# A comprehensive approach to understanding the determinants of metformin pharmacokinetics and pharmacodynamics in youth with type 2 diabetes

> **NIH NIH K23** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $219,303

## Abstract

PROJECT SUMMARY
The prevalence of type 2 diabetes (T2D) is increasing in youth with current management strategies ineffective
at maintaining durability of glycemic control. Metformin is the cornerstone of treatment of T2D in youth, yet
youth with T2D have high treatment failure rates on metformin therapy. The reasons for treatment failure
remain unknown, and need to be comprehensively understood in order to optimize dosing strategies for this
safe and cost-effective therapy. To address this unmet medical need, Shylaja Srinivasan MD proposes to build
on her successful patient-oriented genetic research through this career development award with the overall
objective to use an integrated approach to understand the determinants of metformin response in youth with
T2D. With the assistance of a multi-disciplinary mentoring team, she will evaluate the pharmacological, clinical
and physiological determinants of metformin response in youth with T2D. Dr. Srinivasan proposes the following
aims: (1) develop a population PK model to describe the pharmacokinetics (PK) of metformin in youth with
T2D; (2) characterize the variance in long-term response to metformin, integrating comprehensive clinical,
pharmacological and genetic data with disease progression in youth with T2D and develop a clinically usable
precision dosing tool; and (3) evaluate the precision dosing tool for metformin in a pilot study of youth with T2D
in a real clinical setting. To advance these studies, she has access to large datasets and samples from
pediatric patients with T2D. In Aim 1, Dr. Srinivasan will develop a population PK model using PK data from 60
youth with T2D recruited from UCSF. In Aim 2, she will develop a longitudinal model to characterize the
association between dose, predicted metformin PK (Aim 1), clinical factors, genetic factors if any and
metformin response using samples already collected from 699 youth with T2D from the Treatment Options for
Type 2 Diabetes in Adolescents and Youth (TODAY) study. She will then utilize these results to develop a
clinically usable precision dosing tool. In Aim 3, she will evaluate the precision dosing tool in a pilot study of 20
youth from UCSF, comparing precision dosing with conventional dosing for metformin in a real clinical setting.
Results from this proposal will inform an R01 in which precision dosing algorithms for metformin will be tested
in a large randomized control trial and will be expanded to include other drug classes. Dr. Srinivasan's long-
term career goal is to become an independent clinical researcher and to leverage pharmacological and genetic
methods to improve therapeutic strategies for youth with T2D. In this career development award, her training
goals are to gain experience in clinical pharmacology and quantitative pharmacokinetics; become proficient in
advanced biostatistical methods; gain experience in the conduct of pediatric clinical trials; and engage in
career development activities in preparation for R0...

## Key facts

- **NIH application ID:** 10614937
- **Project number:** 5K23DK120932-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Shylaja Srinivasan
- **Activity code:** K23 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $219,303
- **Award type:** 5
- **Project period:** 2020-07-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10614937

## Citation

> US National Institutes of Health, RePORTER application 10614937, A comprehensive approach to understanding the determinants of metformin pharmacokinetics and pharmacodynamics in youth with type 2 diabetes (5K23DK120932-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10614937. Licensed CC0.

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