Allometric scaling models: history, use, and misuse in translating resveratrol from basic science to human clinical applications

Abstract

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