Journal Article

A Pilot Randomized, Placebo Controlled, Double Blind Phase I Trial of the Novel SIRT1 Activator SRT2104 in Elderly Volunteers

Hoffman, Ethan, Vlasuk, George P., Dawes, Helen, Jacobson, Eric, Shields, Gregory S., Matthews, Paul M., Pinato, David J., Libri, Vincenzo, Haddad, Jonathan, Brown, Andrew P., Wilkins, Martin R., Gambarota, Giulio, Elliot, Peter J.

2012

Overview

SRT2104 has been developed as a selective small molecule activator of SIRT1, a NAD.sup.+ -dependent deacetylase involved in the regulation of energy homeostasis and the modulation of various metabolic pathways, including glucose metabolism, oxidative stress and lipid metabolism. SIRT1 has been suggested as putative therapeutic target in multiple age-related diseases including type 2 diabetes and dyslipidemias. We report the first clinical trial of SRT2104 in elderly volunteers. Oral doses of 0.5 or 2.0 g SRT2104 or matching placebo were administered once daily for 28 days. Pharmacokinetic samples were collected through 24 hours post-dose on days 1 and 28. Multiple pharmacodynamic endpoints were explored with oral glucose tolerance tests (OGTT), serum lipid profiles, magnetic resonance imaging (MRI) for assessment of whole body visceral and subcutaneous fat, maximal aerobic capacity test and muscle 31P magnetic resonance spectroscopy (MRS) for estimation of mitochondrial oxidative capacity. SRT2104 was generally safe and well tolerated. Pharmacokinetic exposure increased less than dose-proportionally. Mean Tmax was 2-4 hours with elimination half-life of 15-20 hours. Serum cholesterol, LDL levels and triglycerides decreased with treatment. No significant changes in OGTT responses were observed. 31P MRS showed trends for more rapid calculated adenosine diphosphate (ADP) and phosphocreatine (PCr) recoveries after exercise, consistent with increased mitochondrial oxidative phosphorylation. SRT2104 can be safely administered in elderly individuals and has biological effects in humans that are consistent with SIRT1 activation. The results of this study support further development of SRT2104 and may be useful in dose selection for future clinical trials in patients.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adenosine / Adenosine diphosphate / ADP / Aerobic capacity / Age / ATPases / Biological effects / Biology / Cholesterol / Clinical trials / Diabetes / Diabetes mellitus / Diabetes mellitus (non-insulin dependent) / Disease / Double-blind studies / Drug dosages / Elderly / Elderly people / Energy balance / Energy law / Exercise / Family medical history / Geriatrics / Glucose / Glucose metabolism / Glucose tolerance / Glucose tolerance test / Health aspects / Homeostasis / Insulin resistance / Lipid metabolism / Lipids / Lipoproteins (low density) / Liver / Low density lipoprotein / Low density lipoproteins / Magnetic resonance / Magnetic resonance imaging / Magnetic resonance spectroscopy / Medical research / Medicine / Metabolic pathways / Metabolism / Mitochondria / Molecular chains / Muscles / Musculoskeletal system / NAD / Nuclear magnetic resonance spectroscopy / Older people / Oxidative metabolism / Oxidative phosphorylation / Oxidative stress / Pharmaceuticals / Pharmacodynamics / Pharmacokinetics / Pharmacology / Phosphocreatine / Phosphorylation / Physiological aspects / Resonance / Spectroscopy / Studies / Triglycerides / Type 2 diabetes / Weight control