Preclinical pharmacokinetics, disposition, and translational pharmacokinetic/pharmacodynamic modeling of savolitinib, a novel selective cMet inhibitor.

Preclinical pharmacokinetics, disposition, and translational pharmacokinetic/pharmacodynamic modeling of savolitinib, a novel selective cMet inhibitor. Eur J Pharm Sci. 2019 May 24;: Authors: Gu Y, Sai Y, Wang J, Yu M, Wang G, Zhang L, Ren H, Fan S, Ren Y, Qing W, Su W Abstract Savolitinib is a novel small-molecule selective cMet inhibitor. This work characterized its pharmacokinetics in preclinical phase, established the preclinical relationships between PK, cMet modulation and anti-tumor efficacy. In vitro and in vivo animal studies were performed for PK characterization. Savolitinib showed good absorption, moderate tissue distribution, low to intermediate clearance, and low accumulation. Hepatic oxidative metabolism followed by urinary and biliary excretions was the major elimination pathway. Based on preclinical PK data, human PK profiles were predicted using empirical methods. Pharmacodynamic studies for evaluating cMet inhibition and anti-tumor efficacy were conducted in nude mice bearing Hs746t xenograft. PK/PD models were built to link the PD measurements to nude mouse PK. The established integrated preclinical PK/PD model contained a two-compartment non-linear PK model, a biomarker link model and a tumor growth transit model. The IC50 of cMet inhibition and the concentration achieving half of the maximal Hs746t tumor reduction by savolitinib were equal to 12.5 and 3.7 nM (free drug), respectively. Based on the predicted hu...
Source: European Journal of Pharmaceutical Sciences - Category: Drugs & Pharmacology Authors: Tags: Eur J Pharm Sci Source Type: research