Microdose (MD) clinical study for antibody pharmaceuticals has not been defined by any guidance. The exploratory investigational new drug application (IND) guidance published in 2006 by the Food and Drug Administration (FDA) defined MD for protein products as less than 1/100^th of the therapeutic range or 30 nanomoles. In Japanese domestic guidances for MD studies (2008) including ICH-M3R2, definition of MD is provided for low molecular weight compounds but not for biologics. In this study, we examined retrospectively the starting dose in first-in-human (FIH) clinical trials of antibody pharmaceuticals.

We studied 52 antibody agents listed in the website of National Institute of Health Sciences as of October 2018, which were approved in Japan. We searched the online databases including the Pharmaceuticals and Medical Devices Agency (PMDA) website and reviewed the information from package inserts, interview forms, and review reports.

We defined the lowest approved therapeutic dose as minimum clinical dose (MIN), and the smallest starting dose used in clinical trials as first human dose (FHD). In 45 of 52 agents, FHD was greater than 1/100^th of MIN. FHD was less than 100 micrograms in 3 agents. Also, FHD was approximately 30 nanomoles in 10 agents and exceeding 30 nanomoles in 38 agents.

FHD is usually selected assuming to be just below the lower limit of the therapeutic range. The MD is expected to be lower than the dose expected not to exert any pharmacological actions. One hundred microgram or 30 nanomole appears to be low enough as MD for antibody pharmaceuticals, and may be set as one of the starting doses for clinical trials.

In clinical bioequivalence studies (BES) of generic products (GE), area under the curve (AUC) is the representative parameter for evaluating bioequivalence. The mean values of AUC are frequently different between original products (OP) and standard products (SP) used as references in BES for GE, and also different among SP. We investigated the differences in AUC between the OP of montelukast (Singulair^®) chewable tablet and each of the SP used in 25 BES of GE containing montelukast, and the differences in AUC among the SP. The ratios of AUC for SP to that for OP ranged from 1.15 to 1.69. The half-lives of OP, SP and intravenous administration were approximately 5.0 hours. The differences in AUC between OP and SP may be caused by racial differences in absorption because the half-lives are almost the same. The differences and distribution of AUC for SP relative to the data for OP were analyzed using a meta-analysis method. Standardized mean difference was 0.55 (95％ confidence interval: 0.33, 0.77). The AUC for SP were significantly larger than the minimum value in 11 of 13 BSE. On the other hand, absolute bioavailability (F) was 72.5 and 77.4％ for OP, and mean F (range) was 97.7 (77.9-113.9％) for SP, with a difference of approximately 20％ between OP and SP. From our results, better methods of assessment in BES should be proposed because of the large variation in AUC for SP.