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

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Abstract

Background: SRT2104 has been developed as a selective small molecule activator of SIRT1, a NAD+-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. Methods: 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. Results: 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. Conclusions: 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. Trial Registration: ClinicalTrials.gov NCT00964340. © 2012 Libri et al.

Figures

  • Figure 1. CONSORT 2010 Flow Diagram. The schema graphically outlines the design and conduct of the clinical study. doi:10.1371/journal.pone.0051395.g001
  • Table 1. Summary of subject demographics at screening.
  • Table 2. Incidence of all treatment-emergent adverse events by subject treatment group.
  • Table 2. Cont.
  • Table 3. Summary of derived SRT2104 pharmacokinetic parameters by dose level.
  • Table 4. Summary of Statistical Analysis of SRT2104 Pharmacokinetic Data: Day 28 vs Day 1.
  • Table 5. Summary of Statistical Analysis of SRT2104 Pharmacokinetic Data: Dose Proportionality.
  • Figure 3. Lipid profile at baseline and after 28 days treatment with placebo and SRT2104 (0.5 g/day and 2.0 g/day). [Black dots indicate points that are two interquartile ranges outside the means; * P,0.05 and ** P,0.001 at day 28 relative to baseline.] doi:10.1371/journal.pone.0051395.g003

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Libri, V., Brown, A. P., Gambarota, G., Haddad, J., Shields, G. S., Dawes, H., … Matthews, P. M. (2012). A Pilot Randomized, Placebo Controlled, Double Blind Phase I Trial of the Novel SIRT1 Activator SRT2104 in Elderly Volunteers. PLoS ONE, 7(12). https://doi.org/10.1371/journal.pone.0051395

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