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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

An Algorithm to Identify Compounded Non-Sterile Products that Can Be Formulated on a Commercial Scale or Imported to Promote Safer Medication Use in Children.

The lack of commercially-available pediatric drug products and dosage forms is well-known. A group of clinicians and scientists with a common interest in pediatric drug development and medicines-use systems developed a practical framework for identifying a list of active pharmaceutical ingredients (APIs) with the greatest market potential for development to use in pediatric patients. Reliable and reproducible evidence-based drug formulations designed for use in pediatric patients are needed vitally, otherwise safe and consistent clinical practices and outcomes assessments will continue to be difficult to ascertain.

Does maternal intrapartum antibiotic treatment prolong the incubation time required for blood cultures to become positive for infants with early-onset sepsis?

Background: We hypothesized that maternal intrapartum antibiotic treatment delays the growth of the organism in the blood culture obtained during the work-up for infants with suspected early-onset sepsis (EOS).

Methods: Single center, retrospective review of infants with blood culture-proven EOS over 13.5 years period.

Sildenafil for pulmonary hypertension complicating bronchopulmonary dysplasia.

Sildenafil, a phospohodiesterase-5 inhibitor, is widely used to treat pulmonary hypertension in infants with bronchopulmonary dysplasia despite a lack of evidence to support either safety or efficacy and US FDA advice against its use.

Population pharmacokinetics of unbound hydrocortisone in critically ill neonates and infants with vasopressor-resistant hypotension.

Objectives: To determine the population pharmacokinetics of unbound hydrocortisone in critically ill neonates and infants receiving IV hydrocortisone for treatment of vasopressor-resistant hypotension and to identify patient-specific sources of pharmacokinetic variability.

Design: Prospective observational cohort study.

Setting: Level 3 neonatal ICU.