Determination Of Both Prototype Drug And Metabolism Of Tafetinib Malate And Sabarubicin Hydrochloride, And Phase Ⅰ Clinical Pharmacokinetics Study Of Sabarubicin In Chinese SCLC Patients

This paper is study on the novel anti-cancer agents -- tafetinib malate and sabarubicin hydrochloride. To support the pharmacokinetics study and detectiton of these two agents, this study have established a rapid and sensitive ultra performance liquid chromatography-mass spectrometry (UPLC-MS/MS) method to determine tafetinib and its metabolism SCR868, and another UPLC-MS/MS method for the quantitation of Sabarubicin and its metabolites M3. And studied the pharmacokinetics of sabarubicin in advanced small cell lung cancer (SCLC) patients. Provided reference data for the safety, effective and rational use of these novel drugs in clinical. The main content is divided into two parts:Part I:Methodology study of determination of tafetinib and its metabolism SCR868 with UPLC-MS/MS in patients with advanced solid tumor.Tafetinib malate (SIMO10603) is a novel compound with outstanding anti-tumor activity. Its chemical structure is synthesized on the basis of sunitinib’s pharmacophore with a 2-indolinone structure as core structure, improved the lipophicity and binding capacity to specific target with construction of unsaturated six ring in non-pharmacophore domain. Tafetinib malate is a yellow crystalline powder, odorless, molecular weight 558.60, with a melting point of 168 ℃-172 ℃, and almost no hygroscopicity. It’s soluble in glacial acetic acid, sparingly soluble in water, slightly soluble in methanol, and almost insoluble in ethanol or acetone. Preclinical studies have shown that tafetinib and its metabolite SCR868 both are multi-targeted receptor tyrosine kinase inhibitors. The inhibit effect are slightly stronger than sunitinib in molecular level, and comparable in transplanted tumor models. In this study, a UPLC-MS/MS method were developed and fully verifyied to determine the concentration of tafetinib and SCR868 in human plasma. The results suggested that the established method show excellent linearity over 0.2-50 ng/mL for both analytes, the precision range of inta-and inter-day is 1.8%-11.2%, the accuracy range is-0.3% to 5.7%, the recovery is above 80% for both analytes. This method have been verified completely according to the guideline on bioanalytical method validation, which could satisfy the need of pharmacokinetics study of tafetinib in patients with advanced solid tumors.Part II:Phase I study of the pharmacokinetics of sabarubicin in patients with extensive SCLC.Sabarubicin is a novel anti-cancer angent synthesized by Menarini Ricerche SpA Company through extension and modification of disaccharide. As novel compound with disaccharide, sabarubicin has similar anti-tumor effect and mechanism with agents of the same kind, but with stronger and more slightly cardiotoxicity. Preclinical data suggested that sabarubicin have excellent anti-cancer efficacy on a variety of cell lines, including doxorubicin resistant ones. Sabarubicin has completed its phase I, II clinical trial in Europe, which preliminary proved the good anti-cancer effect in ovarian and lung cancer. This study developed a UPLC-MS/MS method for detecting plasma concentrations of sabarubicin and M3, further studied the pharmacokinetic characteristics of this drug in patients with extensive stage SCLC. The specific contents are as follows:Chapter I:This study has established and verified a UPLC-MS/MS method to detect concentration of sabarubicin and its metabolite M3 in human plasma. The data of results indicated, for sabarubicin and M3, calibration curves over 2-400ng/mL and 0.5-100ng/mL could achieve excellent linearity respectively. Precision of intra-and inter-day were less than 12.8%, and accuracy was from-9.6% to 2.6%. Sabarubicin, M3 and internal standard extraction recoveries were 68.3%-83.2%,84.6%-75.6% and 80.2%-84.7%, matrix effects were consistent between three concentrations. This method could meet requirements of clinical pharmacokinetic studies of sabarubicin.Chapter II:This article studied the pharmacokinetics of sabarubicin in patients with extensive SCLC. This study was designed as a single-center, non-randomized, open and dose escalation study. It planed to enroll five dose group, a dose escalation was designed as 20mg/m~2,40mg/m~2,60mg/m~2,80mg/m~2,100mg/m~2. Now enrollment and detection of 20mg/m~2,40mg/m~2,60mg/m~2 and 80 mg/m~2 dose group have finished. Pharmacokinetics of sabarubicin were analyzed on basis of the data of plasma concentration acquired in chapter I.