MTOR Inhibitors in Older Adults

Официальное название

Characterization of mTOR Inhibitor Pharmacokinetics and Pharmacodynamics in Older Adults .

Обзор

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

Подробное описание

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

Вмешательства

• Препарат 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.
• Препарат 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.
• Препарат 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.
• Препарат 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.
• Препарат 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.
• Препарат 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.

Первичные конечные точки

• Cmax for Sirolimus [Срок оценки: 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 [Срок оценки: Predose (0 hour) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 12-hour post dose]
• Ctrough for Sirolimus [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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]

Вторичные конечные точки (6)

• Change in SASP response at 3 months follow-up [Срок оценки: Baseline, 3 months]
• Change in Laboratory Biomarker response (ESR) from baseline at 3 months follow-up [Срок оценки: Baseline, 3 months]
• Change in laboratory Biomarker response (CRP) from baseline at 3 months follow-up [Срок оценки: Baseline, 3 months]
• Change in laboratory Biomarker response (S6K activity) from baseline at 3 months follow-up [Срок оценки: Baseline, 3 months]
• Change in laboratory Biomarker response (mitochondrial function) from baseline at 3 months follow-up [Срок оценки: Baseline, 3 months]
• Change in laboratory Biomarker response (metabolomics) from baseline at 3 months follow-up [Срок оценки: Baseline, 3 months]

Критерии участия

Критерии включения

• Community-dwelling adults
• Patients should be 65 Years and older
• Patients is able to understand and follow trial procedures

Критерии исключения

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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Профилактика

Центры проведения

США · 1 центр

• UT Southwestern Medical Center — Dallas

Идентификаторы

NCT: NCT06727305 · STU-2024-0798 · 1U01AG081450-01A1

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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