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  1. Advancing Regulatory Science

Predicting Pediatric Dosing for Medical Countermeasures

CERSI Collaborators: University of California San Francisco (UCSF): Kathy Giacomini, PhD; Formerly of UCSF; Sook Wah Yee, PhD; Kelsey Trumbach, MPH
Trainees who have completed training and benefited from this project: Kathy Cheung, PharmD, Mina Azimi, PhD, Xujia Zhou, PhD

FDA Collaborators: Center for Drug Evaluation and Research (CDER): Shiew Mei Huang, PhD; Lei Zhang, PhD; Qi Liu, PhD

Project Start Date: May 1, 2018

Regulatory Science Challenge

Medical Countermeasures (MCMs) are medicines and tests that can diagnose, prevent, or treat diseases in the event of a national emergency such as a chemical or biological threat. MCMs need to be administered quickly in an emergency. Therefore, it is important to have guidelines for dosing all people. Unfortunately, children’s doses for many medications are not known, as the medications were only tested in adults.

To determine how to best dose medicines in children, including MCMs, it is important to consider the role of drug transporters in the kidney that eliminate the medications into the urine and transporters in the brain that prevent drugs from entering the brain. Transporters are proteins found in the kidney and brain and help the body eliminate and remove drugs. In children, these transporters may not be fully developed, which can increase the risk of dangerous side effects to medications.

Project Description and Goals

Researchers will measure the levels of transporters in the kidney and brain using kidney and brain samples from babies, children, and adults. These measurements will be used to determine whether there are age-related changes in the levels of the transporters, also known as transporter expression. Age-related changes in the levels of the transporters will be incorporated into computer models to predict the doses of drugs to safely give to the children. The results will help develop dosing guidelines to treat children with antibiotics and other drugs that may be needed in the event of a public health threat.

Research Outcomes/Results

The outcome of this study resulted in three publications. Below, researchers describe the key outcomes/results from each publication.

  • Cheung KWK et al. 2019, Clinical Pharmacology and Therapeutics: The study by Cheung et al. (2019) examined how the kidney's drug transporters, which help process medications, change as children grow. They found that the levels of certain transporters in the kidney increase with age, while others remain stable, which is crucial for developing accurate drug dosing for children.
  • Cheung KWK et al. 2019, Journal of Clinical Pharmacology: About 40% of prescription drugs lack specific dosing guidelines for children, and understanding how these kidney transporters change with age helps create accurate dosing models. The study found that the levels of some kidney transporters, such as P-glycoprotein and URAT1, increase with age, while others like MATE2K and BCRP do not change significantly. Additionally, certain transporters, like MATE1 and GLUT2, remain consistent across all ages, and there is significant variation in transporter levels, especially in newborns compared to older children.
  • Chen EC et al. 2022, Pharm Research: OCT3 is a protein that helps drugs get into the body and brain, especially when taken orally. The study found drugs that block OCT3, which can potentially cause drug-drug interactions, and developed a model to identify more blockers, highlighting OCT3's importance in drug transport to the brain.

Research Impacts

Disseminating Scientific Knowledge: The goal of two of the three published studies was to obtain information on transporter expression levels to predict pediatric dosing for drugs that may be used in medical countermeasures. The third study was to predict drug-drug interactions in which one drug may interfere with the intestinal absorption of another drug (through inhibition of OCT3). This study would also inform medical countermeasures in all populations. By publishing these three manuscripts (see publications list below and in our progress report), researchers have made information available to the FDA scientists as well as others that can be used in predicting drug disposition and dosing in pediatric populations.

Developing New Tools and Approaches: This CERSI project focuses on creating new methodologies and tools that can be integrated into regulatory practices. For instance, the integration of quantitative proteomics data on transporter expression into physiologically based pharmacokinetic (PBPK) models has been emphasized to enhance predictive accuracy for drug disposition and dosing in pediatric populations. This approach considers factors such as membrane localization and protein functionality to ensure accurate PBPK modeling. In addition, the project aimed to develop high throughput screening assays and structure-activity relationship (SAR) models for identification of inhibitors of critical drug transporters such as OCT3. These tools are crucial for understanding drug-drug interactions and their impact on drug absorption and disposition, particularly in the context of the intestine, the human blood-brain barrier and CNS drug delivery. Overall, these projects have developed predictive models to inform drug discovery and development, enhancing regulatory science and improving therapeutic outcomes.

Publications

Cheung KWK, van Groen BD, Spaans E, van Borselen MD, de Bruijn ACJM, Simons-Oosterhuis Y, Tibboel D, Samsom JN, Verdijk RM, Smeets B, Zhang L, Huang SM, Giacomini KM, de Wildt SN. A Comprehensive Analysis of Ontogeny of Renal Drug Transporters: mRNA Analyses, Quantitative Proteomics, and Localization. Clin Pharmacol Ther. 2019 Nov;106(5):1083-1092. doi: 10.1002/cpt.1516. Epub 2019 Jul 3. PMID: 31127606; PMCID: PMC6777991.

Cheung KWK, van Groen BD, Burckart GJ, Zhang L, de Wildt SN, Huang SM. Incorporating Ontogeny in Physiologically Based Pharmacokinetic Modeling to Improve Pediatric Drug Development: What We Know About Developmental Changes in Membrane Transporters. J Clin Pharmacol. 2019 Sep;59 Suppl 1(Suppl 1):S56-S69. doi: 10.1002/jcph.1489. PMID: 31502692; PMCID: PMC7408403.

Chen EC, Matsson P, Azimi M, Zhou X, Handin N, Yee SW, Artursson P, Giacomini KM. High Throughput Screening of a Prescription Drug Library for Inhibitors of Organic Cation Transporter 3, OCT3. Pharm Res. 2022 Jul;39(7):1599-1613. doi: 10.1007/s11095-022-03171-8. Epub 2022 Jan 28. PMID: 35089508; PMCID: PMC9246766.

 

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