Search

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]

Objective: This study aimed at ascertaining the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) combined with donafenib versus HAIC alone in the treatment of unresectable hepatocellular carcinoma (HCC). Methods: Seventy HCC patients were enrolled for our study, and they were randomized by simple randomization using computer‐generated random numbers into two groups: control group and observation group. Regular follow‐up reviews were conducted to assess the efficacy of treatments. The levels of apoptotic factors, the levels of hepatic fibrosis indices, the levels of serum tumor vascular factors and tumor markers, and the occurrence of adverse reactions in the two groups were recorded and compared. Results: Disease control rate, objective response rate, and progression‐free survival (PFS) of patients in the observation group were higher in contrast to the control group. After 12 weeks of treatment, lower mRNA expression of c‐mesenchymal‐epithelial transition factor, telomerase, and Fas Ligand and higher mRNA expression of Fas and Caspase‐3 were observed in HCC tissues of the observation group versus the control group (p < 0.05); lower detection values of serum laminin, hyaluronic acid, collage type IV, vascular endothelial growth factor receptor 2, and alpha‐fetal protein (AFP) were noted in HCC patients of the observation group in comparison to the control group (p < 0.05); there was no difference in the incidence of adverse reactions between the two groups. Conclusion: Donafenib combined with HAIC in the treatment of unresectable HCC patients can notably reduce serum AFP levels, improve hepatic fibrosis, enhance short‐term efficacy, prolong PFS, and have a favorable safety profile. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Dermatovenereology is the property of Xi'an Jiaotong University Periodicals Center and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract Liver cancer is the sixth most commonly diagnosed cancer and the third leading cause of cancer death in the world, and hepatocellular carcinoma (HCC) is the most common form of liver cancer. More than half of the HCC patients are diagnosed at an advanced stage and often require systemic therapy. Dysregulation of the activity of receptor tyrosine kinases (RTKs) is involved in the development and progress of HCC, RTKs are therefore the potential targets for systemic therapy of advanced HCC (aHCC). Currently, a total of six small molecule tyrosine kinase inhibitors (TKIs) have been approved for aHCC, including first-line sorafenib, lenvatinib, and donafenib, and second-line regorafenib, cabozantinib, and apatinib. These TKIs improved patients survival, which are associated with disease stage, etiology, liver function, tumor burden, baseline levels of alpha-fetoprotein, and treatment history. This review focuses on the clinical outcomes of these TKIs in key clinical trials, retrospective and real-world studies and discusses the future perspectives of TKIs for aHCC, with an aim to provide up-to-date evidence for decision-making in the treatment of aHCC.

Jinpeng Li,1,2 Yan Li,3 Jinlong Song,2 Lujun Zhao1 1Department of Radiation Oncology,Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People’s Republic of China; 2Department of Interventional Therapy I, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, People’s Republic of China; 3Department of Radiology, Shanghai People’s Hospital, Jinan, 250000, People’s Republic of ChinaCorrespondence: Lujun Zhao, Department of Radiation Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People’s Republic of China, Tel +86 15360855162, Email zhaolujun@tjmuch.com Jinlong Song, Department of Interventional Therapy I, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, People’s Republic of China, Tel +86 531-67 626 412, Email jls7286@163.comPurpose: To observe and assess the efficacy and safety of donafenib combined with transarterial chemoembolization (TACE) to treat unresectable hepatocellular carcinoma (HCC).Patients and Methods: This prospective, single-arm, single-center, phase II clinical study enrolled 36 patients with initial unresectable HCC who had not undergone any systemic treatment. The patients received donafenib plus TACE (n = 26) or donafenib plus TACE plus programmed death receptor 1 inhibitors (n = 10). The primary endpoint was short-term efficacy, with secondary endpoints including progression-free survival (PFS), time to response (TTR), disease control rate (DCR), and adverse events. The tumor feeding artery diameter was also measured.Results: Efficacy evaluation of all 36 patients revealed 6 cases of complete response, 19 of partial response, 8 of stable disease, and 3 of progressive disease. Six (16.7%) patients successfully underwent conversion surgery, all achieving R0 resection, and 2 (5.6%) achieved a complete pathological response. The objective response rate (ORR) was 69.4% and the DCR was 91.7%. The median PFS was 10.7 months, the median overall survival was not reached, and the median TTR was 1.4 months. The median survival rates at 6, 12, and 18 months were 85.0%, 77.6%, and 71.3%, respectively. The median PFS rates at 6, 12, and 18 months were 65.3%, 45.6%, and 34.2%, respectively. Treatment-related adverse events (TRAEs) occurred in all 25 subjects, including 4 (11.3%) grade 3 TRAEs. No grade 4 or 5 TRAEs occurred. The tumor feeding artery diameter was significantly decreased following treatment (P = 0.036). Multivariable analysis revealed the sum of baseline target lesion diameters, best tumor response, and combined immunotherapy as independent predictors of PFS.Conclusion: TACE plus donafenib reduced the tumor feeding artery diameter in patients with unresectable HCC. The safety profile was good, and a high ORR was achieved.Keywords: hepatocellular carcinoma, donafenib, transarterial chemoembolization, immune checkpoint inhibitors, safety, efficacy

Background: Coinfection with the human immunodeficiency virus (HIV) and the hepatitis B virus (HBV) occurs in 5-67% of patients with HIV. HIV weakens the human immune system and leads to various tumors. Patients with unresectable hepatocellular carcinoma (HCC) and HIV experience poor treatment efficacy and have a short survival period. Approximately 70% of cases of HCC are diagnosed at advanced stages due to the subtle onset of the disease. As a result, most cases are not suits for curative therapy. Transcatheter arterial chemoembolization (TACE) is the first-line treatment for intermediate-stage HCC and is commonly used to treat unresectable HCC in China. Recent advancements in systemic treatments have significantly enhanced the effectiveness of unresectable HCC treatment. Several previous study showed that combination treatment combination therapy can enhance the efficacy. Notably, studies proposed that TACE combined targeted drugs with immune checkpoint inhibitors results in a high objective response rate and overall survival. However, the novelty of this study lies in its report of a complete response using a triple combination in patients with HIV and HCC with main trunk portal vein tumor thrombus. Case presentation: A 57-year-old woman was diagnosed with HCC with a main trunk portal vein tumor thrombus combined with HIV infection, cirrhosis, and chronic viral hepatitis. She underwent TACE and was administered donafenib and tislelizumab. This triple therapy treatment regimen resulted in a clinical complete response according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) based on contrast-enhanced computed tomography. Conclusion: We first used TACE combined with donafenib and tislelizumab for HCC patients with main trunk portal vein tumor thrombus and HIV-HBV coinfection and achieved complete response. [ABSTRACT FROM AUTHOR]

Liver cancer is the sixth most commonly diagnosed cancer and the third leading cause of cancer death in the world, and hepatocellular carcinoma (HCC) is the most common form of liver cancer. More than half of the HCC patients are diagnosed at an advanced stage and often require systemic therapy. Dysregulation of the activity of receptor tyrosine kinases (RTKs) is involved in the development and progress of HCC, RTKs are therefore the potential targets for systemic therapy of advanced HCC (aHCC). Currently, a total of six small molecule tyrosine kinase inhibitors (TKIs) have been approved for aHCC, including first-line sorafenib, lenvatinib, and donafenib, and second-line regorafenib, cabozantinib, and apatinib. These TKIs improved patients survival, which are associated with disease stage, etiology, liver function, tumor burden, baseline levels of alpha-fetoprotein, and treatment history. This review focuses on the clinical outcomes of these TKIs in key clinical trials, retrospective and real-world studies and discusses the future perspectives of TKIs for aHCC, with an aim to provide up-to-date evidence for decision-making in the treatment of aHCC. [ABSTRACT FROM AUTHOR]

Background: Adjuvant therapy is used to reduce the risk of hepatocellular carcinoma (HCC) recurrence and improve patient prognosis. Exploration of treatment strategies that are both efficacious and safe has been extensively performed in the recent years. Although donafenib has demonstrated good efficacy in the treatment of advanced HCC, its use as adjuvant therapy in HCC has not been reported. Objectives: To investigate the efficacy and safety of postoperative adjuvant donafenib treatment in patients with HCC at high-risk of recurrence. Design: Retrospective study. Methods: A total of 196 patients with HCC at high-risk of recurrence were included in this study. Of these, 49 received adjuvant donafenib treatment, while 147 did not. Survival outcomes and incidence of adverse events (AEs) in the donafenib-treated group were compared. Inverse probability of treatment weighting (IPTW) method was used. Results: The median follow-up duration was 21.8 months [interquartile range (IQR) 17.2–27.1]. Before IPTW, the donafenib-treated group exhibited a significantly higher 1-year recurrence-free survival (RFS) rate (83.7% versus 66.7%, p = 0.023) than the control group. Contrarily, no significant difference was observed in the 1-year overall survival (OS) rates between the two groups (97.8% versus 91.8%, p = 0.120). After IPTW, the 1-year RFS and OS rates (86.6% versus 64.8%, p = 0.004; 97.9% versus 89.5%, p = 0.043, respectively) were higher than those in the control group. Multivariate analysis revealed that postoperative adjuvant donafenib treatment was an independent protective factor for RFS. The median duration of adjuvant donafenib treatment was 13.6 (IQR, 10.7–18.1) months, with 44 patients (89.8%) experienced AEs, primarily grade 1–2 AEs. Conclusion: Postoperative adjuvant donafenib treatment effectively reduced early recurrence among patients with HCC at high-risk of recurrence, while exhibiting favorable safety and tolerability profile. However, these findings warrant further investigation. Plain language summary: Comparison of the outcomes of patients with HCC with or without donafenib after radical resection to better understand the efficacy and safety of postoperative adjuvant donafenib Why was this study done? Donafenib is the only new-generation targeted drug developed in the past 14 years that has demonstrated superior efficacy and increased safety in the first-line treatment of HCC. We aimed to explore whether postoperative adjuvant donafenib can improve the prognosis of patients with HCC at high-risk of recurrence. What did the researchers do? Medical data of patients with HCC at high-risk of recurrence who underwent radical resection at two medical centers between April 2021 and October 2022 were collected to compare long-term outcomes of patients treated with and without donafenib and explore the safety of adjuvant donafenib treatment. What did the researchers find? A total of 196 patients with HCC at high-risk of recurrence, including 49 who received adjuvant donafenib treatment and 147 who did not, were analyzed. At a median follow-up of 21.8 months, it was observed that adjuvant donafenib treatment effectively reduced early recurrence among patients with HCC at high-risk of recurrence, while exhibiting favorable safety and compliance profiles. What do the findings mean? The study provides real-world clinical empirical data on adjuvant donafenib treatment for patients with HCC at high-risk of recurrence, and these results may provide new directions for adjuvant treatment of HCC. [ABSTRACT FROM AUTHOR]

Abstract Aims Neovascularization plays a crucial role in liver fibrosis (LF), and blocking vascular endothelial growth factor receptors (VEGFR) has been shown to improve fibrosis. The aim of our study was to investigate the role of dual neovascularization targets, VEGFR, and platelet‐derived growth factor receptor (PDGFR), in ameliorating fibrosis. Methods In vitro, we observed the effects of apatinib (APA) (a VEGFR inhibitor) and donafenib (DON) (a VEGFR and PDGFR inhibitor) on the activation, proliferation, and apoptosis of hepatic stellate cells (HSCs) from rats and humans. In vivo, we established a thioacetamide (TAA)‐induced liver fibrosis rat model to explore the antifibrosis effect of APA and DON. We used the method of random table to randomly divide the rats into 4 groups. We detected the expression of angiogenesis‐related proteins using Western blot and immunohistochemistry. Results APA and DON inhibited the proliferation and activation of HSCs, promoted apoptosis of HSCs, and arrested the S phase of the cell cycle in vitro. We also found that DON had a stronger inhibitory effect on HSCs. In vivo, APA and DON ameliorated liver fibrosis, reduced collagen deposition and α‐SMA expression in rats, and DON had a stronger improvement effect. APA and DON downregulated the expression of VEGFR2 while inhibiting the phosphorylation of Akt and ERK1/2. DON can act through both VEGF and PDGF pathways, whereas APA can only act through the VEGF pathway. Conclusion Antiangiogenesis is a promising approach for the treatment of fibrosis. Compared with a single‐target drug (APA), the dual‐target drug (DON) can achieve better therapeutic effects.

Liwei Deng,1,2 Yanyuan Sun,2 Haiqing Wang,3 Changli Liao,2 Deshan Li,2 Guohui Xu,2,&ast; Xuegang Yang2,&ast; 1School of Medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 2Department of Interventional Therapy, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Chengdu, People’s Republic of China; 3Department of Hepato-Biliary-Pancreatic Surgery, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guohui Xu; Xuegang Yang, Department of Interventional Therapy, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, 55 Renmin South Road 4th Section, Chengdu, Sichuan, 610041, People’s Republic of China, Tel +86-13708010123, Fax +86-02885420195, Email xgh0913@hotmail.com; yanggangxue@163.comPurpose: To compare the efficacy and safety of transarterial chemoembolization (TACE) plus donafenib with immune checkpoint inhibitors (ICIs) (T+D+I) versus TACE plus donafenib (T+D) as the first-line treatment for patients with unresectable hepatocellular carcinoma (HCC).Methods: This retrospective study included patients with unresectable HCC who received T+D+I or T+D between June 2021 and February 2023. The tumor response was analyzed according to the modified Response Evaluation Criteria in Solid Tumors. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs) in the two groups were compared before and after propensity score matching (PSM). Cox’s proportional-hazards regression model was used to analyze factors affecting PFS and OS.Results: This study included 69 patients: 41 patients in the T+D group and 28 patients in the T+D+I group. After PSM, 26 patients in each group were analyzed. Patients in the T+D+I group had a higher DCR (96.2% vs 73.1%, P = 0.021), longer median PFS (13.1 vs 7.2 months, P = 0.017), and longer median OS (23.1 vs 14.7 months, P = 0.021) than those in the T+D group. The ORR in the two groups was similar (53.8% vs 50.0%, P = 0.781). Multivariate analyses revealed that T+D+I treatment and total bilirubin levels of < 20 μmol/L were independent prognostic factors for long PFS. T+D+I treatment, Child–Pugh class A, and single-lobe tumor distribution were independent prognostic factors for long OS. The incidence of TRAEs in the two groups was similar (P > 0.05).Conclusion: In comparison with TACE plus donafenib, TACE plus donafenib with ICIs could significantly improve DCR, PFS, and OS as a potential first-line treatment for unresectable HCC with an acceptable safety profile.Keywords: unresectable hepatocellular carcinoma, transarterial chemoembolization, donafenib, immune checkpoint inhibitor, combined therapy

Background & aims: This multicenter retrospective study evaluated the efficacy and safety of transarterial chemoembolization (TACE) combined with donafenib and a programmed death-1 (PD-1) inhibitor (TACE+DP) and TACE combined with donafenib (TACE+D) for unresectable hepatocellular carcinoma (uHCC). Methods: The clinical data of 388 patients with uHCC who received TACE+DP or TACE+D as first-line treatment at six Chinese academic centers from July 2021 to July 2022 were collected and analyzed retrospectively. Patients in the TACE +DP group received an intravenous administration of a PD-1 inhibitor every three weeks and oral donafenib (0.2 g) twice daily until intolerable toxicity or disease progression. Patients in the TACE+D group received the same dose of donafenib for 3–5 days after TACE. Overall survival (OS) and progression-free survival (PFS) were analyzed by Kaplan-Meier method and log-rank test. The tumor response was compared between the two groups according to modified RECIST criteria. Adverse events were also analyzed between the two groups Results: The TACE+D group included 157 patients and the TACE+DP group included 166 patients. Patients in the TACE+DP group had a longer median OS (18.1 vs. 13.2 months, P<0.001) and longer median PFS (10.6 vs. 7.9 months, P<0.001) than those in the TACE+D group. Patients in the TACE+DP group achieved a greater objective response rate (ORR; 50.6% vs. 41.4%, P=0.019) and greater disease control rate (DCR) (89.2% vs. 82.8%, P=0.010) than those in the TACE+D group. No significant differences were found in the incidence or severity of adverse events between the TACE+DP and TACE+D groups (any grade: 92.9% vs. 94.6%, P=0.270; grade 3 or 4: 33.8% vs. 37.3%, P=0.253). Conclusion: With favorable safety and tolerability, TACE combined with donafenib and PD-1 inhibitors significantly improved PFS, OS, and ORR compared to TACE combined with donafenib. [ABSTRACT FROM AUTHOR]

Abstract Aim This study was aimed to evaluate the safety and the efficacy of gemcitabine and oxaliplatin (GEMOX) combined with donafenib plus tislelizumab as the first‐line treatment for patients with unresectable biliary tract cancer (BTC). Methods This is a prospective single‐center exploratory study. Eligible patients (Stage III/IV BTC, at least one measurable disease according to RECIST v1.1, etc.) received gemcitabine 1000 mg/m2 IV Q3W, oxaliplatin 100 mg/m2 IV Q3W, donafenib 200 mg PO BID, and tislelizumab 200 mg IV Q3W until disease progression, unacceptable toxicity, or withdrawal of consent whichever occurred first. The primary endpoint was safety and secondary endpoints included disease control rate (DCR), objective response rate (ORR), conversion rate, and overall survival (OS). Results A total of 13 patients were enrolled. The median follow‐up time was 420 days (range 345–487). The median duration of treatment was four cycles (range 1–15). The incidence of ≥Grade 3 treatment‐related adverse events (TRAEs) was 53.8% and no Grade 5 TRAE. The most frequent Grade 3–4 TRAEs were rash (4/13, 30.8%), platelet count decreased (2/13, 15.4%), and fatigue (2/13, 15.4%). Tumor response was assessed in eight evaluable patients; ORR was 25.0% (95% CI, 3.2%–65.1%) and DCR 87.5% (95% CI, 47.3%–99.7%). The median PFS was 4.8 months (95% CI, 1.25‐NE). Three Stage III patients underwent subsequent surgery with a conversion rate of 23.1%. The median OS was not estimable. Conclusions GEMOX combined with donafenib plus tislelizumab as the first‐line therapy for unresectable BTC showed manageable toxicity and encouraging efficacy especially in terms of promising conversion rate in Stage III patients.

Background & aimsThis multicenter retrospective study evaluated the efficacy and safety of transarterial chemoembolization (TACE) combined with donafenib and a programmed death-1 (PD-1) inhibitor (TACE+DP) and TACE combined with donafenib (TACE+D) for unresectable hepatocellular carcinoma (uHCC).MethodsThe clinical data of 388 patients with uHCC who received TACE+DP or TACE+D as first-line treatment at six Chinese academic centers from July 2021 to July 2022 were collected and analyzed retrospectively. Patients in the TACE+DP group received an intravenous administration of a PD-1 inhibitor every three weeks and oral donafenib (0.2 g) twice daily until intolerable toxicity or disease progression. Patients in the TACE+D group received the same dose of donafenib for 3–5 days after TACE. Overall survival (OS) and progression-free survival (PFS)were analyzed by Kaplan-Meier method and log-rank test. The tumor response was compared between the two groups according to modified RECIST criteria. Adverse events were also analyzed between the two groupsResultsThe TACE+D group included 157 patients and the TACE+DP group included 166 patients. Patients in the TACE+DP group had a longer median OS (18.1 vs. 13.2 months, P

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide. Donafenib is a multi‐receptor tyrosine kinase inhibitor approved for the treatment of patients with advanced HCC, but its clinical effect is very limited. Here, through integrated screening of a small‐molecule inhibitor library and a druggable CRISPR library, that GSK‐J4 is synthetically lethal with donafenib in liver cancer is shown. This synergistic lethality is validated in multiple HCC models, including xenograft, orthotopically induced HCC, patient‐derived xenograft, and organoid models. Furthermore, co‐treatment with donafenib and GSK‐J4 resulted in cell death mainly via ferroptosis. Mechanistically, through integrated RNA sequencing (RNA‐seq) and assay for transposase‐accessible chromatin with high throughput sequencing (ATAC‐seq) analyses, that donafenib and GSK‐J4 synergistically promoted the expression of HMOX1 and increased the intracellular Fe2+ level is found, eventually leading to ferroptosis. Additionally, through cleavage under targets & tagmentation followed by sequencing (CUT&Tag‐seq), it is found that the enhancer regions upstream of HMOX1 promoter significantly increased under donafenib and GSK‐J4 co‐treatment. A chromosome conformation capture assay confirmed that the increased expression of HMOX1 is caused by the significantly enhanced interaction between the promoter and upstream enhancer under dual‐drug combination. Taken together, this study elucidates a new synergistic lethal interaction in liver cancer. [ABSTRACT FROM AUTHOR]

Aim: This study was aimed to evaluate the safety and the efficacy of gemcitabine and oxaliplatin (GEMOX) combined with donafenib plus tislelizumab as the first‐line treatment for patients with unresectable biliary tract cancer (BTC). Methods: This is a prospective single‐center exploratory study. Eligible patients (Stage III/IV BTC, at least one measurable disease according to RECIST v1.1, etc.) received gemcitabine 1000 mg/m2 IV Q3W, oxaliplatin 100 mg/m2 IV Q3W, donafenib 200 mg PO BID, and tislelizumab 200 mg IV Q3W until disease progression, unacceptable toxicity, or withdrawal of consent whichever occurred first. The primary endpoint was safety and secondary endpoints included disease control rate (DCR), objective response rate (ORR), conversion rate, and overall survival (OS). Results: A total of 13 patients were enrolled. The median follow‐up time was 420 days (range 345–487). The median duration of treatment was four cycles (range 1–15). The incidence of ≥Grade 3 treatment‐related adverse events (TRAEs) was 53.8% and no Grade 5 TRAE. The most frequent Grade 3–4 TRAEs were rash (4/13, 30.8%), platelet count decreased (2/13, 15.4%), and fatigue (2/13, 15.4%). Tumor response was assessed in eight evaluable patients; ORR was 25.0% (95% CI, 3.2%–65.1%) and DCR 87.5% (95% CI, 47.3%–99.7%). The median PFS was 4.8 months (95% CI, 1.25‐NE). Three Stage III patients underwent subsequent surgery with a conversion rate of 23.1%. The median OS was not estimable. Conclusions: GEMOX combined with donafenib plus tislelizumab as the first‐line therapy for unresectable BTC showed manageable toxicity and encouraging efficacy especially in terms of promising conversion rate in Stage III patients. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of hepatic artery infusion chemotherapy combined with targeted and immunotherapy on hepatocellular carcinoma (HCC) with inferior vena cava tumor thrombus (IVCTT). Methods A case of hepatocellular carcinoma with tumor thrombus in the inferior vena cava (IVC) near the right atrium was treated with donafenib combined with hepatic artery infusion chemotherapy (HAIC) and sintilimab. The response of tumor treatment was evaluated by RECEST v1.1. The dynamic changes of alpha-fetoprotein (AFP) and PIVKA-Ⅱ were observed and the surgical procedure was introduced. Results After four cycles of treatment with donafenib combined with HAIC and sintilimab, the diameter of the tumor and the tumor thrombus in IVC were successfully reduced, and AFP was reduced to normal. Both tumor and tumor thrombus were completely removed by total hepatic vascular exclusion (THVE) with the IVC incision. Postoperative pathology showed complete remission of the tumor. Conclusion Donafenib combined with HAIC and sintilimab has a good tumor shrinking effect for HCC with IVCTT, and can be applied for conversion surgery for patients of HCC with IVCTT. [ABSTRACT FROM AUTHOR]

Objective To study the mechanism of donafenib inhibiting the proliferation, migration and invasion of human cholangiocarcinoma TFK-1 cells and promoting apoptosis. Methods Human cholangiocarcinoma TFK-1 cells were divided into the control group (treated with the same amount of dimethyl sulfoxide) and the 2, 5 and 10 µmol/L donafenib groups. CCK-8 assay was used to detect the inhibition rate of cell proliferation. Cell proliferation was detected by plate cloning assay. Cell apoptosis was detected by flow cytometry. Transwell assay was used to detect cell migration and invasion. Western blot assay was used to detect the expression of pathway proteins Wnt, β-catenin, Cyclin D1, anti-apoptotic protein Bcl-2 and pro-apoptotic protein Bax. Immunofluorescence assay was used to detect changes of β-catenin into the nucleus. Results With the increase of donafenib concentration, the proliferation inhibition rate and apoptosis rate of TFK-1 cells increased, the number of plate clone formation, cell migration and invasion decreased gradually, the expression levels of Wnt, β -catenin, Cyclin D1 and Bcl-2 decreased gradually, and the expression of Bax increased gradually (P＜0.05). Immunofluorescence results showed that 2 µmol/L donafenib could inhibit β-catenin from entering the nucleus compared with the control group (P＜0.05). Conclusion Donafenib can inhibit the proliferation, migration and invasion of human cholangiocarcinoma TFK-1 cells, and the mechanism may be related to the inhibition of Wnt/β-catenin pathway activation and the promotion of apoptosis. [ABSTRACT FROM AUTHOR]

Tongqiang Li,1,2,&ast; Qin Shi,1,2,&ast; Jiacheng Liu,1,2,&ast; Yingliang Wang,1,2 Chen Zhou,1,2 Chaoyang Wang,1,2 Shuguang Ju,1,2 Songjiang Huang,1,2 Chongtu Yang,1,2 Yang Chen,1,2 Yaowei Bai,1,2 Bin Xiong1,2 1Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 2Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bin XiongDepartment of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue #1277, Wuhan, 430022, People’s Republic of ChinaEmail herr_xiong@126.comObjective: To investigate the efficiency and safety of callispheres beads loaded with donafenib (DCBs) for embolization in a VX2 liver tumor, as well as the improvement of tumor angiogenesis following embolization.Methods: Forty New Zealand white rabbit VX2 liver tumors were treated with four different drugs via the hepatic artery: NS (normal saline), CB (blank callispheres beads), ACB (adriamycin-loaded callispheres beads) and DCB (DCBs). Hematoxylin-eosin staining was performed to assess tumor necrosis, while MRI was employed to detect the changes in tumor size. The safety was evaluated by the liver and kidney function parameters, and the immunofluorescence and immunohistochemical staining were performed to reflect the tumor hypoxia and tumor angiogenesis following embolization.Results: The DCB group had the smallest tumor growth rate, but the tumor necrosis rate was the highest of the four groups. Compared to the CB and ACB groups, the DCB group did not aggravate the liver damage and had no influence on kidney function. The staining results showed that, although the tumor hypoxia deteriorated after DCBs embolization, the expression of VEGF (vascular endothelial growth factor) reduced, thus inhibiting tumor angiogenesis.Conclusion: DCB administration via hepatic artery is an effective and safe treatment for a preclinical liver cancer model, with the unique benefit of suppressing tumor angiogenesis following embolization.Keywords: hepatocellular carcinoma, donafenib, transcatheter arterial chemoembolization, tumor angiogenesis, efficacy, safety

Donafenib and lenvatinib are approved by China National Medical Products Administration and recommended as first-line treatment of Metastatic Hepatocellular Carcinoma (HCC). The aim of this study was to assess the cost-effectiveness of donafenib compared with lenvatinib for first-line treatment of advanced HCC in China. A partitioned survival model consisting with three health states was developed to simulate lifetime development of advanced HCC from China healthcare payer's perspective. The lifetime costs, quality-adjusted life-years (QALYs), life-years (LYs), and incremental cost-effectiveness ratio (ICER) were calculated. The efficacy data were obtained from ZGDH3 and REFLECT trials. The cost and health outcomes were discounted at a rate of 5%. Sensitivity and scenario analyses were carried out to explore the variation of model results. Compared with lenvatinib, donafenib incurred more costs of $1500.86 and had 0.139 QALYs gained, resulting in an ICER of $10,790.18/QALY. The probability of being cost-effective was 84.9% at a willingness-to-pay threshold of gross domestic product per capita in 2020 in China ($31,499.2/QALY). Sensitive and scenario analysis results were in line with base-case analysis. Donafenib appears to be a cost-effective strategy compared with lenvatinib for the first-line treatment of patients with unresectable or metastatic HCC in China. [ABSTRACT FROM AUTHOR]

Qin Shi,1,2,&ast; Tongqiang Li,1,2,&ast; Songjiang Huang,1,2,&ast; Yaowei Bai,1,2 Yingliang Wang,1,2 Jiacheng Liu,1,2 Chen Zhou,1,2 Yang Chen,1,2 Bin Xiong1,2 1Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 2Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bin XiongDepartment of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue #1277, Wuhan, 430022, People’s Republic of ChinaEmail herr_xiong@126.comPurpose: To evaluate the effect and immune response of transcatheter arterial embolization (TAE) combined with donafenib in rabbit VX2 liver tumor model.Materials and Methods: Thirty-six New Zealand white rabbits with VX2 liver tumor were randomly divided into three groups. The LD group was treated with the emulsion of 0.5 mL lipiodol and 4 mg donafenib via hepatic arterial administration. The LE group was treated with the emulsion of 0.5 mL lipiodol and 4 mg epirubicin. The control group was treated with the equal volume of saline. Four rabbits were euthanized in each group on day 1, 3 and 7 after treatment. The tumor growth, histological markers associated with angiogenesis and immune response were assessed by imaging and histopathology. In addition, immune modulatory cytokines included interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and biochemical hepatorenal function were measured.Results: Compared to other groups, LD group achieved lower tumor growth rate, fewer metastatic lesions, and higher tumor necrosis rate on day 7 after treatment. The percentage of CD31-positive area in the LD group was significantly lower than that in the LE group on day 3 and 7 after treatment. In addition, CD8+ lymphocytes infiltration was more pronounced in LD group than in LE group on day 7 after treatment, regardless of in the tumor or adjacent liver tissue. Serum cytokines including IL-6, TNF-α and IFN-γ were strongly upregulated in the LD group on day 1 after treatment. And there was no significant difference in the hepatorenal function between LD group and LE group after treatment.Conclusion: The combination of TAE and angiogenesis inhibitor donafenib resulted in a potentiated tumoricidal effect, anti-angiogenesis and antitumour T cell response in rabbit VX2 liver tumor model. This may provide a potential basis for exploring the immune-related mechanisms of embolization in liver cancer.Keywords: liver cancer, transcatheter arterial embolization, donafenib, tumor angiogenesis, immune response

Introduction: This study aimed to evaluate the cost-effectiveness of donafenib compared to sorafenib and lenvatinib as first-line treatments for patients with advanced hepatocellular carcinoma (HCC) in China. Methods: A partitioned survival model was developed to estimate the clinical and economic outcomes of donafenib, sorafenib, and lenvatinib for advanced HCC. The key clinical data of these targeted therapies were assessed through a network meta-analysis. The cost and health utilities were mainly collected from the literature. Quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratios (ICER) were the primary outcomes. Model uncertainty was tested with one-way sensitivity analyses, scenario analyses, and probabilistic sensitivity analyses (PSA). Results: For health outcomes, donafenib gained the highest QALYs among the three treatments, followed by lenvatinib and sorafenib (1.106, 0.999, and 0.915 QALYs, respectively). For cost, donafenib was the cheapest option, followed by sorafenib and lenvatinib ($42,116, $43,193, and $44,261). The PSA indicated that the probability of being cost-effective for donafenib was 86.98% and 93.56% when the willingness-to-pay thresholds were one and three times the gross domestic product per capita in China, respectively. The one-way sensitivity analyses and scenario analyses also found the results to be robust. Conclusion: Compared to sorafenib and lenvatinib, donafenib was likely to be a cost-effective treatment with the highest QALYs and the lowest cost for patients with advanced HCC in China. [ABSTRACT FROM AUTHOR]

BackgroundRecent clinical trials have demonstrated that donafenib has superior efficacy and safety compared with sorafenib in Chinese patients with unresectable or metastatic hepatocellular carcinoma (HCC). The objective of this study was to assess the cost effectiveness of donafenib compared with sorafenib for the treatment of patients with unresectable or metastatic HCC in China.MethodsA three-state partitioned survival model was developed to perform a cost-effectiveness analysis comparing donafenib and sorafenib from a Chinese healthcare payer's perspective. The model adopted a lifetime horizon and a 4-week cycle length. Survival data were derived from the ZGDH3 study and fitted with standard parametric functions for extrapolation beyond the trial period. Cost data were obtained from the mean price of publicly listed online bids in 2021 and medical service prices across provinces in China. Utility data were obtained from previous literature. The cost and health outcomes were discounted at an annual rate of 5%. Deterministic and probabilistic sensitivity analyses (PSAs) were carried out to verify the robustness of the model.ResultsCompared with sorafenib, donafenib incurred a higher cost (US$22,330.23 vs. US$14,775.92) but yielded more quality-adjusted life years (1.045 vs. 0.861 QALYs). The incremental cost-effectiveness ratio (ICER) for donafenib was US$41,081.52 per QALY gained (ICER = US$13,439.10/QALY). The PSA results indicated that at a willingness-to-pay threshold of 3 times the GDP in China, the probability of donafenib being cost effective was 16.9%. The ICER (US$13,439.10/QALY) decreased when the branded price of sorafenib was used in the model.ConclusionsDonafenib is unlikely to be cost effective compared with sorafenib for the first-line treatment of unresectable or metastatic HCC in China. Reducing the price of donafenib can increase the possibility of it being cost effective in the future.

Not available.

Purpose: To evaluate the effect and immune response of transcatheter arterial embolization (TAE) combined with donafenib in rabbit VX2 liver tumor model. Materials and Methods: Thirty-six New Zealand white rabbits with VX2 liver tumor were randomly divided into three groups. The LD group was treated with the emulsion of 0.5 mL lipiodol and 4 mg donafenib via hepatic arterial administration. The LE group was treated with the emulsion of 0.5 mL lipiodol and 4 mg epirubicin. The control group was treated with the equal volume of saline. Four rabbits were euthanized in each group on day 1, 3 and 7 after treatment. The tumor growth, histological markers associated with angiogenesis and immune response were assessed by imaging and histopathology. In addition, immune modulatory cytokines included interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and biochemical hepatorenal function were measured. Results: Compared to other groups, LD group achieved lower tumor growth rate, fewer metastatic lesions, and higher tumor necrosis rate on day 7 after treatment. The percentage of CD31-positive area in the LD group was significantly lower than that in the LE group on day 3 and 7 after treatment. In addition, CD8+ lymphocytes infiltration was more pronounced in LD group than in LE group on day 7 after treatment, regardless of in the tumor or adjacent liver tissue. Serum cytokines including IL-6, TNF-α and IFN-γ were strongly upregulated in the LD group on day 1 after treatment. And there was no significant difference in the hepatorenal function between LD group and LE group after treatment. Conclusion: The combination of TAE and angiogenesis inhibitor donafenib resulted in a potentiated tumoricidal effect, anti-angiogenesis and antitumour T cell response in rabbit VX2 liver tumor model. This may provide a potential basis for exploring the immune-related mechanisms of embolization in liver cancer. [ABSTRACT FROM AUTHOR]

Background: An unmet need for more effective and affordable kinase inhibitors remains in patients with progressive radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) in China, where only sorafenib is approved for this indication. This study evaluated the 24-week objective response rate (ORR) to donafenib—a new, domestic multikinase inhibitor—in the treatment of locally advanced or metastatic RAIR-DTC in patients with measurable lesions. Two dose regimens (300 mg twice daily vs. 200 mg twice daily) were used to determine its optimal dosage and safety for further phase III studies. Methods: This study was a randomized, open-label, multicenter phase II trial. Thirty-five adult RAIR-DTC patients with at least one measurable targeted lesion according to RECIST 1.1 were enrolled from 12 centers in China and randomized to receive either 200 mg (17 patients) or 300 mg (18 patients) of donafenib orally twice daily for 24 weeks. The primary endpoint was ORR, and the secondary endpoints included progression-free survival (PFS) among others. Additionally, biochemical (serum thyroglobulin) and structural (total tumor diameter [TTD]) responses were assessed, change (ΔTTD) rates were calculated, and safety was evaluated. Results: The ORRs for the 200- and 300-mg arms were 12.5% and 13.33% (p = 1.000), respectively. The 300-mg arm had a nonsignificant, longer median PFS than the 200-mg arm (14.98 months vs. 9.44 months) (p = 0.351). There was a trend toward more tumor shrinkage in the 300-mg arm compared with the 200-mg arm (average ΔTTD rate −0.52 ± 0.71 vs. −0.04 ± 1.55 mm/month, p = 0.103). Most treatment-related adverse events (AEs) in both arms were grades 1–2. The most common grade 3 treatment-related AEs in both arms were palmar–plantar erythrodysesthesia and hypertension; the sum occurrence rates of these two AEs in the 200-mg and 300-mg arms were 11.43% and 22.86%, respectively. Conclusions: Donafenib was generally well tolerated. Both donafenib regimens demonstrated similar efficacy in terms of the ORR in locally advanced or metastatic RAIR-DTC. The results warrant further studies on donafenib as a new, feasible treatment option for RAIR-DTC patients. Clinical Trials.gov IDs: NCT02870569; CTR20160220. [ABSTRACT FROM AUTHOR]

Objective: Drug resistance greatly limits the therapeutic effect of a drug. This study aimed to explore the role of long noncoding RNA ZFAS1 in Donafenib resistance of hepatocellular carcinoma (HCC) cells., Methods: The expression of CREB3, ZFAS1, and p65 in HCC cell lines was measured by RT-qPCR and western blotting. After transfection with sh-ZFAS1, sh-CREB3, or sh-CREB3 + oe-p65 in Donafenib-resistent (DR) HCC cell lines, the transfection efficiency was evaluated by RT-qPCR and western blotting. The proliferation and IC 50 to Donafenib of HCC cell lines was examined by MTT assay. Cell proliferation and apoptosis were examined by colony formation and flow cytometry assays. Then, the correlation amongst CREB3, ZFAS1, LSD1/CoREST, and p65 was analysed by ChIP, dual-luciferase reporter gene, and RIP assays., Results: ZFAS1, CREB3, and p65 were upregulated in HepG2-DR and Huh7-DR cells. Silencing of ZFAS1 or CREB3 enhanced the sensitivity of HCC cells to Donafenib, inhibited cell proliferation and IC 50 , and increased cell apoptosis, which were reversed by p65 overexpression. Mechanistically, CREB3 bound to ZFAS1 promoter to augment ZFAS1 transcriptional expression, and ZFAS1 recruited LSD1/CoREST to the p65 promoter region to decrease H3K4 methylation and elevate p65 transcriptional expression., Conclusion: CREB3 overexpression contributed to Donafenib resistance in HCC cells by activating the ZFAS1/p65 axis., Competing Interests: Declaration of competing interest The authors declare there is no conflict of interests., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: This Phase I study evaluated the safety, tolerability, food effects, pharmacodynamics, and pharmacokinetics of donafenib in patients with advanced solid tumours.Methods: Eligible patients received a single dose of donafenib (50 mg, 100 mg, 200 mg, 300 mg, or 400 mg) and were then observed over a 7-day period; thereafter, each patient received the corresponding dose of donafenib twice daily for at least 4 weeks. Safety assessment and pharmacokinetic sampling were performed for all patients at the given time points; preliminary tumour response was also assessed.Results: Twenty-five patients were enrolled in this study. Gastrointestinal reactions were the most common treatment-related adverse event, followed by skin toxicity. The maximum tolerated dose (MTD) was 300 mg bid. The dose-limiting toxicities (DLTs) were grade 3 diarrhoea and fatigue at 300 mg bid and grade 3 skin toxicity at 400 mg bid. In the dose range of 100 ~ 400 mg, T1/2 and AUC0-t after multiple doses were 26.9 ~ 30.2 h and 189 ~ 356 h*μg/mL, respectively. Food did not have a significant effect on the pharmacokinetics of donafenib. Twenty-one patients were assessed for efficacy, and two patients achieved a partial response according to Response Evaluation Criteria in Solid Tumors (RECIST), with a disease control rate of 57.1%.Conclusion: Oral donafenib was generally well tolerated and appeared to provide some clinical benefits; adverse events were manageable. Based on the results of this study, oral donafenib at 200 mg ~ 300 mg twice daily is recommended for further studies. [ABSTRACT FROM AUTHOR]

• The first HPLC-MS/MS method for simultaneous determination of donafenib, donafenib-N-oxide, sorafenib, and sorafenib-N-oxide in rat plasma is developed. • The limited sample volume (50 μL), simple sample preparation (protein precipitation), and short analysis time (2.8 min) are the advantages of the method. • The method is suitable for high-throughput analysis of biological samples. • The method successfully applied to comparing the pharmacokinetic behaviors of the donafenib and sorafenib in rat plasma. Donafenib and sorafenib are small molecule chemotherapy drugs for the management of hepatocellular carcinoma, with donafenib being a deuterated derivative of sorafenib. To date, a high liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method that quantify donafenib, sorafenib, and their main metabolites has not yet been developed. The objective of this study was to establish a HPLC-MS/MS method for the simultaneous detection of donafenib, donafenib-N-oxide, sorafenib, and sorafenib-N-oxide and for the pharmacokinetic studies in rat. The extraction of all analytes was achieved by simple protein precipitation utilizing acetonitrile. The Waters XBridge C 18 column (2.1 × 100 mm, 3.5 µm) was selected, and the analytes could be efficiently separated and quantitated during a 2.8 min gradient elution procedure. The method was linear within the predefined quantification ranges and provided acceptable precision (%CV < 9.4%), reproducible extraction recovery (99.4%–111.5%), and low matrix effect (88.1%–98.6%). The hemolysis effect did not interfere with the quantification of all analytes, and similar results were obtained by changing the anticoagulant K 2 -EDTA to heparin or sodium citrate. Plasma pharmacokinetics revealed that the values of t 1/2 , C max , and AUC 0-t of donafenib were 1.4-, 6.2-, and 3.1-fold higher than those of sorafenib, respectively. In conclusion, the proposed bioassay was successfully applied to pharmacokinetic studies in rat after administration of donafenib and sorafenib. Our work not only improves the bioanalytical method for determining the plasma concentrations of donafenib, sorafenib, and their N-oxide metabolites, but also provides a scientific reference for clinical pharmacokinetic studies. [ABSTRACT FROM AUTHOR]

Donafenib (DONA), a deuterium derivative of sorafenib, is used for advanced hepatocellular carcinoma (HCC). Dapagliflozin (DAPA) and canagliflozin (CANA) are sodium–glucose co-transporter 2 (SGLT2) inhibitors used for T2DM, which is frequently comorbid with HCC. Three drugs are substrates of UGT1A9 isoenzyme. This study aimed to evaluate donafenib–dapagliflozin and donafenib–canagliflozin pharmacokinetic interactions and explore the potential mechanisms. Rats were divided into seven groups (n = 6) that received donafenib (1), dapagliflozin (2), canagliflozin (3), dapagliflozin and donafenib (4), canagliflozin and donafenib (5), donafenib and dapagliflozin (6), donafenib and canagliflozin (7). The concentrations of drugs were determined by an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. The messenger RNA (mRNA) expressions were measured by quantitative RT-PCR. Multiple doses of dapagliflozin caused donafenib maximum plasma concentration (C max) to increase 37.01%. Canagliflozin increased donafenib C max 1.77-fold and the area under the plasma concentration–time curves (AUC 0−t and AUC inf) 1.39- and 1.41-fold, respectively, while reducing the apparent clearance (CL z) 28.38%. Multiple doses of donafenib increased dapagliflozin AUC 0−t 1.61-fold, AUC inf 1.77-fold, whereas its CL z reduced 40.50%. Furthermore, donafenib caused similar changes in canagliflozin pharmacokinetics. The PCR results demonstrated that dapagliflozin inhibited the mRNA expression of Ugt1a7 in liver and donafenib decreased the expression of Ugt1a7 mRNA in liver and intestine. Increased exposure to these drugs may be due to their metabolism inhibition mediated by Ugt1a7. These pharmacokinetic interactions observed in this study may be of clinical significance, which may help adjust dose properly and avoid toxicity effects in patients with HCC and T2DM. [Display omitted] • Donafenib is a substrate and inhibitor of UGT1A9 in vivo. • Dapagliflozin and canagliflozin mainly metabolized by UGT1A9. • DDIs may occur when donafenib is combined with dapagliflozin or canagliflozin. • Dapagliflozin and canagliflozin increased plasma concentration of donafenib. • Donafenib increased the systemic exposure of dapagliflozin and canagliflozin. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a global healthcare problem, with a high prevalence in nonindustrialized countries and a rising incidence in industrialized countries. Sorafenib demonstrated its efficacy as the first therapeutic agent for unresectable HCC in 2007. Since then, other multitarget tyrosine kinase inhibitors have demonstrated efficacy in HCC patients. Still, the tolerability of these drugs remains an unsolved problem, with 5-20% of patients permanently discontinuing their therapies due to adverse events. Donafenib is a deuterated form of sorafenib exploiting the increased bioavailability derived from the deuterium-for-hydrogen replacement. In the multicenter, randomized, controlled phase II-III trial ZGDH3, donafenib outperformed sorafenib in terms of overall survival, with favorable safety and tolerability. As a result, donafenib was approved as a possible first-line treatment of unresectable HCC by the National Medical Products Administration (NMPA) of China in 2021. In this monograph, we review the main preclinical and clinical evidence that emerged in the trials of donafenib., (Copyright 2023 Clarivate.)

Purpose: To evaluate the effect and immune response of transcatheter arterial embolization (TAE) combined with donafenib in rabbit VX2 liver tumor model., Materials and Methods: Thirty-six New Zealand white rabbits with VX2 liver tumor were randomly divided into three groups. The LD group was treated with the emulsion of 0.5 mL lipiodol and 4 mg donafenib via hepatic arterial administration. The LE group was treated with the emulsion of 0.5 mL lipiodol and 4 mg epirubicin. The control group was treated with the equal volume of saline. Four rabbits were euthanized in each group on day 1, 3 and 7 after treatment. The tumor growth, histological markers associated with angiogenesis and immune response were assessed by imaging and histopathology. In addition, immune modulatory cytokines included interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and biochemical hepatorenal function were measured., Results: Compared to other groups, LD group achieved lower tumor growth rate, fewer metastatic lesions, and higher tumor necrosis rate on day 7 after treatment. The percentage of CD31-positive area in the LD group was significantly lower than that in the LE group on day 3 and 7 after treatment. In addition, CD8 + lymphocytes infiltration was more pronounced in LD group than in LE group on day 7 after treatment, regardless of in the tumor or adjacent liver tissue. Serum cytokines including IL-6, TNF-α and IFN-γ were strongly upregulated in the LD group on day 1 after treatment. And there was no significant difference in the hepatorenal function between LD group and LE group after treatment., Conclusion: The combination of TAE and angiogenesis inhibitor donafenib resulted in a potentiated tumoricidal effect, anti-angiogenesis and antitumour T cell response in rabbit VX2 liver tumor model. This may provide a potential basis for exploring the immune-related mechanisms of embolization in liver cancer., Competing Interests: All authors declare that they have no potential conflict of interest in the study., (© 2021 Shi et al.)