# Pharmacokinetics (PK) and Pharmacodynamics (PD) Characterization of mTOR Inhibitors in Older Adults

> **NIH NIH U01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $618,401

## Abstract

Abstract
 Aging is the time-dependent functional decline responsible for increased susceptibility to
chronic disease, frailty, and disability. Aging is a substantial public health concern, and new
therapeutic interventions intended to mitigate its effects are needed. While preclinical evidence
supports the crucial role of mTOR inhibitors in slowing aging processes, the lack of
pharmacokinetic (PK) and pharmacodynamic (PD) data in older adults presents a substantial
challenge in designing clinical trials.
 Sirolimus and everolimus are well-studied mTOR inhibitors commonly used in
transplantation. However, both age and severe illness can significantly alter drug PK, and there
is currently limited data in older adults without underlying, confounding illnesses. Additionally,
there is a lack of data to inform the selection of PD biomarkers that optimally demonstrate
improvement in age-related processes. Without well-defined PK characterization and identification
of robust PD biomarkers, future clinical trials will lack the statistical power needed to establish
evidence of effectiveness. To lay the foundation for future studies, we assembled a
multidisciplinary team of clinical pharmacologists and epidemiologists, as well as experts in
geriatrics, gerontology, and immunosuppression. The primary goal of this research is to precisely
estimate fundamental PK/PD parameters of sirolimus and everolimus in older adults without
confounding illness. We will first validate measurement techniques and quantify the in vitro
exposure-response relationship for two different biomarkers: S6K activity and mitochondrial
function (Aim 1). We will then conduct a clinical study to characterize the PK/PD of sirolimus and
everolimus in older adults (Aim 2). Lastly, the biomarkers will be evaluated for their ability to
demonstrate the magnitude of treatment response over an intermediate term follow-up (Aim 3).
We anticipate that our research will address the existing knowledge gaps related to mTOR
inhibitor PK/PD, leading to a transformative shift in the field of aging research.

## Key facts

- **NIH application ID:** 10982433
- **Project number:** 1U01AG081450-01A1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Allison Dunn
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $618,401
- **Award type:** 1
- **Project period:** 2024-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10982433

## Citation

> US National Institutes of Health, RePORTER application 10982433, Pharmacokinetics (PK) and Pharmacodynamics (PD) Characterization of mTOR Inhibitors in Older Adults (1U01AG081450-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10982433. Licensed CC0.

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