MTOR Inhibitors in Older Adults

Characterization of mTOR Inhibitor Pharmacokinetics and Pharmacodynamics in Older Adults .

Over the past decades, healthcare systems face significant challenges to meet the needs of an aging population due to progressive debility, functional decline and chronic diseases development. While there is a growing appreciation of the potential impact of mTOR inhibitors on slowing aging processes, preventing chronic disease and prolonging healthy lifespan, a major challenge in developing clinical trials to establish the clinical efficacy of mTOR inhibitors is the absence of pharmacokinetics (PK) and pharmacodynamics (PD) data in older adults. The proposed study will provide the foundation for future clinical trials assessing the role of mTOR inhibitors on aging related indications

Study Overview

• Status: Recruiting
• Conditions: Aging
• Intervention / Treatment: Drug: Sirolimus 0.5 Mg Oral Tablet; Drug: Sirolimus 1Mg Oral Tablet; Drug: Sirolimus 2 MG Oral Tablet; Drug: Everolimus 0.5 MG Oral Tablet; Drug: Everolimus 1 MG Oral Tablet; Drug: Everolimus 2 MG Oral Tablet

Detailed Description

Study Objectives To characterize Pharmacokinetics (PK) and Pharmacodynamics (PD) of mTOR Inhibitors and determine whether mTOR Inhibitors will improve phenotypic biomarkers of aging as measured by SASP (senescence-associated secretory phenotype) index score at 3 months follow-up in older adults.

Specific Aims:

Aim 1: To characterize Pharmacokinetics (PK) and Pharmacodynamics (PD) of mTOR Inhibitors (sirolimus and everolimus) in older adults.

Aim 2: To determine whether mTOR Inhibitors will improve phenotypic biomarkers of aging as measured by SASP (senescence-associated secretory phenotype) index score at 3 months follow-up.

Exploratory Aim 3: We will also assess the feasibility of collecting the laboratory biomarkers (ESR, CRP, S6K activity, mitochondrial function, metabolomics) and data regarding the functional biomarkers of aging measured by walking speed, chair stand, standing balance, grip strength

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Irina Timofte, MD, MS; Phone Number: 2163347534; Email: Irina.Timofte@utsouthwestern.edu

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75390
      • Recruiting
      • UT Southwestern Medical Center
      • Contact: Rhoda Annoh Gordon, PharmD, MPH; Phone Number: 2146457108; Email: Rhoda.annohgordon@utsouthwestern.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Community-dwelling adults
2. Patients should be 65 Years and older
3. Patients is able to understand and follow trial procedures

Exclusion Criteria:

1. Creatinine clearance <30 mL/min;
2. History of chronic liver disease;
3. Uncontrolled Hypertension (i.e., systolic blood pressure >160 mm Hg);
4. Hemorrhagic central nervous system (CNS) event within 1 year from screening visit;
5. Thrombotic event (DVT,PE) within 1 year from screening visit if not on anticoagulation;
6. Planned major surgical procedures;
7. Cardiovascular diseases ( i.e., admission for heart failure or myocardial infarction within 12 months);
8. Taking medication that increase or decrease sirolimus blood concentrations;
9. Other investigational therapy received within 1 month prior to screening visit;
10. History of dementia; 11 Dependence in any Katz Basic Activities of Daily Living.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: sirolimus 0.5 mg Arm; Participant would receive 0.5 mg of sirolimus.	Drug: Sirolimus 0.5 Mg Oral Tablet; Sirolimus 0.5 mg oral tablets daily for 2 weeks and complete PK/PD testing. After the first 2 weeks, dose increase, or dose reduction will be made to obtain a stable blood level of 5-7 ng/ml.
Active Comparator: sirolimus 1 mg Arm; Participant would receive 1 mg of sirolimus.	Drug: Sirolimus 1Mg Oral Tablet; Sirolimus 1 mg oral tablets daily for 2 weeks and complete PK/PD testing. After the first 2 weeks, dose increase, or dose reduction will be made to obtain a stable blood level of 5-7 ng/ml.
Active Comparator: sirolimus 2 mg Arm; Participant would receive 2 mg of sirolimus.	Drug: Sirolimus 2 MG Oral Tablet; Sirolimus 2 mg oral tablets daily for 2 weeks and complete PK/PD testing. After the first 2 weeks, dose increase, or dose reduction will be made to obtain a stable blood level of 5-7 ng/ml.
Active Comparator: everolimus 0.5 mg Arm; Participant would receive 0.5 mg of Everolimus.	Drug: Everolimus 0.5 MG Oral Tablet; Everolimus 0.5 mg oral tablets daily for 2 weeks and complete PK/PD testing. After the first 2 weeks, dose increase, or dose reduction will be made to obtain a stable blood level of 5-7 ng/ml.
Active Comparator: everolimus 1 mg Arm; Participant would receive 1 mg of Everolimus.	Drug: Everolimus 1 MG Oral Tablet; Everolimus 1 mg oral tablets daily for 2 weeks and complete PK/PD testing. After the first 2 weeks, dose increase, or dose reduction will be made to obtain a stable blood level of 5-7 ng/ml.
Active Comparator: everolimus 2 mg Arm; Participant would receive 2 mg of Everolimus.	Drug: Everolimus 2 MG Oral Tablet; Everolimus 2 mg oral tablets for daily for 2 weeks and complete PK/PD testing. After the first 2 weeks, dose increase, or dose reduction will be made to obtain a stable blood level of 5-7 ng/ml.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax for Sirolimus	Maximum Sirolimus Concentration at Steady State (Cmax)	Predose (0 hour) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24-hour post dose
Cmax for Everolimus	Maximum Everolimus Concentration at Steady State (Cmax)	Predose (0 hour) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 12-hour post dose
Ctrough for Sirolimus	Trough Sirolimus Concentration at Steady State (Ctrough)	Predose (0 hour) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24-hour post dose
Ctrough for Everolimus	Trough Everolimus Concentration at Steady State (Ctrough)	Predose (0 hour) on Day 14 and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 12-hour post dose
AUC for Sirolimus	Sirolimus Area Under the Curve from Time Zero to End of Dosing Interval (AUCtau) at Steady State	Predose (0 hour) on Day 14 and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24-hour post dose
AUC for Everolimus	Everolimus Area Under the Curve from Time Zero to End of Dosing Interval (AUCtau) at Steady State	Predose (0 hour) on Day 14 and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 12-hour post dose
CL/F for Sirolimus	Sirolimus Apparent Oral Clearance (CL/F)	Predose (0 hour) on Day 14 and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24-hour post dose
CL/F for for Everolimus	Everolimus Apparent Oral Clearance (CL/F)	Predose (0 hour) on Day 14 and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 12-hour post dose
S6K Activity, in Sirolimus cohorts	Pharmacodynamic parameter, S6K Activity, in Sirolimus cohorts	Predose (0 hour) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24-hour post dose on Day 1 and Day 14
S6K Activity, in Everolimus cohorts	Pharmacodynamic parameter, S6K Activity, in Everolimus cohorts	Predose (0 hour) on Day 14 and 0.5, 1, 1.5, 2.5, 3, 4, 6, and 12-hour post dose on Day 1 and Day 14
Senescence-associated secretory phenotype (SASP) index	Clinical biomarker parameter (SASP) index is a clinical biomarker parameter that measures the level of proteins secreted by senescent cells in the body.	Day 1 Week 1 (Baseline), Week 5, Week 9, Week 13
Erythrocyte sedimentation rate (ESR)	Clinical biomarker parameter (ESR) is a blood test that detects and monitors inflammation in the body.	Day 1 Week 1 (Baseline), Week 5, Week 9, Week 13
C-reactive protein (CRP)	A measure of Clinical biomarker parameter (CRP), is an inflammatory marker.	Day 1 Week 1 (Baseline), Week 5, Week 9, Week 13
6-minute walk test (6MWT)	The 6MWT is simply a record of the distance (in meters) traveled by a given patient at his or her self-selected walking speed over a period of six minutes.	Day 1 Week 1 (Baseline), Week 5, Week 9, Week 13
Short physical performance battery (SPPB)	Clinical biomarker parameter (SPPB) assesses lower extremity function in older adults. The test battery consists of three physical tasks (walking, sit-to-stand and balance) to assess functional mobility. The test will be performed according to standardized procedure. The maximal total score is 12 and higher total scores indicate a better lower extremity functioning.	Day 1 Week 1 (Baseline), Week 5, Week 9, Week 13

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in SASP response at 3 months follow-up	SASP (senescence-associated secretory phenotype) index score is quantified using blood work comparing results at baseline and at 3 months follow-up. Patients with high SASP scores have a poor survival rate, while patients with low SASP scores have a good survival rate.	Baseline, 3 months
Change in Laboratory Biomarker response (ESR) from baseline at 3 months follow-up	Feasibility of collecting the laboratory biomarker - Erythrocyte sedimentation rate (ESR) is assessed by change in blood work readings ((millimeters per hour [mm/hour])) at 3 months follow-up.	Baseline, 3 months
Change in laboratory Biomarker response (CRP) from baseline at 3 months follow-up	Feasibility of collecting the laboratory biomarker- C-Reactive Protein (CRP) is assessed by change in blood work readings (mg/dl) at 3 months follow-up.	Baseline, 3 months
Change in laboratory Biomarker response (S6K activity) from baseline at 3 months follow-up	Feasibility of collecting the laboratory biomarker- S6 Kinase (S6K) activity is assessed by change in blood work readings (mg/dl) at 3 months follow-up.	Baseline, 3 months
Change in laboratory Biomarker response (mitochondrial function) from baseline at 3 months follow-up	Feasibility of collecting the laboratory biomarker (mitochondrial function) is assessed by change in blood work readings at 3 months follow-up. The mitochondrial function will be measured through the Bioenergetic Health Index. The Bioenergetic Health Index (BHI) is calculated using the following formula: BHI=(ATP-linked×reserve capacity)/(proton leak×non-mitochondrial) - as described by Chacko et al. The expected range is 0-100.	Baseline, 3 months
Change in laboratory Biomarker response (metabolomics) from baseline at 3 months follow-up	Feasibility of collecting the laboratory biomarker (metabolomics) is assessed by change in blood work readings at 3 months follow-up. Changes in blood metabolomics are quantified by measuring the concentration levels of individual metabolites within a blood sample using techniques like mass spectrometry (MS) or nuclear magnetic resonance (NMR) spectroscopy, where the relative abundance of each metabolite is compared between different samples, allowing for identification of changes in metabolic pathways based on variations in metabolite levels. The unit of measure is "concentration", usually expressed in micromolar (µM) or millimolar (mM), as it represents the quantity of a specific metabolite per unit volume of the sample.	Baseline, 3 months

Collaborators and Investigators

• Sponsor: University of Texas Southwestern Medical Center
• Collaborators: University of Maryland, Baltimore; National Institute on Aging (NIA)
• Investigators: Principal Investigator: Irina Timofte, MD, MS, University of Texas Southwestern Medical Center

Study record dates

Study Major Dates

• Study Start (Estimated): February 1, 2026
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): November 13, 2027

Study Registration Dates

• First Submitted: November 20, 2024
• First Submitted That Met QC Criteria: December 8, 2024
• First Posted (Actual): December 10, 2024

Study Record Updates

• Last Update Posted (Actual): February 2, 2026
• Last Update Submitted That Met QC Criteria: January 30, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Aging; Disability; Geriatic
• Additional Relevant MeSH Terms: Organic Chemicals; Pharmaceutical Preparations; Dosage Forms; Macrolides; Lactones; Everolimus; Sirolimus; Tablets
• Other Study ID Numbers: STU-2024-0798; 1U01AG081450-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No