Transplacental methadone exposure and risk of Neonatal Opioid Withdrawal Syndrome.

STUDY OBJECTIVE: Neonatal opioid withdrawal syndrome (NOWS) is a condition that often occurs in neonates born to mothers who received methadone treatment for opioid use disorder during pregnancy. Early identification and treatment of infants at risk of NOWS may improve clinical outcomes. The purpose of this study was to evaluate whether maternal and umbilical cord plasma concentrations of methadone and its metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), could predict the need for NOWS treatment. DESIGN: Single-center prospective study. SETTING: University of Michigan Neonatal Intensive Care Unit. PATIENTS: The study included 11 opioid-dependent mother-infant dyads, where the mothers were treated with methadone at 34 weeks' gestation or later. INTERVENTION: Maternal and cord blood samples were collected from the study participants. MEASUREMENTS AND MAIN RESULTS: Maternal and cord plasma concentrations of methadone and EDDP were determined. Six out of the 11 infants required treatment for NOWS. Maternal methadone plasma concentrations were comparable between infants requiring and not requiring NOWS treatment (329.1 ± 229.7 ng/mL vs. 413.2 ± 329.8 ng/mL). However, the average cord plasma methadone concentration in infants who did not require NOWS treatment was 2.9-fold higher than in those who required the treatment (120.0 ± 88.6 ng/mL vs. 40.9 ± 24.4 ng/mL), although the difference was not statistically significant. The ratios of maternal-to-cord methadone plasma concentrations were significantly higher in patients who required treatment for NOWS compared with those who did not (7.7 ± 1.9 vs. 3.5 ± 1.6, p = 0.003). Maternal and cord plasma EDDP concentrations and the maternal-to-cord plasma EDDP concentration ratios did not differ between patients who required and did not require treatment for NOWS. CONCLUSIONS: The results suggest that methadone permeability across the blood-placental barrier may affect in utero exposure to methadone, and the maternal-to-cord methadone plasma concentration ratio could be a potential biomarker for predicting the need for NOWS treatment.

Obesity Considerations in Pediatric Drug Development, 2016-2021.

Pediatric obesity is a global public health concern. Obesity-related physiological changes may affect the pharmacokinetics of drugs and lead to therapeutic failure or toxicities. An earlier review of pediatric drug development programs from 2007 to 2016 found that, of 89 programs listing obesity-related terms, only 4 (4%) products described pharmacokinetic changes associated with obesity. This review examined obesity considerations for 185 drug products for which pediatric drug development programs were submitted to the US Food and Drug Administration (FDA) between 2016 and 2021. The FDA-authored review documents and drug product labeling were queried for obesity-related terms and the review found 97/185 (52%) drug products had obesity-related terms in these sources. Of the 97 drug products, 55/97 (57%) had obesity-related terms in the FDA-authored reviews only, 13/97 (13%) had obesity-related terms in the drug product labeling only, and 29/97 (30%) had obesity-related terms in both FDA-authored reviews and drug product labeling. Most of the obesity-related information in the drug product labeling originated from data collected from adults. Only 13/185 (7%) drug product labeling contained obesity-related terms in reference to drug pharmacokinetics. Specific dosage recommendations for the use of the drug products in pediatric patients who are obese remain lacking. The dearth of available information to guide drug dosages in the obese pediatric population suggests that further research, innovative approaches, and evidence-based guidelines are needed to inform the optimal therapeutic use of drugs in this population.

Pediatric Efficacy Extrapolation in Drug Development Submitted to the US Food and Drug Administration 2015-2020.

Pediatric extrapolation plays a key role in the availability of reliable pediatric use information in approved drug labeling. This review examined the use of pediatric extrapolation in studies submitted to the US Food and Drug Administration and assessed changes in extrapolation approaches over time. Pediatric studies of 125 drugs submitted to the US Food and Drug Administration that led to subsequent pediatric information in drug labeling between 2015 and 2020 were reviewed. The use of pediatric extrapolation for each drug was identified and categorized as "complete," "partial," or "no" extrapolation. Approaches to pediatric extrapolation of efficacy changed over time. Complete extrapolation of efficacy was the predominantly used approach. "Complete," "partial," or "no" extrapolation was used for 51%, 23%, and 26% of the drugs, respectively. This represents a shift in extrapolation approaches when compared to a previous study that evaluated pediatrics drug applications between 2009 and 2014, which found complete, partial, or no extrapolation was used for 34%, 29%, and 37% of the drugs, respectively. Pediatric extrapolation approaches may continue to shift as emerging science fills gap in knowledge of the fundamental assumptions underlying this scientific tool. The international community continues to collaborate on discussions of pediatric extrapolation of efficacy from adults and other pediatric subpopulations to optimize its use for pediatric drug development.

A Tribute to the Pioneers of Fetal Pharmacology.

Clinical pharmacology is a branch of the field of pharmacology that evolved following the recognition that the nature, duration, and intensity of drug action depend on both the intrinsic properties of the drug and an interaction with the host to whom the drug is given. Advances in drug development have placed highly specific and extremely potent therapeutic agents in the marketplace. While these advances have progressed rapidly in adult medicine, pediatric clinical pharmacology has not kept pace and until very recently has lagged behind the research and attention paid to the proper use of therapeutic and diagnostic drugs in adults. Recognition that advances in the science of developmental pharmacology and pediatric clinical pharmacology were essential in the development of new drugs to treat children came in the 1950s and 1960s mostly through the work of 2 pioneering scientists in fetal and perinatal clinical pharmacology, Drs Sumner Yaffe and Bernard Mirkin. Here we pay a tribute to these most influential pioneers in the United States who were instrumental in paving the path for advancing the field of fetal and perinatal pharmacology concepts and their incorporation into pediatric drug development programs.

The effect of ibuprofen and caffeine prophylaxis on retinopathy of prematurity.

PURPOSE: To determine whether prophylactic caffeine and ibuprofen, which have been shown to have vascular endothelial growth factor-modulating properties in other contexts, have a detectable effect on the incidence of severe retinopathy of prematurity (ROP) when administered in extremely low birth weight infants during the first 48 hours of life. METHODS: In this retrospective cohort study, the incidence and severity of ROP with respect to total exposure to caffeine and ibuprofen were assessed. The effect of oxygen exposure at 28 days' postnatal age (PNA) and 36 weeks' corrected gestational age (GA) was also studied. RESULTS: A total of 109 infants were included; of these, complete data were available for 93 infants (87%), of whom 18 (19%) had severe ROP (ETROP type 1, or stage 3), and 75 (81%) had mild-to-moderate ROP at final diagnosis. Infants with severe ROP had lower GA (P = 0.0006). Total caffeine and ibuprofen exposure did not vary with severity of ROP (P = 0.86 caffeine; P = 0.57 ibuprofen). Presence of oxygen at 28 days' PNA (P = 0.01) or 36 weeks' corrected GA varied significantly with ROP severity (P = 0.0005). CONCLUSIONS: A relationship between prophylactic caffeine and ibuprofen exposure and severity of ROP could not be detected in our study cohort. Presence of oxygen at 28 days' PNA or 36 weeks' corrected GA was associated with ROP severity.

Regulatory Considerations for the Mother, Fetus and Neonate in Fetal Pharmacology Modeling.

The regulatory framework for considering the fetal effects of new drugs is limited. This is partially due to the fact that pediatric regulations (21 CFR subpart D) do not apply to the fetus, and only US Health and Human Service (HHS) regulations apply to the fetus. The HHS regulation 45 CFR Part 46 Subpart B limits research approvable by an institutional review board to research where the risk to the fetus is minimal unless the research holds out the prospect of a direct benefit to the fetus or the pregnant woman (45 CFR 46.204). Research that does not meet these requirements, but presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health of pregnant women, fetuses, or neonates, may be permitted by the Secretary of the HHS after expert panel consultation and opportunity for public review and comment (45 CFR 46.407). If the product is regulated by the US Food and Drug Administration (FDA), FDA may get involved in the review process. The FDA does however have a Reviewer Guidance on Evaluating the Risks of Drug Exposure in Human Pregnancies from 2005 and this guidance does discuss the intensity of drug exposure. Estimation of that exposure using physiologically based pharmacokinetic (PBPK) modeling has been suggested by some investigators. Given that drug exposure during pregnancy will impact the fetus, a number of new guidances in the last 2 years also address inclusion of pregnant women in clinical drug trials. Therefore, the drug-specific information on fetal pharmacology will increase dramatically in the next decade due to interest in drugs administered in pregnancy and with the assistance of model-informed drug development.

Developing a SWATH capillary LC-MS/MS method for simultaneous therapeutic drug monitoring and untargeted metabolomics analysis of neonatal plasma.

Most medications prescribed to neonatal patients are off-label uses. The pharmacokinetics and pharmacodynamics of drugs differ significantly between neonates and adults. Therefore, personalized pharmacotherapy guided by therapeutic drug monitoring (TDM) and drug response biomarkers are particularly beneficial to neonatal patients. Herein, we developed a capillary LC-MS/MS metabolomics method using a SWATH-based data-independent acquisition strategy for simultaneous targeted and untargeted metabolomics analysis of neonatal plasma samples. We applied the method to determine the global plasma metabolomics profiles and quantify the plasma concentrations of five drugs commonly used in neonatal intensive care units, including ampicillin, caffeine, fluconazole, vancomycin, and midazolam and its active metabolite α-hydroxymidazolam, in neonatal patients. The method was successfully validated and found to be suitable for the TDM of the drugs of interest. Moreover, the global metabolomics analysis revealed plasma metabolite features that could differentiate preterm and full-term neonates. This study demonstrated that the SWATH-based capillary LC-MS/MS metabolomics approach could be a powerful tool for simultaneous TDM and the discovery of neonatal plasma metabolite biomarkers.

Antenatal and perinatal factors influencing neonatal blood pressure: a systematic review.

OBJECTIVE: A comprehensive understanding of the factors contributing to perinatal blood pressure is vital to ensure optimal postnatal hemodynamic support. The objective of this study was to review existing literature on maternal and perinatal factors influencing blood pressure in neonates up to 3 months corrected age. METHODS: A systematic search of published literature in OVID Medline, OVID Embase and the COCHRANE library identified publications relating to maternal factors affecting blood pressure of neonates up to corrected age of 3 months. Summary data were extracted and compared (PROSPERO CRD42018092886). RESULTS: Of the 3683 non-duplicate publications identified, 44 were eligible for inclusion in this review. Topics elicited were sociodemographic factors, maternal health status, medications, smoking during pregnancy, and cord management at birth. Limited data were available for each factor. Results regarding the impact of these factors on neonatal blood pressure were inconsistent across studies. CONCLUSIONS: There is insufficient evidence to draw definitive conclusions regarding the impact of various maternal and perinatal factors on neonatal blood pressure. Future investigations of neonatal cardiovascular therapies should account for these factors in their study design. Similarly, studies on maternal diseases and perinatal interventions should include neonatal blood pressure as part of their primary or secondary analyses.

New Pharmacologic Approaches to Bronchopulmonary Dysplasia.

Bronchopulmonary Dysplasia is the most common long-term respiratory morbidity of preterm infants, with the risk of development proportional to the degree of prematurity. While its pathophysiologic and histologic features have changed over time as neonatal demographics and respiratory therapies have evolved, it is now thought to be characterized by impaired distal lung growth and abnormal pulmonary microvascular development. Though the exact sequence of events leading to the development of BPD has not been fully elucidated and likely varies among patients, it is thought to result from inflammatory and mechanical/oxidative injury from chronic ventilatory support in fragile, premature lungs susceptible to injury from surfactant deficiency, structural abnormalities, inadequate antioxidant defenses, and a chest wall that is more compliant than the lung. In addition, non-pulmonary issues may adversely affect lung development, including systemic infections and insufficient nutrition. Once BPD has developed, its management focuses on providing adequate gas exchange while promoting optimal lung growth. Pharmacologic strategies to ameliorate or prevent BPD continue to be investigated. A variety of agents, to be reviewed henceforth, have been developed or re-purposed to target different points in the pathways that lead to BPD, including anti-inflammatories, diuretics, steroids, pulmonary vasodilators, antioxidants, and a number of molecules involved in the cell signaling cascade thought to be involved in the pathogenesis of BPD.

A Cognitive Aid for Neonatal Epinephrine Dosing.

OBJECTIVES: Errors are common when preparing epinephrine for neonatal resuscitation. Epinephrine is available in two concentrations (1 mg/mL and 1 mg/10 mL) and requires weight-based calculations, which increases the risk of dosing errors. We developed a printed cognitive aid to assist with dose preparation. We hypothesized that the cognitive aid would result in a 25% difference in errors in preparing the dose of epinephrine during simulated neonatal resuscitation. METHODS: Nurses (N = 100) in a large academic and community hospital were randomly assigned to calculate the intended dose and prepare epinephrine for neonatal resuscitation with or without the cognitive aid. Scenarios were video recorded and timed. Secondary outcomes included errors in the written intended dose, errors in choosing the correct epinephrine concentration, and time required to prepare the final dose. Proportions were compared by using Fisher's exact test. Variables influencing dosing errors were investigated by using logistic regression. RESULTS: Using the cognitive aid significantly decreased the proportion of doses prepared incorrectly (24% vs 50%; P = .01). The aid also decreased errors in choosing the correct epinephrine concentration (12% vs 44%; P < .001), but there was no difference in the written intended dose or the time to prepare the dose. Years of experience, self-perceived math comfort, and anxiety were not predictive of dosing errors. CONCLUSIONS: A simple cognitive aid decreased epinephrine dosing errors during simulated neonatal resuscitation but did not improve efficiency. Despite the effectiveness of the cognitive aid, errors were not completely eliminated. This is a serious safety risk for newborns and requires additional interventions.

A proposed pediatric biopharmaceutical classification system for medications for chronic diseases in children.

Age-appropriate pediatric formulations for oral administration can be challenging to formulate. Development of such formulations is often time consuming, labor-intensive and costly. The Biopharmaceutical Classification System (BCS), developed more than two decades ago, is used to develop suitable oral drug formulations for adult use. In theory, some of the same principles could be applied to formulate pediatric oral liquid dosage forms. However, the present BCS system was developed using adult gastrointestinal physiologic factors. Direct extrapolation of this method to develop pediatric oral dosage forms is inappropriate due to differences in adult and pediatric gastrointestinal physiologic differences during development. To date age-appropriate BCS to guide pediatric oral liquid formulation development has not been developed for various pediatric subpopulations. The objective of this study was to provisionally classify oral liquid formulations of extemporaneously prepared drugs at our institution into an age-appropriate BCS class after elimination of any duplicate listing when matched with the most current World Health Organization's Essential Medicines List for Children available at the time of this study and other published studies that may have reported BCS classification of drugs used as extemporaneous oral liquid formulations in children to treat chronic or rare diseases. A total of 96 orally administered extemporaneously compounded liquid formulations were included in this classification. Dose numbers were calculated using age-appropriate initial gastric volume for neonates, 6-month-old infants, and children up to 6 years of age. Using age-appropriate initial gastric volumes and pediatric and neonatal Lexicomp® age-specific maximal dosing recommendations for calculation of dose numbers, the solubility classes shifted for 62.5% of the drugs studied. A significant number of currently used extemporaneously compounded oral liquid formulations for age groups of children included in this study may not provide formulations with predictable safety and efficacy. Factors used in development of adult BCS cannot be applied directly to pediatric subpopulations.

Method of Blood Pressure Measurement in Neonates and Infants: A Systematic Review and Analysis.

OBJECTIVES: To determine the recommended blood pressure (BP) measurement methods in neonates after systematically analyzing the literature regarding proper BP cuff size and measurement location and method. STUDY DESIGN: A literature search was conducted in MEDLINE, PubMed, Embase, Cochrane Library, and CINAHL from 1946 to 2017 on BP in neonates <3 months of age (PROSPERO ID CRD42018092886). Study data were extracted and analyzed with separate analysis of Bland-Altman studies comparing measurement methods. RESULTS: Of 3587 nonduplicate publications identified, 34 were appropriate for inclusion in the analysis. Four studies evaluating BP cuff size support a recommendation for a cuff width to arm circumference ratio of approximately 0.5. Studies investigating measurement location identified the upper arm as the most accurate and least variable location for oscillometric BP measurement. Analysis of studies using Bland-Altman methods for comparison of intra-arterial to oscillometric BP measurement show that the 2 methods correlate best for mean arterial pressure, whereas systolic BP by the oscillometric method tends to overestimate intra-arterial systolic BP. Compared with intra-arterial methods, systolic BP, diastolic BP, and mean arterial pressure by oscillometric methods are less accurate and precise, especially in neonates with a mean arterial pressure <30 mm Hg. CONCLUSIONS: Proper BP measurement is critical in neonates with naturally lower BP and attention to BP cuff size, location, and method of measurement are essential. With decreasing use of intra-arterial catheters for long-term BP monitoring in neonates, further studies are urgently needed to validate and develop oscillometric methodology with enhanced accuracy.

Use of normalized prediction distribution errors for assessing population physiologically-based pharmacokinetic model adequacy.

Currently employed methods for qualifying population physiologically-based pharmacokinetic (Pop-PBPK) model predictions of continuous outcomes (e.g., concentration-time data) fail to account for within-subject correlations and the presence of residual error. In this study, we propose a new method for evaluating Pop-PBPK model predictions that account for such features. The approach focuses on deriving Pop-PBPK-specific normalized prediction distribution errors (NPDE), a metric that is commonly used for population pharmacokinetic model validation. We describe specific methodological steps for computing NPDE for Pop-PBPK models and define three measures for evaluating model performance: mean of NPDE, goodness-of-fit plots, and the magnitude of residual error. Utility of the proposed evaluation approach was demonstrated using two simulation-based study designs (positive and negative control studies) as well as pharmacokinetic data from a real-world clinical trial. For the positive-control simulation study, where observations and model simulations were generated under the same Pop-PBPK model, the NPDE-based approach denoted a congruency between model predictions and observed data (mean of NPDE = - 0.01). In contrast, for the negative-control simulation study, where model simulations and observed data were generated under different Pop-PBPK models, the NPDE-based method asserted that model simulations and observed data were incongruent (mean of NPDE = - 0.29). When employed to evaluate a previously developed clindamycin PBPK model against prospectively collected plasma concentration data from 29 children, the NPDE-based method qualified the model predictions as successful (mean of NPDE = 0). However, when pediatric subpopulations (e.g., infants) were evaluated, the approach revealed potential biases that should be explored.

Volume Versus Mass Dosing of Epinephrine for Neonatal Resuscitation: A Randomized Trial.

BACKGROUND: Intravenous epinephrine for neonatal resuscitation requires weight-based calculations. Epinephrine is available in 2 different concentrations, increasing the risk of dosing errors. Expert panels have conflicting recommendations for the ordering method. The Neonatal Resuscitation Program recommends the volume (milliliters per kilogram) method, whereas the Institute for Safe Medication Practices recommends the mass (milligrams per kilogram) method. In this study, we aim to determine if the mass method is more accurate and efficient than the volume method. METHODS: In a randomized crossover simulation study, 70 NICU and pediatric emergency department nurses calculated the intended dose then prepared epinephrine using both the mass and volume methods. Both epinephrine concentrations were available. Scenarios were video recorded and timed. The primary outcome was the proportion of epinephrine doses prepared correctly. Variables associated with correct dosing were analyzed by using logistic regression. RESULTS: Of 136 total doses, 77 (57%) were prepared correctly. The correct intended dose was calculated more frequently by using the mass method (82% vs 68%; risk difference 15%; 95% confidence interval 3% to 26%), but there was no difference in the proportion of doses that were actually prepared correctly (53% of mass method doses versus 60% of volume method doses; risk difference -7%; 95% confidence interval -24% to 9%). There was no difference between methods in the time required to prepare the dose. Selecting the correct epinephrine concentration was the only variable associated with correct dosing. CONCLUSIONS: The mass method was neither more accurate nor more efficient. Nurses made frequent errors when using both methods. This is a serious patient safety risk. Additional educational and medication safety interventions are urgently needed.

Assessment of long-term neurodevelopmental outcome following trials of medicinal products in newborn infants.

There is significant uncertainty over the role of assessment of long-term neurodevelopmental outcome (LTO) in neonatal clinical trials. A multidisciplinary working group was established to identify key issues in this area and to make recommendations about optimal approaches to evaluate LTO in therapeutic trials in newborns, which can be developed by sponsors and investigators with other key stakeholders. A key consideration for neonatal trials is the potential for the investigational product to cause widespread effects and drives the need to assess outcome in multiple organs. Thus investigators must assess whether the product has an impact on the brain and the potential for it to cause potential effects on LTO. Critically, is assessment of LTO an important direct therapeutic target or a safety outcome? Such decisions and outcomes need to be specific to the product being studied and use published data, only considering expert opinion when prior evidence does not exist. In designing the trial, the balance of benefits, costs, and burdens of assessments to the researcher and families need to be considered. Families and parent advocates should be involved in design and execution of the study. A framework is presented for use by all key stakeholders to determine the need, nature, and duration of LTO assessments in regulatory trials involving newborn infants.

Impact of In-utero Exposure to Selective Serotonin Reuptake Inhibitors and Opioids on Neonatal Opioid Withdrawal Syndrome.

OBJECTIVE: The objective of this study was to compare short-term outcomes of neonatal opioid withdrawal syndrome (NOWS) treatment in infants exposed in-utero to opioids and selective serotonin reuptake inhibitors (SSRIs) or opioids alone. METHODS: This was a retrospective cohort study of mother-infant dyads, 34 weeks or greater gestation, receiving opioids and/or SSRIs during pregnancy. Intravenous or oral methadone was administered according to a pre-existing protocol for NOWS treatment guided by withdrawal scores. Primary outcome was length of treatment (LOT). Secondary outcomes included length of stay (LOS), total methadone exposure, time to symptom control, need for a second agent, and NOWS medications at discharge. RESULTS: Fifty-five mother-infant dyads were included in the study. LOT was longer in the infants in the SSRI plus opioid group but not significantly different [24 ±â€Š23 days (SSRI plus opioid) vs 20 ±â€Š14 days (opioid alone); P = 0.78]. There was a trend towards shorter LOS (30 ±â€Š22 day vs 27 ±â€Š15 days; P = 0.86), lower total methadone exposure (3.2 ±â€Š4.3 mg/kg vs 2.7 ±â€Š5.1 mg/kg; P = 0.66), less time to control symptoms (1 ±â€Š1.7 days vs 0.5 ±â€Š0.36 days; P = 0.31) and less need for a second agent (OR 2.65, 95% CI 0.69-10.5) in the opioid only group, although these observations also did not reach statistical significance. CONCLUSIONS: This study could not demonstrate a statistically significant difference in short-term NOWS outcome of LOT between the 2 groups. However, there was a trend towards longer LOT and LOS in the SSRI plus opioid group which could be clinically significant. A larger cohort may detect a true significant difference in these short-term outcomes.

Recommendations for the design of therapeutic trials for neonatal seizures.

Although seizures have a higher incidence in neonates than any other age group and are associated with significant mortality and neurodevelopmental disability, treatment is largely guided by physician preference and tradition, due to a lack of data from well-designed clinical trials. There is increasing interest in conducting trials of novel drugs to treat neonatal seizures, but the unique characteristics of this disorder and patient population require special consideration with regard to trial design. The Critical Path Institute formed a global working group of experts and key stakeholders from academia, the pharmaceutical industry, regulatory agencies, neonatal nurse associations, and patient advocacy groups to develop consensus recommendations for design of clinical trials to treat neonatal seizures. The broad expertise and perspectives of this group were invaluable in developing recommendations addressing: (1) use of neonate-specific adaptive trial designs, (2) inclusion/exclusion criteria, (3) stratification and randomization, (4) statistical analysis, (5) safety monitoring, and (6) definitions of important outcomes. The guidelines are based on available literature and expert consensus, pharmacokinetic analyses, ethical considerations, and parental concerns. These recommendations will ultimately facilitate development of a Master Protocol and design of efficient and successful drug trials to improve the treatment and outcome for this highly vulnerable population.

Dalbavancin Pharmacokinetics and Safety in Children 3 Months to 11 Years of Age.

BACKGROUND: Dalbavancin is a novel lipoglycopeptide antibiotic that has potent in vitro activity against Gram-positive microorganisms. METHODS: We performed a phase 1, open-label, multicenter study to investigate the pharmacokinetics (PK) and safety of a single dose of intravenous dalbavancin in hospitalized pediatric subjects 3 months to 11 years of age. We combined these data with previously collected adolescent PK data and performed a population PK analysis. RESULTS: Model development was performed using 311 dalbavancin plasma concentrations from 43 subjects. The median age was 5.9 years (range: 0.3-16.9). A 3-compartment, linear PK model was developed. Based on simulations, the following age-dependent dosing regimen was found to achieve similar dalbavancin exposure to that in adults administered a 2-dose regimen: children 6 to <18 years of age, 12 mg/kg (1000 mg maximum) on day 1 and 6 mg/kg (500 mg maximum) on day 8 and children 3 months to <6 years of age, 15 mg/kg (1000 mg maximum) on day 1 and 7.5 mg/kg (500 mg maximum) on day 8. Similarly, the following age-dependent regimen was found to match adult exposure after a single-dose (1500 mg): 6 to <18 years of age, 18 mg/kg (1500 mg maximum) on day 1 and 3 months to <6 years of age, 22.5 mg/kg (1500 mg maximum) on day 1. Nineteen subjects experienced 36 treatment-emergent adverse events. Five of 36 adverse events were assessed as possibly or probably related to treatment. CONCLUSIONS: Dalbavancin pediatric dosing that matched adult exposure was identified. Overall, dalbavancin was well tolerated in our study population.