抄録
We conducted a retrospective study to review the no-observed-adverse-effect levels (NOAEL) in nonclinical studies and the first-human-doses (FHD) in first-in-human (FIH) studies, and to investigate the safety factors used in past FIH studies. In addition, we examined several potential factors that may influence the dose setting. Ethical drugs containing a new chemical entity approved in Japan from 2008 to 2012 were included in the present study. A human-equivalent dose of NOAEL (NHD) was calculated from NOAEL obtained from toxicity studies, based on the body surface area. The ratio of NHD to FHD was defined as the “FHD index” in this study, which was a synonym of safety factor based on body surface area. Drugs in the following categories were excluded from the study: biopharmaceuticals, derivatives of existing drug (including prodrug, active metabolite, and optical isomer), historically established medicines, combination drugs, topical application drugs, and general anaesthesia and relative medicines. In many therapeutic areas other than oncology, the safety factor to determine the starting dose in FIH studies was greater than 10, which was recommended by FDA guidance document. This finding suggested that the starting doses had been determined very prudently in past FIH studies. No apparent differences in FHD index were observed with respect to administration route (oral versus injection), subject population in FIH study (Japanese versus non-Japanese), and the most sensitive species in toxicity studies. No apparent relationship between the FHD index and the quantity of species-difference in NOAEL was identified in this study.
