymphadenopathy, streptococcal infection at unspecified site, and infected bone graft (n = 1 each). Among the subjects, treatment for the underlying infection had been started 1 to 2 days (n = 5), 3 to 6 days (n = 6), and 12 days (n = 1) prior to study entry. Concurrent anti-infectives included clindamycin (n = 9); amoxicillin-clavulanate (n = 3); cefdinir (n = 3); trimethoprim-sulfamethoxazole (n = 2); metronidazole (n = 2); and cefazolin, cefepime, cefotaxime, ceftriaxone, meropenem, and vancomycin (n = 1 each).
Pharmacokinetic indices for the 2 dosing groups are summarized in Table 1. When comparing the groups, proportional increases were observed with respect to Cmax and AUC. In contrast, t½, CL, and Vss were similar between the dosing cohorts. Compared with group 2, Tmax was slightly lower in group 1 due to 2 subjects whose Cmax occurred at 0.5 hours. It could not be determined whether the infusion was terminated early in these children or the samples were mislabeled. Consequently, exposure parameters were also evaluated for group 1 with the data from these children removed. Mean (±standard deviation) Cmax, AUC0–last, and AUC0–∞ were 65.6±10.6 μg/mL, 347.5±115.6 μg·h/mL, and 399.6±115.6 μg·h/mL, respectively. Figure, Supplemental Digital Content 2, http://links.lww.com/INF/A753, shows the median daptomycin plasma concentrations over time for the 8- and 10-mg/kg doses for all subjects (Fig. A, Supplemental Digital Content 2, http://links.lww.com/INF/A753) and excluding 2 subjects whose Cmax occurred 0.5 hour after administration (Fig. B, Supplemental Digital Content 2, http://links.lww.com/INF/A753) is provided in Table, Supplemental Digital Content 1, http://links.lww.com/INF/A752.
Two participants in group 1 and 4 in group 2 experienced 1 or more treatment-emergent adverse event(s) while receiving daptomycin. Tonsillar hypertrophy, cerumen impaction, groin abscess, and increased body temperature were preexisting conditions present at the end of the drug infusion that were not judged by the investigator to be related to study drug administration. Other adverse events reported in 1 subject each included irritability, extremity pain, and transient lower extremity numbness in group 1 and catheter-related complication, headache, cough, dry skin, pruritis, and phlebitis in group 2. No adverse events of severe intensity were reported, and no subject discontinued the study due to adverse events. Two of the adverse events (phlebitis and headache) in group 2 were judged by the investigators to be related or possibly related to study drug. Both events occurred on day 1 and resolved on that same day without intervention.
There were no clinically notable changes in hematology or chemistry laboratory values apart from a decrease in leukocyte count. The absolute neutrophil count decreased from baseline means of 2712 × 106/L and 5331 × 106/L in groups 1 and 2, respectively, to 1786 × 106/L and 3636 × 106/L on day 2. None of the subjects experienced clinically significant elevations in CPK, and no subject experienced clinically relevant electrocardiogram abnormalities.
The current study is the second prospective trial to describe the pharmacokinetics of daptomycin in a pediatric population. The previous study evaluated a single dose of 4 mg/kg in 22 subjects stratified by age.4 While pharmacokinetic variables for adolescents (12–17 years) were comparable with those in adults,5,6 AUC and t½ for the same dose were significantly lower, and CL was significantly higher, in subjects 2 to 6 years of age. These findings were attributed to the known ontogeny of renal function7,8 and the renal elimination of daptomycin.5
Analyses from previous pediatric studies are compared with the current results (Table, Supplemental Digital Content 3, http://links.lww.com/INF/A754).4,9 The non–dose-dependent indices (t½, CL, Vss) were similar between the 8- and 10-mg/kg groups in this study and were consistent with those in the corresponding age group in the previous studies. The dose-dependent parameters (Cmax, AUC) showed increases that were consistent with the higher dosages administered in the current study and with the linear pharmacokinetics exhibited by daptomycin.
Daptomycin was well tolerated in this study, and no subject developed clinically significant CPK elevations or myalgias. To date, steady-state pharmacokinetics remain uncharacterized in the pediatric population. Previous data for adult doses of 6 to 12 mg/kg found that daptomycin pharmacokinetic values did not vary significantly between first dose and steady state and that these doses were well tolerated in adults.10 Given the relatively short t½ of daptomycin in children >2 years of age (5–7 hours),4 we would not expect to see significant accumulation after multiple doses in this age group. The results from this study suggest that a dose of 8 to 10 mg/kg in patients aged 2 to 6 years would provide systemic exposure comparable to that seen in adults treated with US-approved daptomycin doses of 4 to 6 mg/kg.5
The authors thank Min Jung Yoon, MPH, of Cubist Pharmaceuticals, Inc., for statistical analysis and the clinical coordinators and subinvestigators at each of the participating institutions. Under the direction of the authors, Jeff Kuper, PharmD, and Sarah Mizne, PharmD, of PharmaWrite, LLC (Princeton, NJ), and Saira Choudry, PharmD, agent of PharmaWrite, provided assistance in preparing and editing the manuscript.
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