NIH/NIMH – Developmental Pharmacodynamics and Models of Drug Effects in Pediatrics (R01, R03 Clinical Trial Optional)

March 5, 2018 by School of Medicine Webmaster

The description below was taken from the R01 version of this FOA.

Clinical pharmacology is the science that describes the effects of drugs in humans, by correlating drug concentration (the amount of drug in the body) with drug effect. Despite continued efforts via multiple avenues (such as legislation, patient advocacy, and funding announcements) there is still a dearth of data related to pediatric efficacy and tolerability for a very large number of drugs used in pediatrics.

Pharmacokinetics (PK) describes the time course of drug concentrations in body fluids and tissues, while pharmacodynamics (PD) elucidates the relationship between drug concentration and effect. Drug pharmacodynamics (PD) is related to the effect of drugs.  Usually, inter-individual variability in PD processes exceeds the inter-individual variability in PK. Failure to properly account for the variability in the PD of a drug may cause therapy failure or toxicity for individual patients.

Developmental Pharmacodynamics has been defined as “the study of age-related maturation of the structure and activity of biologic systems and their effects on response of children to pharmacotherapy” (Mulla H Pediatric Drugs 2010 12).  Changes in PD may affect the potency (sensitivity of the organ/tissue to a drug) or efficacy (maximum pharmacologic response) of a drug.

There are several examples of altered PD responses in children compared to adults related to developmental differences. Examples include: increased sensitivity to opioids in newborns due alterations in opioid receptors, occurrence of paradoxical seizures with anti-epileptics due to increases in excitatory GABA receptors, and relative lack of effect of tricyclic antidepressants secondary to neurodevelopmental delays in the norepinephrine system.

In pediatrics, there is a discrepancy between the great strides made in PK studies, compared with the limited number and sophistication of PD studies. There is a paucity of pharmacodynamic studies in children that can be compared to similar measurements in adults. Most pediatric studies only provide pharmacokinetic data, preventing the determination of pharmacokinetics-pharmacodynamics correlations and the target concentration that produces the desired drug effect.

The lack of PD research is related to several factors, including lack of suitable juvenile animal models which would reliably predict pediatric drug response. Animal models have been used as surrogates for developmental PD studies for years. However, differences in ADME (absorption, distribution, metabolism and excretion) mechanisms, differences in body size and developmental differences in the expression of receptors and transporters may all invalidate extrapolation of the results to humans.

There is a lack of knowledge of the range of pediatric responses over a large range of ages, from premature infants through to adolescents.  There is also a lack of non-invasive methodologies and technologies used to successfully collect metrics in this population, and a history of poor recruitment and retention likely related to small sample sizes in pediatric and clinical studies.

Age-related changes in pharmacodynamics

The nature of PD measurements depends on the specifics of the drug class and chemical properties, developmental stage and disease process. It varies from the use of measurement scales (e.g., pain intensity) to sophisticated biomarkers (i.e., pharmacometabolomic biomarkers). The consequences of the lack of PD data are far-reaching, since PD measurements play a key role in the prediction of efficacy from different patient populations or drug doses.

Validation of PD outcome measures have the potential to permit extrapolation of adult efficacy data to pediatric conditions, without the need to conduct additional efficacy trials in children. Great strides have been made in adults in which the efficacy of therapeutic strategies can be simulated using virtual patients and simulations.  Virtual populations enable robust statistical predictions that can be compared to and validated by actual clinical data.

Pharmacokinetics and pharmacodynamics correlation and integration

PK and PD measurements were considered separately in the past. PK or PK/PD models have recently changed from empirical descriptive models to mechanistic-based physiological models. The latter relates underlying physiologic processes to the observed pharmacologic response. The integration of PK/PD has allowed the characterization of onset, potency and duration of pharmacologic effects and correlation of these effects to drug’s mechanism of action. Physiologically based PK/PD (PBPKPD) modeling and simulation has been recently applied in the study of pediatric drugs for the prediction of drug exposure. PBPK models can incorporate in vitro and in silico predictions to generate models. As PBPK models move further towards Quantitative Systems Pharmacology (Geerts et al. 2013), the ability of the in silico models to accelerate the entire drug development process provides much promise.

Goals
  • Recognize that there is an urgent need to promote development and validation of pharmacodynamic endpoints in children.
  • Identify and validate PD endpoints of drug effect, including efficacy and safety measures, using clinical and pre-clinical models.
  • Identify gaps in the current understanding of mechanisms of pharmacologic response in children.
  • To quantitatively characterize changes in clinical outcome measures of pediatric disease trial results.

Research approach

The type of research to be performed under this FOA will require interdisciplinary collaboration.  Pediatric clinical pharmacologist or pharmacologists with training in pharmacometrics will need to pair up with pediatric subspecialists (e.g. neonatologists, endocrinologists, neurologists, infectious diseases specialists, etc.) to develop projects.  This collaboration will provide insights for each participating discipline necessary to address therapeutic specific issues that are influenced by the stage of growth and development in the pediatric population.

Developmental pharmacodynamics research depends upon two approaches “bottom up” and “top down.” A top down approach is necessary to design clinical studies to unravel maturational changes in the exposure-response relationship using pharmacokinetics-pharmacodynamic measurements.  Integrated population pharmacokinetics/pharmacodynamics models and models of disease progression are important to advance the goal of precision medicine in pediatrics.  It is important to understand and elucidate key differences in disease progression and disease response to therapy between children and adults.  A bottom-up approach is needed to study the ontogeny of the drug target-organ interactions.  Limited body of knowledge is available on measurements of drug target engagement in pediatrics. However, “omics” technologies are being developed and apply to pediatrics. Studies in clinical metabolomics and pharmacometabolomic related drug efficacy and safety data in pediatrics are beginning to be published

Scope

The type of pediatric studies appropriate to this FOA include, but are not limited to, the following:

  • Identification of appropriate pediatric pharmacodynamics endpoints for inclusion in PK/PD modeling.
  • Inclusion of a PD component in PBPK models including co-variants related to receptor interactions at different developmental strata.
  • Identification or discovery of PD surrogate endpoints that can accurately determine drug effects.
  • Discovery or identification of biomarkers that can be used as surrogate endpoints that are in the pathway of a drug mechanism of action and closely link with drug effect at the cellular level.
  • Studies that permit the characterization of how ontogeny influences the dose-response relationship for drugs in pediatrics.
  • Studies for the development, evaluation and validation of new approaches to assess drug effects at various stages of child development.
  • Studies to develop dosage form(s) to support proposed PD measures and/or in vivo studies.
  • Studies to confirm that therapeutic agents reach and engage the target site (directly or indirectly) at a level that exceeds pharmacological potency over the desired period.
  • Studies to inform design, refinement, and validation of the PD measure and/or in vivo efficacy models and testing procedures, including the following: examination of model variability to estimate sample size in pediatrics; calibration of the model according to positive and negative controls, the age, time course and window of disease that are relevant for therapeutic testing; and determination of meaningful clinically relevant outcome measures.
  • Studies of dose (exposure)-response activity with the intended route of administration.
  • Development of in vitro and or in silico systems and appropriate animal studies to determine the effect of the ontogeny of receptors and transporters of drugs target organ systems on pharmacodynamics.
  • Development of quantitative systems pharmacology (QSP) models that bridge multiple scales in physiological models of children.
  • Development of QSP model frameworks that are scalable from adults to children.

NIMH Area of Interest:  The NIMH is specifically interested in clinical studies supporting the establishment of pharmacodynamic (PD) markers of psychopharmacologic drugs in pediatric populations.  For instance, a study using an EEG measure that would change in proportion to an administered drug dose (a CNS PD marker of drug action) would be of interest.  It is expected studies include dose ranging PK/PD measures.  Age-dependent effects would be of interest as well as the inclusion of comparator drugs. Using the EEG PD example, it is likely that the EEG measures reflecting drug action would be different in grade school children vs adults.

Deadlines:  standard dates and standard AIDS dates apply

URLs:

Filed Under: Funding Opportunities