Phase I - Human Pharmacology

3. Estimation of the First Dose in Humans

Early non-clinical studies should provide sufficient information to support selection of the initial human dose and safe duration of exposure of a new medicine. In general, the No Observed Adverse Effect Level (NOAEL) determined in non-clinical safety studies performed in the most sensitive and relevant animal species, adjusted with allometric factors or on the basis of pharmacokinetics gives the most important information. The relevant dose is then reduced/adjusted by appropriate safety factors.

An additional approach to dose calculation is “The Minimal Anticipated Biological Effect Level” (MABEL). This is the anticipated dose level leading to a minimal biological effect level in humans. When using this approach, potential differences of sensitivity for the mode of action of the investigational medicinal product between humans and animals need to be taken into consideration, e.g., derived from in vitro studies. A safety factor may be applied for the calculation of the first dose in human from MABEL.