Search

Osimertinib is the only third-generation epidermal growth factor receptor tyrosine-kinase inhibitor (EGFR-TKI) approved by Food and Drug Administration (FDA). This study aimed to know the inhibitory effect of osimertinib on human UDP-glucosyltransferases (UGTs) and human liver microsomes (HLMs), as well as to identify its potential to cause drug-drug interaction (DDI) arising from the modulation of UGT activity. High inhibitory effect of osimertinib was shown towards UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A10, 2B7 and 2B15. Especially, osimertinib exhibited competitive inhibition against UGT1A1 with a Ki,u of 0.87 ± 0.12 μM. It also noncompetitively inhibited SN-38 glucuronidation in pooled HLMs with a Ki,u of 3.32 ± 0.25 μM. Results from quantitative prediction study indicated that osimertinib administered at 80 mg/day may result in a 4.83 % increase in the AUC of drugs mainly metabolized by UGT1A1, implying low risk of DDI via liver metabolism. However, the ratios of [I]gut/Ki,u are much higher than 11 in HLMs and recombinant UGT1A1, indicating a risk for interaction in intestine. The effects of osimertinib on intestinal UGT should be paid more attention on to avoid unnecessary clinical DDI risks.

Background: The survival of patients with chronic myeloid leukemia (CML) has improved substantially in the last decade with the development of BCR-ABL tyrosine kinase inhibitors (BCR-ABL TKIs). However, clinically apparent liver disease and even death has been found with the treatment of ponatinib, and serious cases of liver injury were also associated with imatinib, nilotinib and dasatinib. The aim of this systematic review and meta-analysis was to compare the relative risk (RR) of hepatotoxicity of new-generation BCR-ABL TKIs with that of imatinib, and to provide an overall assessment of the clinical benefit. Methods: Two independent investigators selected citations and clinical trials from PubMed, Embase, Cochrane library databases and clinicaltrials.gov from January 2000 to April 2020 to include RCTs comparing four new-generation BCR-ABL TKIs (dasatinib, bosutinib, nilotinib and ponatinib) with the first generation BCR-ABL TKI imatinib. Data extracted included study characteristics, baseline patient information, interventions and data on all grades and high grades alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation, overall survival (OS), and major molecular response (MMR). The relative risk (RR) and 95% confidence interval (CI) were calculated using the inverse variance method. Findings: Nine trials involving 3475 patients were analyzed. Increased risks were observed for each new-generation TKI except for dasatinib. The pooled RRs of all grades ALT and grade 3-4 ALT elevation were 2.89 (95% CI 1.78-4.69; P

Cancer therapy with tyrosine kinase inhibitors (TKIs) is a rapidly developing field, and several TKIs have been reported to have an impact on the activities of UDP-glucosyltransferases (UGTs), implying a potential risk for drug-drug interaction (DDI). Herein, we investigated the inhibitory effects of two commonly used TKIs, midostaurin and ruxolitinib, on human UGTs and quantitatively evaluated their DDI potential via UGT inhibition. It was found that midostaurin was a potent inhibitor of the majority of human UGTs, including UGT1A3, 1A4, 1A7, 1A8, 1A9, 1A10, 2B7, 2B15, and 2B17, with IC50 values lower than 4 μM (IC50 0.0128-3.85 μM), while ruxolitinib exhibited weak inhibition towards the activity of almost all the tested UGT isoforms. Furthermore, based on reversible inhibition, the co-administration of midostaurin at the clinical available dose was predicted to increase the plasma exposure to sensitive UGT1A3, 1A7, and 1A8 substrates by at least 61.4%, 25.6%, and 651%, respectively. In summary, our data identify that midostaurin is a potent inhibitor of the majority of human UGTs and may bring a potential risk of DDI via inhibition against UGT1A3, 1A7, and 1A8, while ruxolitinib cannot trigger UGT-mediated DDI due to its weak inhibition towards UGTs.

Importance Although BCR-ABL fusion oncoprotein tyrosine kinase inhibitors (BCR-ABL TKIs) can substantially improve the survival rate of chronic myeloid leukemia (CML), they are clinically accompanied by severe hepatotoxicity. Objective To compare the relative risk (RR) of hepatotoxicity of new-generation BCR-ABL TKIs with that of imatinib, and to provide an overall assessment of the clinical benefit. Data Sources PubMed, Embase, Cochrane library databases, and ClinicalTrials.gov were searched for clinical trials published between January 2000 and April 2020. Study Selection Study selection was conducted independently by 2 investigators according to the inclusion and exclusion criteria published previously in the protocol: only randomized phase 2 or phase 3 clinical trials that compared bosutinib, dasatinib, nilotinib, or ponatinib with imatinib were included. Among the 2666 records identified, 9 studies finally fulfilled the established criteria. Data Extraction and Synthesis Two investigators extracted study characteristics and data independently using a standardized data extraction form. Data were extracted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. When substantial heterogeneity was observed, pooled estimates were calculated based on the random-effect model; otherwise, the fixed-effect model was used. Main Outcomes and Measures Data extracted included study characteristics, baseline patient information, interventions and data on all-grade and high-grade (grades 3 and 4) elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, overall survival, and major molecular response (MMR). The RRs and 95% CIs were calculated using the inverse variance method. Results Nine trials involving 3475 patients were analyzed; the median (range) age was 49 (18-91) years; 2059 (59.2%) were male patients. Increased risks were observed for each new-generation TKI except for dasatinib. Patients receiving new-generation TKIs were more likely to experience all grades of ALT elevation (pooled RR, 2.89; 95% CI, 1.78-4.69;P Conclusions and Relevance When compared to imatinib, bosutinib, nilotinib, and ponatinib had higher relative risks of hepatotoxicity. Treatment with new-generation TKIs was associated with a higher MMR rate at 1 year but not with 1-year overall survival.

This research work has been demonstrated the growth of ZnInO thin films using thermal evaporation technique for thermoelectric power generation applications. The pure zinc powder and indium metal were evaporated on the multi-crystalline Si substrate using the vacuum tube furnace. Deposited thin films were annealed at various temperatures (500–700 °C) for 30 min in a programmable muffle furnace. XRD data concluded that the sample annealed at temperature 500 °C, has a weak structure of ZnO. But as we have increased the annealing temperature, indium atoms get thermal energy from the annealing process and reacted with ZnO molecule to form ZnInO composite. The vibrational and rotational modes of the samples were studied by the Raman spectroscopic analysis and morphology of annealed samples was verified by SEM. The Seebeck coefficient data suggested that the value of Seebeck coefficient varies between (140.9–182.2) μV/oC. The maximum value of the Seebeck coefficient was obtained for the sample annealed at 600 °C because the mobility of carriers is highest at that temperature. But the value of electrical conductivity and power factor for the sample annealed at 600 °C is minimum due to low carrier concentration. Because of these conclusions, it may be suggested that this material can be a potential choice soon for thermoelectric power generation applications.