George P. Giacoia

Antifungals in Systemic Neonatal Candidiasis

Fungal infections are common in the newborn period, especially among premature neonates, and are responsible for considerable morbidity and mortality. Currently, three classes of antifungals are commonly used in the treatment of systemic fungal infections in neonates: the polyene macrolides (e.g. amphotericin B [deoxycholate and lipid preparations]); the azoles (e.g. fluconazole); and the fluorinated pyrimidines (e.g. flucytosine). The echinocandins (e.g. caspofungin and micafungin) are a newer class of antifungals which shows promise in this population.The available kinetic data on amphotericin B deoxycholate in neonates are derived from very small studies and exhibit considerable variability. There are no kinetic data available for the use of lipid preparations in this population and, again, much has been inferred from adult studies. The information available for flucytosine is also limited but appears similar to what is observed in adults. Fluconazole has the most neonatal pharmacokinetic data, which show slightly less variability than the other antifungals. Genomic factors which affect the metabolism of amphotericin B and fluconazole may explain some of the observed variability.Most of the data for the efficacy of antifungal drugs in neonates are derived from retrospective studies and case reports. The data for amphotericin B deoxycholate and flucytosine are limited. There are more data for the liposomal and lipid complex preparations of amphotericin B and for fluconazole in this population. These support the use of these drugs in neonates, but because of their largely noncomparative nature they can not define the optimal dosage or duration of therapy.Amphotericin B deoxycholate is primarily nephrotoxic. It also induces electrolyte abnormalities and is to a lesser degree cardiotoxic. This toxicity in neonates appears similar to published data in older children and adults. While the lipid preparations of amphotericin B owe their existence to a presumed decrease in toxicity, the observed toxicity in neonates appears to be equal to that seen with the deoxycholate, although it should be noted that the lipid preparations are usually given at much higher dosages. Fluconazole toxicity appears to be milder and less frequent in this population than is seen with amphotericin B.In the final analysis, we do not have sufficient data to define the pharmacokinetic profiles, optimal dose or duration of therapy, or toxicity for any of these compounds in neonates. Further studies are necessary if the optimisation of antifungal therapy in this population is to continue.

Human Ontogeny of Drug Transporters: Review and Recommendations of the Pediatric Transporter Working Group

The critical importance of membrane‐bound transporters in pharmacotherapy is widely recognized, but little is known about drug transporter activity in children. In this white paper, the Pediatric Transporter Working Group presents a systematic review of the ontogeny of clinically relevant membrane transporters (e.g., SLC, ABC superfamilies) in intestine, liver, and kidney. Different developmental patterns for individual transporters emerge, but much remains unknown. Recommendations to increase our understanding of membrane transporters in pediatric pharmacotherapy are presented.

Asthma across the ages: Knowledge gaps in childhood asthma

The Eunice Kennedy Shriver National Institute of Child Health and Human Development convened an Asthma Group in response to the Best Pharmaceuticals for Children Act. The overall goal of the Best Pharmaceuticals for Children Act Program is to improve pediatric therapeutics through preclinical and clinical drug trials that lead to drug-labeling changes. Although significant advances have been made in the understanding and management of asthma in adults with appropriately labeled medications, less information is available on the management of asthma in children. Indeed, many medications are inadequately labeled for use in children. In general, the younger the child, the less information there is available to guide clinicians. Because asthma often begins in early childhood, it is incumbent on us to continue to address the primary questions raised in this review and carefully evaluate the medications used to manage asthma in children. Meanwhile, continued efforts should be made in defining effective strategies that reduce the risk of exacerbations. If the areas of defined need are addressed in the coming years, namely prevention of exacerbations and progression of disease, as well as primary intervention, we will see continuing reduction in asthma mortality and morbidity along with improved quality of life for children with asthma.

Obstetric Clinical Pharmacology: Coming of Age

Little is known about changes in drug disposition and effect during pregnancy. In this issue, which is devoted to maternal and child health, Andrew and colleagues 1 from the University of Washington present research describing significant changes in the disposition of amoxicillin during pregnancy. The clinical significance is the potential for inadequate dosing during pregnancy of compounds that are renally cleared. Further research is needed to guide the appropriate, safe, and effective medical treatment of pregnant women. In 2003, the National Institute of Child Health and Human Development (NICHD) formed the Obstetric Pharmacology Research Units Network. This network serves in part as a proof‐of‐concept platform, to demonstrate that clinical investigations can be performed in pregnant women.

The newborn drug development initiative.

The Best Pharmaceuticals for Children Act (BPCA; Pub L 107-109) was enacted in January 2002 and will sunset in October 2007. The BPCA established processes for studying off-patent and on-patent drugs that are used in pediatric population. Although some drugs have been successfully developed for the neonate (eg, surfactant, nitric oxide), drug development for the youngest, least mature, and most vulnerable pediatric patients is generally lacking. Most drugs are empirically administered to newborns once efficacy has been demonstrated in adults and usefulness is suspected or demonstrated in the older pediatric population. Unfortunately, this process undermines the ability to perform the appropriate studies necessary to demonstrate a drugs short- and long-term safety and efficacy and establish appropriate dosing in neonates. The Newborn Drug Development Initiative Workshop I (held March 29–30, 2004) specifically addressed scientific, clinical, and ethical concerns in the development of trials of pediatric therapeutic agents for neonates. Implementation of the BPCA for all pediatric populations will foster collaboration among federal agencies and academic institutions on scientific investigation, clinical-study design, and consideration of the weight of evidence and address ethical issues related to the performance of drug studies.

Eunice Kennedy Shriver National Institute of Child Health and Human Development Pediatrics Formulation Initiative: Proceedings from the Second Workshop on Pediatric Formulations

BACKGROUND The Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH) organized a workshop held in November 2011 to address knowledge gaps that limit the availability of adequate pediatric formulations. This workshop was used as a means to identify the types of research innovations needed and to stimulate research efforts designed to improve the availability of pediatric formulations and the technologies required to make these formulations. METHODS Information for this article was gathered from the proceedings of the Second US PFI Workshop sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development in Bethesda, Maryland, on November 1 and 2, 2011, as well as from post-workshop discussions. The workshop preparation began with formation of 4 working groups: Biopharmaceutics, Biopharmaceutics Classification System (BCS), New Technology and Drug Delivery Systems, and Taste and Flavor. RESULTS The recommendations of the 4 working groups will form the basis for the development of a blueprint to guide future research efforts. The pediatric-specific problems identified include the heterogeneity of the population, the small size of the pediatric drug market, the limited number of new formulations for the large number of off-patent and unlabeled drugs, and the lack of universal agreement on how to define appropriate formulations for different ages and stages of development. There was consensus on the need to develop a universal technology platform for flexible pediatric dosage forms, transforming an empirical process into a science-based platform. A number of problems affect the availability of drugs in the developing world. Age-appropriate solid oral pediatric medicines for common diseases can have a global impact. Success on a global scale depends on the commitment of policy makers, regulators, scientists, pharmaceutical companies, sponsors, government, and research foundations to address gaps in knowledge and solve public health issues related to the availability of formulations in the developing world. CONCLUSIONS Solutions to the worldwide lack of appropriate pediatric formulations will require the development of a road map and the commitment of policy makers, regulators, scientists, pharmaceutical sponsors, academic institutions, governments, and research foundations. The development of a universal, cost-effective platform using existing or developing innovative technology that produces flexible pediatric dosage forms remains an important but elusive goal.

Drug Studies in Newborns: A Therapeutic Imperative

Although some drugs have been developed for the neonate, drug development for the least mature and most vulnerable pediatric patients is lacking. Most of the drugs are off-label or off-patent and are empirically administered to newborns once efficacy has been demonstrated in adults and usefulness is suspected or demonstrated in the older pediatric population. Few drugs are approved by the Food and Drug Administration for use in this population. The factors that prevent the demonstration of efficacy and safety in the newborn are discussed and a change in the current approach for neonatal drug studies is suggested.

Expanding Treatment Options for Youth With Type 2 Diabetes: Current Problems and Proposed Solutions: A White Paper From the NICHD Diabetes Working Group.

The Best Pharmaceuticals for Children Act of 2002 mandated that the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) carries out critical reviews of the gaps in knowledge and unmet needs regarding safe and effective pharmacologic treatment of infants, children, and adolescents in a broad range of disease areas. In 2012, NICHD selected diabetes mellitus as one of the pediatric disorders for review. Dr. William V. Tamborlane was named chair, and Dr. Linda DiMeglio, vice-chair, of the Diabetes Working Group. Together with Dr. George Giacoia of NICHD, they assembled a distinguished group of medical experts in childhood diabetes, including clinicians/clinical investigators from leading academic centers and from industry and representatives from the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), to carry out this review. It is very important to note that the views expressed in this article, as well as in other reports from the Diabetes Working Group, are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the FDA or EMA or any of the organizations or pharmaceutical companies represented in our working group. As shown in Supplementary Table 1, the large Diabetes Working Group was divided into five committees: Type 1 Diabetes (T1D): Therapeutics, Type 2 Diabetes (T2D): Therapeutics, T1D: Natural History and Biomarkers, T2D: Natural History and Biomarkers, and Diabetes Pharmacology. The consensus of the T2D Therapeutics Committee was that its efforts should address the crisis in care that clinicians face in treating this disorder in adolescents. Despite a plethora of new drug classes and new agents within each class that have been approved for use in adults with T2D, in …

Conclusions and Recommendations of the Expert Panel: Technical Workshop on Human Milk Surveillance and Biomonitoring for Environmental Chemicals in the United States

We thank the following organizations for generously providing support for the workshop: the AmericanChemistry Council; the Centers for Disease Control and Prevention (C13/CCU323635-01); the Departmentof Health and Human Services, Health Resources and Services Administration (HHSH240200415021P);Health Canada (H405-03-ExSD079/4500078209); 3M; Pennsylvania State University College of Medicine;the Research Foundation for Health and Environmental Effects; and the U.S. Environmental ProtectionAgency, Office of Children’s Health (CH-83213101-0).The opinions expressed in this article are those of the authors and do not necessarily reflect the viewsand/or policies of their affiliations.Address correspondence to Cheston M. Berlin, Jr., MD, Department of Pediatrics Children’s Hospital,Milton S. Hershey Medical Center, Pennsylvania State University College of Medi cine, M.C. HO85, PO Box850, Hershey, PA 17033, USA. E-mail: cmb6@psu.edu

Reply: To PMID 24290281.

To the Editor: The correspondence from Chipps et al highlights a new questionnaire for preschool children titled the ‘‘Test for Respiratory and Asthma Control in Kids’’ (TRACK). Although our recent review on childhood asthma indeed stated that ‘‘there are no instruments available [for asthma control] for children in the 0to 4-year age group,’’ that statement was adapted from the recent National Institutes of Health and the Agency for Healthcare Research and Quality Asthma Outcomes Workshop Report, which identified no core or supplemental measures for baseline characterization or prospective efficacy analyses in children younger than 4 years. It is important to note that this Asthma Outcomes Workshop Report was published in February 2012, and at that time, only 1 publication on the TRACK instrument was available. Although this TRACK publication was promising in that it demonstrated more than 80% correct classification of preschool childrenwith asthma-like respiratory disease, theWorkshop committee was constrained to strict definitions of ‘‘core’’ and ‘‘supplemental’’ outcome measures of asthma control, which were largely based on well-documented standardization of methods and crosssectional and longitudinal validity. Consequently, the TRACK questionnaire was named as an ‘‘emerging’’ outcome given its potential to improve disease monitoring, although it was recognized that further studies were needed at the time. As Chipps et al correctly point out, several key articles on the TRACK questionnaire have been published since the Asthma Outcomes Workshop. There is now evidence supporting both the clinical meaningfulness and the longitudinal validity of the TRACK tool in 20 representative pediatric practices in the United States. The reliability of the TRACK questionnaire in a Turkish population of preschool children has also been established, suggesting that the tool may be of relevance to the larger global community of asthma physicians. Although clinical trials utilizing the TRACK questionnaire are yet to be conducted, it may now be appropriate to move this new assessment tool from the ‘‘emerging’’ category of research. Given the limited number of available questionnaires for the assessment of asthma control in young children, the TRACK tool may offer novel advantages for future pharmaceutical study in young children. Stanley J. Szefler, MD James F. Chmiel, MD, MPH Anne M. Fitzpatrick, PhD George Giacoia, MD Thomas P. Green, MD Daniel J. Jackson, MD Heber C. Nielsen, MD Wanda Phipatanakul, MD, MS Hengameh H. Raissy, PharmD From the Department of Pediatrics and Pharmacology, National Jewish Health, and the University of Colorado School of Medicine, Denver, Colo; University Hospitals Rainbow Babies and Children’s Hospital and Case Western Reserve University School of Medicine, Cleveland, Ohio; Emory University Department of Pediatrics and Children’s Healthcare of Atlanta Center for Developmental Lung Biology, Atlanta, Ga; the National Institute of Child Health and Development, Bethesda, Md; Ann and Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Ill; the Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wis; Floating Hospital for Children at Tufts Medical Center, Tufts University School of Medicine, Boston, Mass; Boston Children’s Hospital and Harvard Medical School, Boston, Mass; and the Department of Pediatrics, University of New Mexico School of Medicine, Albuquerque, NM. E-mail: Stanley.szefler@childrenscolorado.or. Disclosure of potential conflict of interest: S. J. Szefler has received consultancy fees from Merck, Genentech, Boehringer Ingelheim, and GlaxoSmithKline; has received research support from GlaxoSmithKline; has received lecture fees from Merck; has received payment for manuscript preparation from Genentech; and has a pending patent with the National Heart, Lung, and Blood Institute (NHLBI) CARE Network for a beta adrenergic receptor polymorphism. J. F. Chmiel has received consultancy fees from Genentech, CSL Behring, and Boehringer Ingelheim; has received research support and honoraria for grant reviews from the National Institutes of Health and the Cystic Fibrosis Foundation; has received payment for the development of educational presentations from KaloBios Pharmaceuticals; has received travel support from the American College of Chest Physicians; and has received honorarium from the American Board of Pediatrics for question writing activities. A. M. Fitzpatrick has received consultancy fees from MedImmune, Merck, GlaxoSmithKline, Genentech, and Boehringer Ingelheim. D. J. Jackson has received consultancy fees from GlaxoSmithKline and Genentech. W. Phipatanakul has received research support from the National Institutes of Health. H. H. Raissy has received research support from the NHLBI/subcontract with National Jewish Health and has received travel support from Genentech. The rest of the authors declare that they have no relevant conflicts of interest.