ADR Signal Mining and Analysis of Adverse Drug Reaction of Ceritinib / 中国药房

OBJECTIVE：To initially evaluate the safety of ceritinib after it is marketed ，and to provide reference for the rational use of drug. METHODS The report odd ratio method and proportional reporting ratio method were used to mine the signals of ceritinib-related adverse events from FDA adverse event reporting system （FAERS）during the second quarter of 2014 to the third quarter of 2019. The patients ’gender，age，body weight ，daily dose and course of treatment were collected. SPSS 26.0 software was used to test the number of ADR cases of this system group and other system groups by chi square test. RESULTS ：A total of 10 318 ADR reports with ceritinib as the first suspicious drug were collected ， and 236 ADR signals of seretinib were excavated. After excluding the ineffective treatment ，187 ADR signals were obtained ，involving 16 systems. Inaddition to those mentioned in the drug instructions ，the signals also included various nervous disease ，blood and lymph system disease ，infections and infectious disease ，etc.，such as hand-foot-genital syndrome ，mutation of anaplatic lymphoma kinase gene. Among them ，the ADR reports of gastrointestinal diseases were the most （576 cases）. Compared with ADR of other systems ，gender，age，body weight，daily dose and treatment course had significant effects on ADR of gastrointestinal diseases （P＜0.05）. Most of the patient with gastrointestinal ADR after using ceritinih were female （59.9％），45 years old and above （70.3％），body weight ≤65 kg （68.1％），daily dose 451-750 mg/d（50.2％），and medication duration less than 3 months（75.7％）. CONCLUSIONS ：The risk of gastrointestinal ADR in female patients over 45 years old and with body weight less than 65 kg after using seretinib is relatively high. This kind of ADRs are also related to daily dose ，and most of which occur within 3 months. Therefore ，great importance should be attached to drug monitoring during clinical use.

Safety and Preliminary Efficacy of Ceritinib 450 mg with Food in Chinese ALK-positive Non-small Cell Lung Cancer / 中国肺癌杂志

BACKGROUND@#Anaplastic lymphoma kinase (ALK) rearrangement is a common driver gene of non-small cell lung cancer (NSCLC). Ceritinib is a second-generation ALK inhibitor, which can bring survival benefits to ALK-positive metastatic NSCLC. However, few studies focus on the safety and efficacy of ceritinib in China. Therefore, this study intends to investigate the safety and preliminary efficacy of ceritinib 450 mg with meals in Chinese patients with ALK-positive NSCLC through a real world study.@*METHODS@#From October 2018 to December 2019, patients with ALK-positive NSCLC from 8 medical centers in Sichuan province were recruited in this study. All of these participants received ceritinib 450 mg/d with food. The basic characteristics, adverse effects (AEs) and responses were collected and analyzed in order to evaluate the safety and efficacy of ceritinib.@*RESULTS@#A total of 109 patients were included in this study. Data cutoff was January 23, 2020. The median duration of treatment exposure was 5.87 mon (range: 0.4 mon-15.7 mon). Total AEs were reported in 98 (89.9%) of 109 patients and grade 3 or 4 AEs were reported in 22.9% of patients. Most common AEs (mainly grade 1 or 2) were diarrhea (60.6%), elevated alanine aminotransferase (ALT)(38.5%) and aspartate aminotransferase (AST)(37.6%). As of data cutoff, 45 patients discontinued ceritinib. The overall response rate (ORR) was 37.6% (95%CI: 28.5%-47.4%) and disease control rate (DCR) was 86.2% (95%CI: 78.3%-92.1%).@*CONCLUSIONS@#The treatment of ceritinib 450 mg with food for Chinese ALK-positive NSCLC patients had a good safety profile and favorable DCR in real-world setting. However, this conclusion needs to be further verified by large sample, prospective trials.

A liquid chromatography with tandem mass spectrometry method for quantitating total and unbound ceritinib in patient plasma and brain tumor / 药物分析学报

A rapid,sensitive,and robust reversed-phase liquid chromatography with tandem mass spectrometrymethod was developed and validated for the determination of total and unbound ceritinib,a secondgenerationALK inhibitor,in patient plasma and brain tumor tissue samples.Sample preparation involvedsimple protein precipitation with acetonitrile.Chromatographic separation was achieved on a Waters ACQUITYUPLC BEH C18 column using a 4-min gradient elution consisting of mobile phase A(0.1% formic acidinwater)andmobile phase B(0.1% formic acid in acetonitrile),at a flow rate of 0.4 mL/min.Ceritinib and theinternal standard([13C6]ceritinib)were monitored using multiple reaction monitoring mode under positiveelectrospray ionization.The lower limit of quantitation(LLOQ)was 1 nM of ceritinib in plasma.The calibrationcurve was linear over ceritinib concentration range of 1–2000 nM in plasma.The intra-and interdayprecision and accuracy were within the generally accepted criteria for bioanalytical method(<15%).The method was successfully applied to assess ceritinib brain tumor penetration,as assessed by the unbounddrug brain concentration to unbound drug plasma concentration ratio,in patients with brain tumors.

The spermostatic and plasma membrane injury effects of ceritinib in vitro / 复旦学报（医学版）

Objective To explore the in vitro spermostatic effects and the mechanisms of ceritinib,a novel candidate from the active compound pools previously screened for the regulation of sperm function.Methods The vigor sperm of human and mouse were incubated with ceritinib for 20seconds,and the sperm motility was evaluated by computer assistant sperm analysis (CASA).The integrity of the sperm plasma membrane and the survival ratio of sperm was assessed by hypo-osmotic swelling (HOS) assay and SYBR-14/PI staining.The damage of sperm plasma membrane was detected by electron microscope.The cytotoxicity of ceritinib to VK2/E6E7,End1/E6E7 and Ect1/E6E7 cells was measured by CCK-8 assay and fluorescent staining.Results The minimal effective concentration (MEC) of ceritinib to (5-10) × 106/mL human sperm within 20 seconds was (74.87 ± 31.46)μmol/L,which was significantly lower than the MEC of nonoxynol-9 (219.75 ± 20.89) μmol/L measured in the same condition.The time-dose related spermostatic effects of ceritinib were measured by CASA system.Ceritinib was able to damage sperm membrane and caused sperm death with HOS and SYBR-14/PI staining.With electron microscopy,the sperm membrane was observed to be ruptured,and the heads and tails of sperm were separated by ceritinib.Ceritinib was also able to damage the epithelial cells.Conclusions Ceritinib has acute spermostatic effects and potential contraceptive effects.