Interpretation of Animal Dose and Human Equivalent Dose for Drug Development

We usually perform animal studies to provide scientific data or to explain the mechanisms of traditional Korean medicines (TKM) based on their demonstrated efficacy in clinical application or as mentioned in old TKM literature. Similarly, we focus on toxic and safety aspects of TKM using preclinical models so as to promote them as effective over the counter (OTC) or ethical drugs. Often a prescribed drug that works well in humans is not as effective in animals as we expected and in many occasions the misinterpretation of allometric translation of dose in toxicological evaluation also creates some critical trouble for starting dose calculation in clinical studies. In addition, doctors or investigators in the TKM field are not always greatly familiar with new drug development; because of resulting misunderstanding of allometric dose conversion and safety factor application, lots of time and money are Objectives: To introduce to TKM scientific dose conversion methods of human to animal or animal to human for new drug investigations. Methods: We searched guidelines of the FDA and KFDA, and compared them with references for drug-dose conversion from various databases such as PubMed and Google. Then, we analyzed the potential issues and problems related to dose conversion in safety documentation of new herbal drugs based on our experiences during Investigational New Drug (IND) applications of TKM. Results: Dose conversion from human to animal or animal to human must be appropriately translated during new drug development. From time to time, investigators have some difficulty in determining the appropriate dose, because of misunderstandings of dose conversion, especially when they estimate starting dose in clinical or animal studies to investigate efficacy, toxicology and mechanisms. Therefore, education of appropriate dose calculation is crucial for investigators. The animal dose should not be extrapolated to humans by a simple conversion method based only on body weight, because many studies suggest the normalization method is based mainly on body surface area (BSA). In general, the body surface area seems to have good correlation among species with several parameters including oxygen utilization, caloric expenditure, basal metabolism, blood volume and circulating plasma protein. Likewise, a safety factor should be taken into consideration when deciding high dose in animal toxicology study. Conclusion: Herein, we explain the significance of dose conversion based on body surface area and starting dose estimation for clinical trials with safety factor.