The objective of RAP PAC is to identify safe and effective weekly dose(s) for the mTOR inhibitors sirolimus and everolimus that intervene on the underlying fundamental biology of aging. Participants who are 55-89 years old that are free of overt chronic diseases will be assigned to either 6 weeks of sirolimus or everolimus (5 mg, 10 mg, or 15 mg once per week). The investigators will complete the everolimus arm first and then subsequently complete the sirolimus arm of the study. Total time on study would be up to 17 weeks to complete baseline and follow up visits.
The mTOR inhibitor rapamycin and rapamycin analogs (rapalogs) extend healthspan and/or lifespan in multiple model systems. However, the risk of adverse events and dose limiting toxicities in humans have thus far precluded the long-term prophylactic use of mTOR inhibitors as a therapy for aging and age-related diseases. The pharmacokinetics and pharmacodynamics (PK/PD) data for mTOR inhibitors in older adults is currently unknown and has prevented the identification of a safe dosage that could maximize health-span extension and minimize adverse effects. RAP PAC will identify a recommended phase 2 trial dose for sirolimus and everolimus in older men and women by performing a phase 1, dose finding study that evaluates PK/PD, safety and tolerability, and mTOR signaling using conventional as well as novel approaches. Overall, the investigators will pair comprehensive molecular and pharmacologic approaches to evaluate PK/PD in humans and identify dosing regimens that safely inhibit mTOR complex 1 (mTORC1) to intervene in the biology of aging.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
72
5mg, 10mg, or 15mg once weekly sirolimus
5mg, 10mg, or 15mg once weekly everolimus
University of Wisconsin
Madison, Wisconsin, United States
RECRUITINGDose Limited Toxicities (DLTs)
A recommended phase 2 dose (RP2D) will be determined through evaluating dose limiting toxicities (DLT), which is defined as ≥Grade 2 adverse event following CTCAE v6.0.
Time frame: Through study completion, an average 3 years
Time course of drug concentration in blood
Using PK parameters of Peak Plasma Concentration (Cmax, Cmin), determine duration of concentration of drug in blood measured pre dose, and 0.5, 1.5, 4, 48, and 168 hours post dose
Time frame: First dose to 168 hours post dose
Time course of drug concentration in blood
Using PK parameters of Area under the plasma concentration versus time curve (AUC, T1/2), determine duration of concentration of drug in blood measured pre dose, and 0.5, 1.5, 4, 48, and 168 hours post dose
Time frame: First dose to 168 hours post dose
Change in mTOR signaling in blood and muscle
To be evaluated through immunoblotting and immunoprecipitation
Time frame: 0 (pre-intervention) and 6 weeks (post-intervention)
Change in concentration of metabollites
Metabolomics: Change in concentration of blood and/or skeletal muscle metabolites as assessed by liquid chromatography mass spectrometry
Time frame: 0 (pre-intervention) and 6 weeks (post-intervention)
Change in concentration of lipid species
Lipidomics: Change in the concentration of lipid species in blood and/or skeletal muscle as assessed by liquid chromatography mass spectrometry
Time frame: 0 (pre-intervention) and 6 weeks (post-intervention)
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Change in transcriptome
Change in skeletal muscle and whole blood transcripts assessed via RNA sequencing
Time frame: 0 (pre-intervention) and 6 weeks (post-intervention)
Change in glucose tolerance
Assess change in glucose tolerance by area under the curve
Time frame: 0 (pre-intervention) and 6 weeks (post-intervention)
Change in whole body insulin sensitivity
Insulin sensitivity as assessed by the Matsuda Index.
Time frame: 0 (pre-intervention) and 6 weeks (post-intervention)
Change in glucose variability
Glucose Variability will be assessed via continuous glucose monitoring during two occasions during weeks 0, and 6 by measuring the change in range.
Time frame: 0 (pre-intervention) and 6 weeks (post-intervention)
Change in glucose variability
Glucose Variability will be assessed via continuous glucose monitoring during two occasions during weeks 0, and 6 by measuring the change in total standard deviation.
Time frame: 0 (pre-intervention) and 6 weeks (post-intervention)
Change in glucose variability
Glucose Variability will be assessed via continuous glucose monitoring during two occasions during weeks 0, and 6 by measuring the change in mean daily differences (MODD).
Time frame: 0 (pre-intervention) and 6 weeks (post-intervention)
Change in glucose variability
Glucose Variability will be assessed via continuous glucose monitoring during two occasions during weeks 0, and 6 by measuring the change in the overall net glycemic action over a 4-h and 8-h period (CONGA4; CONGA8).
Time frame: 0 (pre-intervention) and 6 weeks (post-intervention)
Change in insulin resistance
Measured by change in homeostatic model of insulin resistance (HOMA-IR).
Time frame: 0 (pre-intervention) and 6 weeks (post-intervention)