Film-coated Tablets And Toxicological Study Of Piroxantinib（PN17-1）,a New Generation Tyrosine Kinase C-KIT Inhibitor

PN17-1 is a new class of antitumor drug candidates obtained by skeleton leap to obtain a new parent nucleus structure based on the structure of imatinib.PN17-1 is a new generation tyrosine kinase inhibitor targeting the c-KIT mutant target and is mainly used for the treatment of drug-resistant gastrointestinal mesenchymal tumors（GIST）.Preliminary pharmacological results show that PN17-1 significantly inhibits the kinase activity of GIST1219,Ba/F3-TEL-KIT cells and c-KIT mutants.Currently,PN17-1 is in the preclinical research and development stage.In this study,the physicochemical properties of PN17-1,film-coated formulation,and pharmacokinetic,tissue distribution and some toxicological studies of PN17-1 were conducted.In this paper,pre-prescription physicochemical properties,and in vitro analytical method establishment studies were conducted to determine the analytical method of PN17-1.The prescription of PN17-1 was determined based on its physicochemical properties,the results of the single-factor study and the results of the orthogonal design,and its dosage form was a film-coated tablet.In this paper,quality studies were conducted on the raw materials and film-coated tablets of piconitinib（PN17-1）,and the quality standard of PN17-1 film-coated tablets was developed.Influencing factors,accelerated tests and long-term stability studies were conducted on piconitinib（PN17-1）raw materials and film-coated tablets,and the results showed that PN17-1was stable.The pharmacokinetic and tissue distribution studies of PN17-1 were also carried out,and the pharmacokinetic parameters were measured by oral gavage administration in mice,and the pharmacokinetic curves and tissue distribution maps were drawn,which showed that PN17-1 was widely distributed in mice,especially in the gastrointestinal tissues.The reproductive toxicity and genotoxicity studies of PN17-1 were also conducted,and the results showed that PN17-1 has no teratogenic or mutagenic toxicity,but has slight toxicity to liver and kidney at high doses,and the toxicity decreases to disappear after the recovery period,with good safety.