Safety and pharmacokinetics of a highly bioavailable resveratrol preparation (JOTROL TM)

Resveratrol exhibits a wide range of biological properties, including anti-glycation, antioxidant, anti-inflammation, neuroprotective (including against advanced dementia and Alzheimer’s disease), anti-cancer, and anti-aging activity in experimental models. Unfortunately, this compound exhibits low bioavailability and solubility, requiring large doses that can cause nausea and GI distress. JOTROL^TM is a micellar 10% resveratrol solubilization formulation that is thought to increase bioavailability of resveratrol via lymphatic system absorption. Jupiter Neurosciences (formerly Jupiter Orphan Therapeutics;  “Jupiter”) is pursuing the use of resveratrol in mucopolysaccharidosis type 1 (MPS 1), Friedreich’s Ataxia, and Alzheimer’s Disease/Mild Cognitive Impairment.

This paper describes a first in human study (FIH) to evaluate the bioavailability of resveratrol after ascending, single oral doses up to 700 mg resveratrol as JOTROL^TM. After a single 500 mg dose of JOTROL^TM, a Cmax of 455 ng/mL was observed, vs. 85 ng/mL Cmax after a 1g encapsulated dose[2]and 1942 ng/mL after a 2.5 g micronized dose[3]. In this study, resveratrol exposures (AUCs and Cmax) increased with increasing doses. This increase appears to be higher than dose-proportional for AUC_0-t and Cmax. Resveratrol and its three major conjugates accounted for 40 to 55% of the dose in urine, consistent with a high extent of absorption, but <1% of drug related material was intact relative to key metabolites in plasma and urine. Studies in Alzheimer’s patients and in MPS 1 are currently in development to test the effect this improved bioavailability has on those patient populations. (Clintrials.gov, NCT04668274, 12/16/2020, https://clinicaltrials.gov/ct2/show/NCT04668274).