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

Abstract

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 (Galiniak et al., Acta Biochim Pol 66:13-21, 2019). Unfortunately, this compound exhibits low bioavailability and solubility (Galiniak et al., Acta Biochim Pol 66:13-21, 2019), requiring large doses that can cause nausea and GI distress. JOTROLTM 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 JOTROLTM. After a single 500 mg dose of JOTROLTM, a Cmax of 455 ng/mL was observed, vs. 85 ng/mL Cmax after a 1 g encapsulated dose (Turner et al., Neurology 85:1383-91, 2015) and 1942 ng/mL after a 2.5 g micronized dose (Howells et al., Cancer Prev Res (Phila) 4:1419-1425, 2011). In this study, resveratrol exposures (AUCs and Cmax) increased with increasing doses. This increase appears to be higher than dose-proportional for AUC0-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://ichgcp.net/clinical-trials-registry/NCT04668274).

Supplementary information: The online version contains supplementary material available at 10.1186/s41120-022-00058-1.

Keywords: Bioavailability; JOTROLTM; Neuroinflammation; Pharmacokinetics; Resveratrol.

Conflict of interest statement

Competing interestsCK is a paid consultant of Jupiter Neurosciences (Jupiter). DBenham is a principle of the company which has licensed technology to Jupiter but has no direct remunerative relationship with Jupiter. Aquanova owns no equity but does have unexecuted stock options. SB and CW are Jupiter founders and have an equity position in the company. They are also paid consultants of Jupiter. Both hold unexecuted stock options. CV is a paid consultant of Jupiter and has unexecuted stock options. DBennett has no direct financial relationship with Jupiter other than as a paid employee of Syneos Health, the CRO for the PK study. MH is a founder, employee, and member of the board of directors of Jupiter, has an equity position in Jupiter, is remunerated per an employment contract, and holds unexecuted stock options.

© The Author(s) 2022.

Figures

Fig. 1

Resveratrol or 3,5,4′-stilbenotriol

Fig. 2

Log-linear concentration (ng/mL) vs. time plots of Resveratrol (RES) and its metabolites Resveratrol Sulfate (3S_RES), Resveratrol 3-Glucuronide (3G_RES) and Resveratrol 4-Glucuronide (4G_RES) in Human Plasma

Fig. 3

Column plots of Cmax (ng/mL), AUC (ng.hr/mL), amount (Ae0-t (ng) ) and fraction collected in urine of RES, 3_RES, 3S_RES, and 4G_RES