Accomplishments

Since the inception of the PPRU network, the PPRU has made significant accomplishments and contributions in Pediatric Pharmacology.

Contents
Labeling
Influence on Legislation and Policy Related to the Study of Drugs in Children
Contribution to Pivotal Science
Pharmacometrics
Accomplishments
Studies across the Continuum of Age (Ontogeny)
Pharmacogenetics
Transition from Pediatric Pharmacology to Pediatric Therapeutics
Development of Complements to Clinical Investigation
In vitro, in silico and animal models
Biomarkers
Data Integration and the Data Repository
Goals of PeDaR
The process of developing PeDaR

Labeling

During the first five years, pediatric labeling was a focus of the Network and contributed to the labeling of
7 drugs:

Metformin Famotidine Midazolam Propofol
Enalapril Ibuprofen (2 products) Ranitidine  

In addition, the Network studied an additional 13 drugs for the same indication for which they were labeled:

Fexofenadine Fluticasone Fosinopril Glimepiride
Levetiracetam Linezolid Lisinopril Losartan
Montelukast Omeprazole Ondansetron Rofecoxib
Tolterodine      

Over time, the PPRU, at the direction of the NICHD, re-focused their efforts on innovative studies to answer clinical questions related to pediatric therapeutics including a focus on:

  • Collaborative clinical research
  • Translational research
  • Research on novel methodologies

To that end, research that has contributed to the dialogue about designing studies to answer the important questions about pediatric drug development that will ultimately lead to drug labeling. Examples include:

  • Models for newborn study design - Approaches to understanding the unique developmental needs of newborn and pre-term neonates is being studied in trials of antimicrobials and fluconazole, codeine/morphine analgesia, and azithromycin.
  • Sleep - An innovative, first time in children, safety study of Zolpidem for sleep in children as young as 2 years old.
  • Antihypertensives - Studies of ACE inhibitors and receptor blockers in children of all ages.
  • Meropenem - A new paradigm to evaluate the effectiveness of drug therapy in acute exacerbations in Cystic Fibrosis.
  • Oncology - Studies of interventions not previously used in children that have the potential to save lives if they are used properly.

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Influence on Legislation and Policy Related to the Study of Drugs in Children

PPRU investigators played an active role in highlighting the need for pediatric studies and advocating for the inclusion of children in new drug development planning and in studies of marketed drugs.

The Conference Report on S. 830, Food And Drug Administration Modernization Act Of 1997 from the House Of Representatives pointed to the role the PPRU in this effort:

“The conferees expect the Secretary to consult with experts in pediatric research…Such experts should include representatives from the American Academy of Pediatrics, the Pediatric Pharmacology Research Unit (PPRU) Network, and the U.S. Pharmacopeia”

“The conferees note particularly the excellent efforts of NIH, especially through the PPRU Network, which will contribute significantly to this effort.”

Individual members of the PPRU and the PPRU as a whole have influenced the direction of policy and legislation:

  • Pediatric Exclusivity: In 2002, Cheston Berlin MD, Chair of the PPRU Network Steering Committee wrote to the FDA on behalf of the Network commenting on its positive impact on pediatric drug development and suggesting corrective actions for its weaknesses that were ultimately included in the new legislation.
  • Best Pharmaceuticals for Children Act (BPCA) (2002): As the number of sponsored pediatric studies grew in response to this legislation, the PPRU performed Phase I and II and PK/PD studies. BPCA reauthorized the six month additional exclusivity provisions of FDAMA and provided some funding for studies of off patent drugs and an emphasis on neonatal studies. This legislation mentioned the PPRU Network as one of the venues to conduct the studies.
  • Representing PPRU in Congress and Key Panels: Individual members have been active in testifying before Congress on issues important to the understanding of pharmacology in children and in serving on panels that have influenced policy and legislation including but not limited to the following:
  • United States Pharmacopeia General Committee of Revision Expert Advisory Panel on Pediatrics
  • FDA Pediatric Subcommittee on ethical guidelines
  • FDA meeting regarding adverse effects of drugs during pregnancy and lactation (2000),
  • U.S. House of Representatives Commerce Committee Public Hearing on the 1997 Food and Drug Administration Modernization Act
  • Committee on Drugs, American Academy of Pediatrics since 1989-1993
  • FDA Antiviral Drugs Advisory Committee
  • NHLBI Working Group on Asthma & Pregnancy
  • NIH Panel for the Consensus Development Conference (CDC) on the Effect of Corticosteroids on Perinatal Outcomes (1993-1994)
  • FDA/NIH Workshop on Psychopharmacology in Children & Adolescents (1995)
  • Pediatric and Perinatal Pharmacology, American Society for Clinical Pharmacology and Therapeutics (1996)
  • Board of Directors, American Society for Clinical Pharmacology and Therapeutics (1996-2000)
  • NICHD Expert Panel, BPCA Priority Off Patent Drug List (2002)
  • Medicine and Pharmaceuticals Working Group, NICHD National Children’s Study (2002)
  • American Board of Clinical Pharmacology

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Contribution to Pivotal Science

PPRU has made significant contributions to the design and development of new approaches to performing pediatric research specifically in pharmacometrics, ontogeny and pharmacogenetics.

Pharmacometrics

PPRU’s approach to pharmacometrics includes the various quantitative methodologies used to integrate exposure-response information and simulation of clinical trials. It encompasses:

  • Pharmacokinetics
  • Pharmacodynamics
  • Drug analysis
  • Modeling and simulation
  • Bioinformatics
Image of PPRU Pharmacometrics Group

Accomplishments include:

  • Integration of prior information results into “Developmental Road Map” of drug disposition.
    • Renal drug clearance, Transporters, Drug Metabolizing Enzymes.
    • In vitro, in silico, published studies, data within PPRU Network.
  • Development of mechanistic and physiologic models.
  • PK/PD modeling using sparse data.
    • Disease progression models.
  • Maturation adjustments for extrapolated adult models.
  • Clinical Trial Simulation Technology.
  • Pediatric knowledge base for drug disposition.
    • PK/PD study design and dosing – e.g. Childhood Absense Epilepsy.
    • Design for targeted therapies and PK/PD model based analysis.

Studies across the Continuum of Age (Ontogeny)

Ontogeny encompasses all changes drive the “normal” variation in the dose-exposure-response profile across the continuum of age from infancy through adolescence. PPRU performed studies to detail the impact of maturation on drug disposition and response. They were designed to address changes to the structure and function of the relevant pathways over time.

Studies included:

  • Developmental changes in morphine disposition.
  • Disposition of methadone in preterm newborns.
  • Disposition of inhaled corticosteroids from preterm newborns to adolescents.
  • Lansoprazole Disposition in Young Children with Cystic Fibrosis (ages 2-10 years).
  • Childhood Absence Epilepsy (CAE) Rx, PK-PD-Pharmacogenetics.

Pharmacogenetics

PPRU investigators conducted studies on the developmental characteristics and genetic polymorphism of drug metabolizing enzymes, pharmacokinetic modeling and simulation technology. They integrated pharmacogenetics into the context of clinical/translational research focused on clinical pharmacology.

Investigators developed:

  • Validated PCR-RFLP technique for small scale pilot projects for genes involved in drug disposition and response.
  • Methods to use a variety of sources of genetic materials, including tissue (fresh and archived), whole blood, buccal brushes and saliva.
  • Genotyping methods for specific drugs such as mycophenolic acid (UGT2B7, UGT1A9 and IMDPH) and midazolam (CYP3A4) allelic variants to examine pharmacokinetics and pharmacodynamics.
  • Molecular techniques to search for new polymorphisms such as DNA cloning and sequencing.

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Transition from Pediatric Pharmacology to Pediatric Therapeutics

The PPRU assisted with the transition from Pediatric Pharmacology to Pediatric Therapeutics with an emphasis on:

  • Multidisciplinary, collaborative work.
  • Expansion of research on developmental pharmacology to answer questions raised in the clinic and provide knowledge base for pediatric personalized medicine and
  • Integration of knowledge between studies, within and across drug therapeutic groups and different pediatric conditions and diseases and at different developmental levels.
  • Understanding the use of drugs in children and the important clinical problems that derive from patient oriented therapeutics with a focus on:
    • Genomics
    • Proteomics
    • Biomarkers
    • Functional imaging
    • Pharmacogenetics
    • Bench to bedside/bedside to bench investigation
Image of PPRU Pharmacometrics Group

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Development of Complements to Clinical Investigation

In vitro, in silico and animal models

The PPRU Network has developed a library of models that can be used to inform study design. Using existing data in adults, preclinical, in vitro and in silico models help to optimize pediatric study and have resulted in improved study design in studies of:

  • Inositol
  • Azithromycin
  • Ibuprofen
  • Lorazepam
  • Midazolam
  • Morphine

Biomarkers

Biomarkers are characteristics of biological or pathogenic process or pharmacologi responses to therapy that can be objectively measured. PPRU investigators have performed biomarker studies including:

  • Pain fiber response as surrogate for opiate effect using pupilometery and EEG.
  • 13C-acetate breath test as PD surrogate to evaluate promotility agents.
  • Measurement of Nitrotyrosine Adducts and Cytokines in Acetaminophen Overdose Patients.
  • Using PET scans as neuroimaging marker in autism for the rational design of treatment with buspirone.

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Data Integration and the Data Repository

The PPRU developed a research resource, the PPRU Clinical Data Repository (PeDaR). PeDaR to store all investigator initiated study data using a common set of terms and definitions to promote data sharing and metadata analysis.

Goals of PeDaR are to:

  • Facilitate the interchange and aggregation of data on small populations.
  • Facilitate analyses.
  • Provide guidance for data collection and organization in future studies.

PeDaR is built upon existing and widely adopted standards such as CDISC and BRIDG models.

The process of developing PeDaR has involved the following:

  • Development of a core set of data collection forms, definitions, and data dictionary to capture data in future PPRU studies.
  • Creation of a storage structure for study data and protocol descriptors so that data can be aggregated across studies.
  • Mapping of legacy or completed studies to the data dictionary to provide a prototype of capabilities.
  • Development of a query system to stimulate exploration of the data from completed studies and address research questions across studies to subsets of the aggregate data.

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