A Study on the Starting Dose in the First-in-human Study for New Drugs Approved in Japan

Abstract

It is necessary to set a first-in-human dose (FHD) cautiously in the development of new drugs, but relevant information available at the time is limited. We evaluated the safety factors applied in setting the FHD for new drugs approved in Japan between 2009 and 2018 by calculating the human-equivalent-dose (HED) based on the no-observed-adverse-effect level (NOAEL) in the repeated dose toxicity study. We also calculated the HED based on the clearance (CL) and investigated the relationship between the HED and the approved dose. For most drugs investigated in this study, the safety factor was greater than 10, a figure recommended by the US Food and Drug Administration guidance document. This suggested that the starting dose had been determined very cautiously in the past first-in-human studies. In most drugs, the FHD, calculated by applying a safety factor of 10 to the HED obtained from either NOAEL or CL, was lower than the approved dose, which suggested that it was possible to set a FHD lower than the approved dose in most cases by applying a safety factor of 10 to the HED.