Predicting Method for the Human Plasma Concentration–Time Profile of a Monoclonal Antibody from the Half-life of Non-human Primates

• Published in: Biological & pharmaceutical bulletin Vol. 43; no. 5; pp. 823 - 830
• Main Authors: Nakamura, Genki, Ozeki, Kazuhisa, Nagayasu, Miho, Nambu, Takeru, Nemoto, Takayuki, Hosoya, Ken-ichi
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01.05.2020; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: Administration, Intravenous; Animal welfare; Animals; Antibodies, Monoclonal - blood; Antibodies, Monoclonal - pharmacokinetics; clinical pharmacokinetics; Drug development; Drug Evaluation, Preclinical; Half-Life; Humans; Intravenous administration; Macaca fascicularis; Macaca mulatta; Models, Biological; Monoclonal antibodies; monoclonal antibody; Pharmacokinetics; Plasma; preclinical pharmacokinetics; simulation; clinical pharmacokinetics; monoclonal antibody; simulation; preclinical pharmacokinetics
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b19-01042

Efficiency (speed and cost) and animal welfare are important factors in the development of new drugs. A novel method (the half-life method) was developed to predict the human plasma concentration–time profile of a monoclonal antibody (mAb) after intravenous (i.v.) administration using less data compared to the conventional approach; moreover, predicted results were comparable to conventional method. This new method use human geometric means of pharmacokinetics (PK) parameters and the non-human primates (NHP) half-life of each mAb. PK data on mAbs in humans and NHPs were collected from literature focusing on linear elimination, and the two-compartment model was used for analysis. The following features were revealed in humans: 1) the coefficient of variation in the distribution volume of the central compartment and at steady state of mAbs was small (22.6 and 23.8%, respectively) and 2) half-life at the elimination phase (t1/2β) was the main contributor to plasma clearance. Moreover, distribution volume showed no significant correlation between humans and NHPs, and human t1/2β showed a good correlation with allometrically scaled t1/2β of NHP. Based on the features revealed in this study, we propose a new method for predicting the human plasma concentration–time profile of mAbs after i.v. dosing. When tested, this half-life method showed reasonable human prediction compared with a conventional empirical approach. The half-life method only requires t1/2β to predict human PK, and is therefore able to improve animal welfare and potentially accelerate the drug development process.