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Background: Previous studies evaluating antiangiogenic agents plus immune checkpoint inhibitors for unresectable hepatocellular carcinoma (HCC) have shown encouraging results. This study was conducted to investigate the efficacy and safety of donafenib combined with sintilimab (Don-Sin) for advanced HCC. Methods: This was a single-center, single-arm phase II trial recruiting patients with BCLC stage C HCC. A safety run-in cohort was planned with the first 6 patients receiving oral donafenib 200 mg twice daily and intravenous sintilimab 200 mg once every 3 weeks. Dose-limiting toxicities (DLTs) were evaluated to determine the recommended dose of donafenib for those enrolled thereafter. The primary endpoint of this study was progression-free survival (PFS) per mRECIST. Results: 30 patients were enrolled. As 3 patients (50.0%) experienced DLTs during safety run-in, the initial dose of donafenib was adjusted to 200 mg once daily for subsequent patients. The primary endpoint was met with a median PFS of 6.2 (95% confidence interval [CI], 4.4-8.0) months per mRECIST (6.3 [95% CI, 5.4–7.2] months per RECIST 1.1). The objective response rate was 23.3% per mRECIST and 16.7% per RECIST 1.1, while the disease control rate reached 76.7% per mRECIST/RECIST 1.1. The median overall survival was 16.0 (95% CI, 13.5–18.5) months. Treatment-related adverse events (TRAEs) occurred in 28 patients (93.3%) and grade 3 TRAEs were observed in 9 patients (30.0%). Conclusions: Don-Sin showed promising antitumor effects with an acceptable safety profile in patients with advanced stage HCC. The preliminary findings need to be further evaluated in phase III randomized controlled trials. Trial registration: ClinicalTrials.gov (identifier: NCT05162352; date of registration: December 4, 2021). [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of sorafenib and donafenib on the pharmacokinetics of ertugliflozin in rats， and to provide a theoretical basis for drug combination in clinical practice. Methods: A total of 24 male Sprague-Dawley rats were randomly divided into groups A， B， C， and D， with 6 rats in each group. The rats in groups A and B were given sorafenib control solvent and sorafenib （100 mg/kg）， respectively， by gavage for 7 consecutive days， followed by ertugliflozin （1.5 mg/kg） by gavage on day 7. Blood samples were collected from the angular vein plexus at different time points， and ultra-performance liquid chromatography-tandem mass spectrometry was used to determine the mass concentration of ertugliflozin and plot the plasma concentration-time curves， while the non-compartment model in DAS 2.1.1 software was used to calculate related pharmacokinetic parameters. The independent-samples t test was used for comparison of normally distributed continuous data between two groups， and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups. Results: Compared with group A， group B had significant increases in the AUC0-t and AUC0-∞ of the plasma concentration-time curve of ertugliflozin （both P<0.05）， significant prolongation of t1/2， MRT0-t， and MRT0-∞ （all P<0.05）， and a significant reduction in CLZ/F （P<0.05）. Compared with group C， group D had significant increases in the AUC0-t and AUC0-∞ of ertugliflozin （both P<0.05）， significant prolongation of Tmax， t1/2， MRT0-t， and MRT0-∞ （all P<0.01）， and significant reductions in VZ/F and CLZ/F （both P<0.05）. Conclusion: Both sorafenib and donafenib can affect the pharmacokinetics of ertugliflozin in rats and significantly increase the plasma exposure of ertugliflozin. The efficacy and adverse drug reactions of ertugliflozin should be closely monitored during combined use in clinical practice and the dose should be adjusted when necessary to avoid the potential risk of drug interaction. [ABSTRACT FROM AUTHOR]

Donafenib is an improved version of sorafenib in which deuterium is substituted into the drug's chemical structure, enhancing its stability and antitumor activity. Donafenib exhibits enhanced antitumor activity and better tolerance than sorafenib in preclinical and clinical studies. However, the specific mechanism of its effect on hepatocellular carcinoma has not been reported. Iron deposition is a cell death pattern caused by disturbances in iron metabolism. Apoptosis is a form of programmed cell death. They may interact with each other during cell death. This study mainly explores the potential mechanism of donafenib activating the p53 signaling pathway, inducing iron deposition, and enhancing cell apoptosis in hepatocellular carcinoma. Hepa1-6 and Huh7 cells were treated with various concentrations of donafenib. Scratch healing and pore migration tests were conducted. Analyze apoptosis through flow cytometry and TUNEL fluorescence labeling. RNA sequencing was conducted on both untreated and donafenib-treated Huh7 cells. The key proteins involved in ferroptosis (SLC7A11, GPX4) and apoptosis (caspase3, caspase8, Bax, Bcl-2, p53) were then evaluated using immunoblotting and immunohistochemical staining. Reactive oxygen species (ROS) levels in the cancer cells were measured. Donafenib treatment resulted in a dose-dependent decrease in the proliferation, migration, and invasion capabilities of cancer cells. There was an increase in apoptosis rates and ROS accumulation, and a reduction in tumor volume. The key proteins involved in ferroptosis and apoptosis underwent significant changes. Donafenib activates the p53 signaling pathway, induce ferroptosis, and enhance apoptosis, suggesting its potential as an effective therapeutic agent for HCC. [ABSTRACT FROM AUTHOR]