Pharmacokinetics of icotinib, a novel anti-tumor agent, and its tissue distribution in preclinical species

Objective; To evaluate the pharmacokinetics of icotinib and its tissue distribution in preclinical species. Methods: The pharmacokinetic profiles were characterized in single oral and intravenous doses to rats and dogs as suspension and solution formulations. Tissue distribution was assessed following a single oral dose in rats and the extent of protein binding was determined in rat and human plasma. Biological samples from the in vivo and in vitro studies were analyzed using HPLC-UV and LC/MS/MS methods for the quantification of icotinib. Results: Icotinib declined both in rat and dog systemic circulation, with a terminal t1/2 of 3.23 and 5.6 h and a relatively low clearance of 8.95 and 9.57 mL��min-1��kg-1, respectively. It showed an approximately linear pharmacokinetic profile over the tested dosage range following oral administration. The absolute oral bioavailability of icotinib given as suspension was 51.3% in rats and 27.4% in dogs, respectively, and that given as solution was 62.8% in dogs. The exposure of icotinib was 3 to 5-fold higher in female than in male rats, but no sex difference was found in dogs. Icotinib exhibited high plasma protein binding(>98%) which was concentration and species independent. Tissue distribution studies in rats showed that icotinib distributed to tissues rapidly and extensively. Stomach, intestine and liver showed higher exposure than plasma within 4 h post dose. Conclusion: Icotinib exhibits good pharmacokinetic profile in preclinical species, which supports its development in human.