# GOLDILOKs: Project 2: Translational

> **NIH NIH P50** · CHILDREN'S MERCY HOSP (KANSAS CITY, MO) · 2020 · $70,305

## Abstract

The responseexposuredose paradigm and “exposure escalation” dosing strategy to be utilized in
GOLDILOKs Project 1 (Clinical) is highly dependent on the ability to individualize dosing and achieve
the desired exposure at the level of the individual child. Controlling the doseexposure relationship
requires appropriate pharmacokinetic (PK) models that take into consideration factors contributing to
the observed variability in exposure. Physiologically based pharmacokinetic (PBPK) models are of
considerable interest in pediatrics due to their potential to take multiple factors into consideration at a
systems level. These include developmental changes in tissue volumes and composition, organ blood
flow, gastric acidity, intestinal transit time, protein binding, among others that occur during growth and
development. In building and applying PBPK models, both “uncertainty” – potential vulnerabilities
related to parameter estimates and implicit assumptions that may be based on limited data – and
“variability” -- ontogeny, genetic variation and environmental factors – need to be considered. In this
translational project, we will address several challenges relevant to building individualized Genome-
Ontogeny PK (iGO-PK) models to inform optimal ATX dosing for an individual patient within the
GOLDILOKs initiative. Aim 1 applies short read and long read next generation sequencing technology
to refine phenotype predictions within the CYP2D6 gene locus and to resolve long range haplotypes
with a distal (112kb) regulatory single nucleotide polymorphism (SNP) and the CYP2D6 coding region.
By determining the content and characterizing the ontogeny of microsomal protein per gram liver
(MPPGL) in pediatric liver tissue, Aim 2 will reduce uncertainty in a critical scaling factor for in vitro-in
vivo extrapolations that form the basis of PBPK models. In Aim 2 we also propose to use the Simcyp
PBPK framework and our pediatric liver bank to create a group of iGO-PK “virtual individuals”, each
with their own unique genotype data, quantitative (proteomic) abundance values for >50 drug
metabolizing enzymes and transporters and corresponding MPPGL scaling factor. We anticipate that
optimized CYP2D6 phenotype prediction from genotype data and improved PBPK models will result in
improved dosing algorithms for dose individualization in children.

## Key facts

- **NIH application ID:** 9976569
- **Project number:** 5P50HD090258-05
- **Recipient organization:** CHILDREN'S MERCY HOSP (KANSAS CITY, MO)
- **Principal Investigator:** JAMES STEVEN LEEDER
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $70,305
- **Award type:** 5
- **Project period:** — → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976569

## Citation

> US National Institutes of Health, RePORTER application 9976569, GOLDILOKs: Project 2: Translational (5P50HD090258-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9976569. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*