Abstract:Resveratrol has emerged as a leading candidate for improving healthspan through potentially slowing the aging process and preventing chronic diseases. The poor bioavailability of resveratrol in humans has been a major concern for translating basic science findings into clinical utility. Although a number of positive findings have emerged from human clinical trials, there remain many conflicting results, which may partially be attributed to the dosing protocols used. A number of theoretical solutions have been developed to improve the bioavailability of resveratrol, including consumption with various foods, micronized powders, combining it with additional phytochemicals, controlled release devices, and nanotechnological formulations. While laboratory models indicate these approaches all have potential to improve bioavailability of resveratrol and optimize its clinical utility, there is surprisingly very little data regarding the bioavailability of resveratrol in humans. If bioavailability is indeed a limitation in the clinical utility of resveratrol, there is a need to further explore methods to optimize bioavailability in humans. This review summarizes the current bioavailability data, focusing on data from humans, and provides suggested directions for future research in this realm.

Body surface area (BSA) scaling has been used for prescribing individualized dosages of various drugs and has also been recommended by the U.S. Food and Drug Administration as one method for using data from animal model species to establish safe starting dosages for first-in-human clinical trials. Although BSA conversion equations have been used in certain clinical applications for decades, recent recommendations to use BSA to derive interspecies equivalents for therapeutic dosages of drug and natural products are inappropriate. A thorough review of the literature reveals that BSA conversions are based on antiquated science and have little justification in current translational medicine compared to more advanced allometric and physiologically based pharmacokinetic modeling. Misunderstood and misinterpreted use of BSA conversions may have disastrous consequences, including underdosing leading to abandonment of potentially efficacious investigational drugs, and unexpected deadly adverse events. We aim to demonstrate that recent recommendations for BSA are not appropriate for animal-to-human dosage conversions and use pharmacokinetic data from resveratrol studies to demonstrate how confusion between the "human equivalent dose" and "pharmacologically active dose" can lead to inappropriate dose recommendations. To optimize drug development, future recommendations for interspecies scaling must be scientifically justified using physiologic, pharmacokinetic, and toxicology data rather than simple BSA conversion.-Blanchard, O. L., Smoliga, J. M. Translating dosages from animal models to human clinical trials-revisiting body surface area scaling. FASEB J. 29, 1629-1634 (2015). www.fasebj.org

Resveratrol provides multiple physiologic benefits which promote healthspan in various model species and clinical trials support continued exploration of resveratrol treatment in humans. However, there remains concern regarding low bioavailability and wide inter-individual differences in absorption and metabolism in humans, which suggests a great need to develop novel methods for resveratrol delivery. We hypothesized that oral transmucosal delivery, using a lozenge composed of a resveratrol-excipient matrix, would allow resveratrol to be absorbed rapidly into the bloodstream. We pursued proof of concept through two experiments. In the first experiment, the solubility of trans-resveratrol (tRES) in water and 2.0 M solutions of dextrose, fructose, ribose, sucrose, and xylitol was determined using HPLC. Independent t-tests with a Bonferroni correction were used to compare the solubility of tRES in each of the solutions to that in water. tRES was significantly more soluble in the ribose solution (p = 0.0013) than in the other four solutions. Given the enhanced solubility of tRES in a ribose solution, a resveratrol-ribose matrix was developed into a lozenge suitable for human consumption. Lozenges were prepared, each containing 146±5.5 mg tRES per 2000 mg of lozenge mass. Two healthy human participants consumed one of the prepared lozenges following an overnight fast. Venipuncture was performed immediately before and 15, 30, 45, and 60 minutes following lozenge administration. Maximal plasma concentrations (C max) for tRES alone (i.e., resveratrol metabolites not included) were 325 and 332 ng⋅mL−1 for the two participants at 15 minute post-administration for both individuals. These results suggest a resveratrol-ribose matrix lozenge can achieve greater C max and enter the bloodstream faster than previously reported dosage forms for gastrointestinal absorption. While this study is limited by small sample size and only one method of resveratrol delivery, it does provide proof of concept to support further exploration of novel delivery methods for resveratrol administration.

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Background: Determination of the first-in-human and pharmacologically active dosage for drugs and nutraceutical compounds is a critical step in study design and product development.  Allometric scaling is a form of mathematic modeling commonly used to convert dosages between species.  While allometric scaling allows for quick and straightforward conversions between species, it is often misunderstood and misused in translational clinical applications.  This is readily demonstrated in the case of resveratrol – a polyphenol which is found in red wine.  In the past decade, a considerable amount of research has emerged regarding the health benefits of the resveratrol supplementation.  Although data from rodent models suggests that resveratrol can have major effects on cardiometabolic and neurologic health, human clinical trials have had mixed results.  While some human clinical trials have yielded encouraging results, a few noteworthy trials have reported that seemingly appropriate allometry-derived dosages of resveratrol did not provide the expected health benefits reported in animal models.Here, we discuss the history of various models within allometry, including their advantages, disadvantages, and nuances from a clinical perspective.  This historical information will provide some insight into why dosages recommended from allometric scaling are appropriate in some circumstances and inappropriate in others.  We will then demonstrate how allometric models have been utilized to translate dosages of resveratrol from rodent models into the dosages recommended for human clinical trials.  Pharmacokinetic data from various human clinical trials will be summarized and compared to data predicted from allometric models.  Data from selected human clinical trials will then synthesized to demonstrate the dosage-dependent effects of resveratrol, and provide further insight into the appropriate use of allometric models for selecting resveratrol dosage.  Together, this information will promote a greater understanding of the role of allometric scaling in dose selection and provide an explanation for some of the apparent inconsistencies in translational research regarding resveratrol.Keywords: allometric scaling, dose conversion, bioavailability, pharmacokinetics, resveratrol