Human dose extrapolation Suggest an improvement to this article

Animal models used widely in biomedical research to predict toxicity, safety, and efficacy of interventions in humans (including drugs, nutritional components, and bioactive compounds) are complicated by differences in xenobiotic or drug metabolism between animals and humans.

These differences arise from physiological, anatomical, metabolic, life span, and genetic diversity between species. Among the more straightforward is the simple fact that larger animals, such as humans, generally require smaller drug doses than a strict weight basis would predict due to differences in body surface area.

Body surface area

A simple empirical approach called allometric scaling allows a dose to be scaled and normalized based on differences in body surface area to extrapolate doses from animal science to human research, resulting in a correction factor that is unique to the species.

For example:

• 10 milligrams (mg) per kilogram (kg) body weight dose in rats is divided by a correction factor of 6.2, resulting in a 1.62 mg/kg body weight approximation in humans for the same drug or compound.
• Similarly, a 10 mg/kg body weight dose in mice is divided by a correction factor of 12.3, resulting in a 0.821 mg/kg body weight approximation in humans.

In the open access paper "A simple practice guide for dose conversion between animals and human," authors Anroop B. Nair and Shery Jacob highlight several key points that should be understood about this approach of allometric scaling for calculating human doses from animal research:

• Larger animals have lower metabolic rates
• Physiological processes of larger animals are slower
• Larger animals require smaller relative drug doses, based on weight
• Allometry accounts for the difference in physiological time among species
• Allometric scaling should not be applied to scaling adult doses to children

The U.S. Food and Drug Administration (FDA) has established guidelines for determining doses for humans – referred to as the human equivalent dose – in clinical trials. The process involves determining the no observed adverse effect level (NOAEL) in a particular animal species and then converting the NOAEL to the human equivalent dose based on body surface area.

This table (adapted by Nair and Jacob) presents the factors used in converting a known dose for commonly used research animals to a human equivalent dose.

For more information about determining human equivalent doses, please see these resources:

• A simple practice guide for dose conversion between animals and human.

• Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers.

• Design and Conduct Considerations for First‐in‐Human Trials