Characterization of mTOR Inhibitor Pharmacokinetics and Pharmacodynamics in Older Adults .
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Cmax for Sirolimus
研究概览
简要总结
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
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 年龄范围
- 65 Years 至 80 Years（Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Community-dwelling adults
- •Patients should be 65 Years and older
- •Patients is able to understand and follow trial procedures
排除标准
- •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.
研究组 & 干预措施
sirolimus 1 mg Arm
Participant would receive 1 mg of sirolimus.
干预措施: Sirolimus 1Mg Oral Tablet (Drug)
sirolimus 2 mg Arm
Participant would receive 2 mg of sirolimus.
干预措施: Sirolimus 2 MG Oral Tablet (Drug)
everolimus 0.5 mg Arm
Participant would receive 0.5 mg of Everolimus.
干预措施: Everolimus 0.5 MG Oral Tablet (Drug)
everolimus 1 mg Arm
Participant would receive 1 mg of Everolimus.
干预措施: Everolimus 1 MG Oral Tablet (Drug)
everolimus 2 mg Arm
Participant would receive 2 mg of Everolimus.
干预措施: Everolimus 2 MG Oral Tablet (Drug)
sirolimus 0.5 mg Arm
Participant would receive 0.5 mg of sirolimus.
干预措施: Sirolimus 0.5 Mg Oral Tablet (Drug)
结局指标
主要结局
Cmax for Sirolimus
时间窗: Predose (0 hour) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24-hour post dose
Maximum Sirolimus Concentration at Steady State (Cmax)
Cmax for Everolimus
时间窗: Predose (0 hour) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 12-hour post dose
Maximum Everolimus Concentration at Steady State (Cmax)
Ctrough for Sirolimus
时间窗: Predose (0 hour) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24-hour post dose
Trough Sirolimus Concentration at Steady State (Ctrough)
Ctrough for Everolimus
时间窗: Predose (0 hour) on Day 14 and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 12-hour post dose
Trough Everolimus Concentration at Steady State (Ctrough)
AUC for Sirolimus
时间窗: 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
Sirolimus Area Under the Curve from Time Zero to End of Dosing Interval (AUCtau) at Steady State
AUC for Everolimus
时间窗: Predose (0 hour) on Day 14 and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 12-hour post dose
Everolimus Area Under the Curve from Time Zero to End of Dosing Interval (AUCtau) at Steady State
CL/F for Sirolimus
时间窗: 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
Sirolimus Apparent Oral Clearance (CL/F)
CL/F for for Everolimus
时间窗: Predose (0 hour) on Day 14 and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 12-hour post dose
Everolimus Apparent Oral Clearance (CL/F)
S6K Activity, in Sirolimus cohorts
时间窗: 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
Pharmacodynamic parameter, S6K Activity, in Sirolimus cohorts
S6K Activity, in Everolimus cohorts
时间窗: 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
Pharmacodynamic parameter, S6K Activity, in Everolimus cohorts
Senescence-associated secretory phenotype (SASP) index
时间窗: Day 1 Week 1 (Baseline), Week 5, Week 9, Week 13
Clinical biomarker parameter (SASP) index is a clinical biomarker parameter that measures the level of proteins secreted by senescent cells in the body.
Erythrocyte sedimentation rate (ESR)
时间窗: Day 1 Week 1 (Baseline), Week 5, Week 9, Week 13
Clinical biomarker parameter (ESR) is a blood test that detects and monitors inflammation in the body.
C-reactive protein (CRP)
时间窗: Day 1 Week 1 (Baseline), Week 5, Week 9, Week 13
A measure of Clinical biomarker parameter (CRP), is an inflammatory marker.
6-minute walk test (6MWT)
时间窗: Day 1 Week 1 (Baseline), Week 5, Week 9, Week 13
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.
Short physical performance battery (SPPB)
时间窗: Day 1 Week 1 (Baseline), Week 5, Week 9, Week 13
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.
次要结局
- Change in SASP response at 3 months follow-up(Baseline, 3 months)
- Change in Laboratory Biomarker response (ESR) from baseline at 3 months follow-up(Baseline, 3 months)
- Change in laboratory Biomarker response (CRP) from baseline at 3 months follow-up(Baseline, 3 months)
- Change in laboratory Biomarker response (S6K activity) from baseline at 3 months follow-up(Baseline, 3 months)
- Change in laboratory Biomarker response (mitochondrial function) from baseline at 3 months follow-up(Baseline, 3 months)
- Change in laboratory Biomarker response (metabolomics) from baseline at 3 months follow-up(Baseline, 3 months)
研究者
Irina Timofte
Associate Professor
University of Texas Southwestern Medical Center