title: Bridging from preclinical to clinical studies for tyrosine kinase inhibitors based on pharmacokinetics/pharmacodynamics and toxicokinetics/toxicodynamics.
abstract: The purpose of this study was to provide a pharmacokinetics/pharmacodynamics and toxicokinetics/toxicodynamics bridging of kinase inhibitors by identifying the relationship between their clinical and preclinical (rat, dog, and monkey) data on exposure and efficacy/toxicity. For the eight kinase inhibitors approved in Japan (imatinib, gefitinib, erlotinib, sorafenib, sunitinib, nilotinib, dasatinib, and lapatinib), the human unbound area under the concentration-time curve at steady state (AUC(ss,u)) at the clinical dose correlated well with animal AUC(ss,u) at the no-observed-adverse-effect level (NOAEL) or maximum tolerated dose (MTD). The best correlation was observed for rat AUC(ss,u) at the MTD (p < 0.001). E(max) model analysis was performed using the efficacy of each drug in xenograft mice, and the efficacy at the human AUC of the clinical dose was evaluated. The predicted efficacy at the human AUC of the clinical dose varied from far below E(max) to around E(max) even in the tumor for which use of the drugs had been accepted. These results suggest that rat AUC(ss,u) at the MTD, but not the efficacy in xenograft mice, may be a useful parameter to estimate the human clinical dose of kinase inhibitors, which seems to be currently determined by toxicity rather than efficacy.
authors: Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo, Japan.
authors: Azusa
authors: A
authors: Hoshino-Yoshino
authors: Motohiro
authors: M
authors: Kato
authors: Kohnosuke
authors: K
authors: Nakano
authors: Masaki
authors: M
authors: Ishigai
authors: Toshiyuki
authors: T
authors: Kudo
authors: Kiyomi
authors: K
authors: Ito
mesh_terms: D000818:Animals; D019540:Area Under Curve; D035843:Biomedical Research / Q000379:methods; D002986:Clinical Trials as Topic / Q000379:methods; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods; D000882:Haplorhini; D006801:Humans; D007564:Japan; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051381:Rats
chemical_list: D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases