Dose translation between laboratory animals and human in preclinical and clinical phases of drug development

Abstract

Preclinical Research & Development Appropriate translation and determination of the maximum recommended starting dose in human is a vital task in new drug development and research. Allometric scaling is the most frequently used approach for dose extrapolation based on normalization of dose‐to‐body surface area. Misinterpretation of allometric dose conversion and safety factor application can lead to major problems in calculating maximum recommended safe starting dose in first‐in‐human clinical trials. Therefore, dose translation always necessitates careful consideration of body surface area, pharmacological, physiological and anatomical factors, pharmacokinetic parameters, metabolic function, receptor, and life span. The concept of estimating the first‐in‐human dose, interspecies scaling between species and the factors influencing the dose escalation were reviewed. The pros and cons of various approaches to determine first‐in‐human dose including allometric scaling, pharmacokinetically guided approach, minimal anticipated biological effect level, pharmacokinetic–pharmacodynamic modeling, similar drug approach, and microdosing were explained. The five steps to estimate maximum recommended starting dose for human studies by scaling factor were elaborated. Few examples, illustrating the application of different approaches were also demonstrated along with concerns that may be considered while applying such methods. Furthermore, typical considerations in dose administration, dosing through diet, maximum absorbable dose, blood sampling, and anesthesia in animal species were discussed. In summary, this review may serve as a concise guide for predicting human equivalent dose from animal species for researchers involved in various phases of preclinical and early clinical drug development.

Monounsaturated Fatty Acids in a High‐Fat Diet and Niacin Protect from White Fat Dysfunction in the Metabolic Syndrome

“…From the expected water consumption of the C57BL/6J strain, the selected dose for animals was comparable to a human equivalent dose (HED) of 25 mg kg −1 . This HED value had a close similarity to a pharmacological niacin dose of 1500 mg per day for an adult human of 60 kg.…”

A lupine (Lupinus angustifolious L.) peptide prevents non-alcoholic fatty liver disease in high-fat-diet-induced obese mice

“…29 These selected doses for animals were comparable to human equivalent doses (HED) of 40 and 80 µg kg −1 . 30 RNA isolation and real-time quantitative PCR analysis RNA from hepatic tissues was isolated to quantify gene expression by RT-qPCR. Total RNA was extracted by using TRIsure Reagent (Bioline).…”

Pharmacokinetics and Safety of Mitragynine in Beagle Dogs

“…Estimation of a first-in-human dose is an essential element in the clinical development of a drug for approval by the FDA [22]. Research and development of a drug must be demonstrated in more than one animal species in order to predict human pharmacokinetics [23,24]. The objective of this study was to investigate the pharmacokinetics and bioavailability of mitragynine in healthy female beagle dogs after single oral and intravenous administration.…”