Predicted values for human total clearance of a variety of typical compounds with differently humanized-liver mouse plasma data

• Published in: Drug metabolism and pharmacokinetics 2020-08, Vol.35 (4), p.389-396
• Main Authors: Nakayama, Keigo, Kamimura, Hidetaka, Suemizu, Hiroshi, Yoneda, Nao, Nishiwaki, Megumi, Iwamoto, Kazuhiko, Mizunaga, Mari, Negoro, Tamotsu, Ito, Soichiro, Yamazaki, Hiroshi, Nomura, Yukihiro
• Format: Article
• Language: English
• Subjects: Acetamides - blood; Acetamides - pharmacokinetics; Albuterol - blood; Albuterol - pharmacokinetics; Animals; Carbamates - blood; Carbamates - pharmacokinetics; Chimeric mice with humanized liver; Chromatography, Liquid; Diazepam - blood; Diazepam - pharmacokinetics; Diclofenac - blood; Diclofenac - pharmacokinetics; Digitoxin - blood; Digitoxin - pharmacokinetics; Humans; Itraconazole - blood; Itraconazole - pharmacokinetics; Ketoprofen - blood; Ketoprofen - pharmacokinetics; Liver - chemistry; Liver - metabolism; Metabolic Clearance Rate; Mice; Mice, Transgenic; Naproxen - blood; Naproxen - pharmacokinetics; Pharmaceutical Preparations - blood; Pharmaceutical Preparations - metabolism; Phenytoin - blood; Phenytoin - pharmacokinetics; Physiological methods; Piperidines - blood; Piperidines - pharmacokinetics; Pravastatin - blood; Pravastatin - pharmacokinetics; Pyrimidines - blood; Pyrimidines - pharmacokinetics; Quinidine - blood; Quinidine - pharmacokinetics; Single-species allometry; Tandem Mass Spectrometry; Telmisartan - blood; Telmisartan - pharmacokinetics; Terfenadine - analogs & derivatives; Terfenadine - blood; Terfenadine - pharmacokinetics; Unbound fraction; Verapamil - blood; Verapamil - pharmacokinetics
• ISSN: 1347-4367; 1880-0920
• DOI: 10.1016/j.dmpk.2020.05.004

Prediction of human pharmacokinetics is important in the preclinical stage. Values for total clearance of compounds from plasma should be one of the most important pharmacokinetic parameters for predictions. Although several physiological and empirical methods including single-species allometry for prediction of values for human clearance of compounds using humanized-liver mice have been reported, further improvement of prediction accuracies would be still expected. To optimize these approaches, we proposed methods for unbound intrinsic clearance in virtually 100% humanized-liver mouse by incorporating unbound plasma fractions of compounds in differently humanized-liver mice. Comparisons of prediction accuracies of values for human clearance of 15 model compounds were performed among our current physiological and previously reported models and single-species allometry using humanized-liver mice. Incorporation of the actual unbound plasma fractions of compounds and correction of residual mice hepatocyte in humanized-liver mice showed comparable prediction accuracy to that by single-species allometry. After exclusion of 3 compounds with large species differences in values of clearance and unbound plasma fractions between mice and humans out of 15 compounds, prediction accuracies were improved in the methods investigated. The previously and present reported physiological methods could show the good prediction accuracy of values for clearance of drugs from plasma. [Display omitted]