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Expert Opinion on Investigational Drugs Apr 2011Angiogenesis inhibition represents a rational therapeutic strategy in the management of solid tumors. Brivanib is a dual tyrosine kinase inhibitor with selectivity... (Review)
Review
INTRODUCTION
Angiogenesis inhibition represents a rational therapeutic strategy in the management of solid tumors. Brivanib is a dual tyrosine kinase inhibitor with selectivity against VEFGR-2 and FGFR.
AREAS COVERED
This review provides an updated summary of preclinical and clinical experience with brivanib in cancer. Data presented in abstract form from international conferences or journal articles found with a PubMed search of published literature up to December 2010 are described in this review.
EXPERT OPINION
Brivanib appears tolerable and exhibits favorable pharmacokinetic and pharmacodynamic profiles with evidence of target inhibition in surrogate tissues. Clinical and pharmacodynamic data support an oral once daily administration at 800 mg. Brivanib shows promising activity as single agent in hepatocellular carcinoma and in combination with cetuximab in colorectal cancer. Further evaluations with cytotoxic chemotherapy and in other solid tumors are currently ongoing.
Topics: Alanine; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Clinical Trials as Topic; Drug Screening Assays, Antitumor; Humans; Neoplasms; Pyrroles; Receptor, Fibroblast Growth Factor, Type 1; Triazines; Vascular Endothelial Growth Factor Receptor-2
PubMed: 21391890
DOI: 10.1517/13543784.2011.565329 -
Pharmacological Research Aug 2021Dengue virus (DENV) is the most prevalent arthropod-borne viral disease of humans and has a major impact on global public health. There is no clinically approved drugs...
Dengue virus (DENV) is the most prevalent arthropod-borne viral disease of humans and has a major impact on global public health. There is no clinically approved drugs for DENV infection. Since intracellular VEGFR2 is increased in DENV infected patients, we thus hypothesized that VEGFR2 participated DENV proliferation and its inhibitors could be served as antivirals against DENV. Actually our results showed that VEGFR2 was induced by DENV infection. Also the agonist of VEGFR2, VEGF-A, promoted DENV proliferation. Therefore, we screened the inhibitors of VEGFR2 and found that brivanib alaninate (brivanib) showed the best anti-DENV ability with the lowest cellular cytotoxicity. Mechanically, our results indicated VEGFR2 directly interacted with PTP1B to dephosphorylate AMPK to provide lipid environment for viral replication. However, this effect could be inhibited by brivanib, which significantly reversed the reduction of AMPK phosphorylation caused by DENV infection, thus improving the cellular lipid environment. Moreover, the antiviral effect of brivanib could be reversed by AMPK inhibitor, Compound C. In addition, oral administration of brivianib (20-50 mg/kg/day) clearly improved the survival rate of DENV2 infection, and this effect was abolished in accompanied with Compound C (10mg/kg/day). Collectively, our study disclosed the mechanism of VEGFR2 in DENV2 and evaluated the antiviral ability of brivanib, which deserved more attention for clinical usage in DENV infection.
Topics: AMP-Activated Protein Kinases; Alanine; Animals; Antiviral Agents; Cells, Cultured; Dengue; Dengue Virus; Disease Models, Animal; Endothelial Cells; Host-Pathogen Interactions; Humans; Mice; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Signal Transduction; Triazines; Vascular Endothelial Growth Factor Receptor-2; Virus Replication
PubMed: 34116207
DOI: 10.1016/j.phrs.2021.105721 -
Clinical Cancer Research : An Official... Oct 2008Hepatocellular carcinoma (HCC) is the fifth most common primary neoplasm; surgery is the only curative option but 5-year survival rates are only 25% to 50%. Vascular...
Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma.
PURPOSE
Hepatocellular carcinoma (HCC) is the fifth most common primary neoplasm; surgery is the only curative option but 5-year survival rates are only 25% to 50%. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) are known to be involved in growth and neovascularization of HCC. Therefore, agents that target these pathways may be effective in the treatment of HCC. The aim of this study was to determine the antineoplastic activity of brivanib alaninate, a dual inhibitor of VEGF receptor (VEGFR) and FGF receptor (FGFR) signaling pathways.
EXPERIMENTAL DESIGN
Six different s.c. patient-derived HCC xenografts were implanted into mice. Tumor growth was evaluated in mice treated with brivanib compared with control. The effects of brivanib on apoptosis and cell proliferation were evaluated by immunohistochemistry. The SK-HEP1 and HepG2 cells were used to investigate the effects of brivanib on the VEGFR-2 and FGFR-1 signaling pathways in vitro. Western blotting was used to determine changes in proteins in these xenografts and cell lines.
RESULTS
Brivanib significantly suppressed tumor growth in five of six xenograft lines. Furthermore, brivanib-induced growth inhibition was associated with a decrease in phosphorylated VEGFR-2 at Tyr(1054/1059), increased apoptosis, reduced microvessel density, inhibition of cell proliferation, and down-regulation of cell cycle regulators. The levels of FGFR-1 and FGFR-2 expression in these xenograft lines were positively correlated with its sensitivity to brivanib-induced growth inhibition. In VEGF-stimulated and basic FGF stimulated SK-HEP1 cells, brivanib significantly inhibited VEGFR-2, FGFR-1, extracellular signal-regulated kinase 1/2, and Akt phosphorylation.
CONCLUSION
This study provides a strong rationale for clinical investigation of brivanib in patients with HCC.
Topics: Alanine; Animals; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Humans; Liver Neoplasms; Male; Mice; Models, Chemical; Neoplasm Transplantation; Neovascularization, Pathologic; Receptors, Fibroblast Growth Factor; Receptors, Vascular Endothelial Growth Factor; Triazines
PubMed: 18829493
DOI: 10.1158/1078-0432.CCR-08-0509 -
Medicine Mar 2019Hepatocellular carcinoma (HCC) is one of the most frequent causes of cancer-related death worldwide. Its poor prognosis is due to the high invasiveness of the disease...
RATIONALE
Hepatocellular carcinoma (HCC) is one of the most frequent causes of cancer-related death worldwide. Its poor prognosis is due to the high invasiveness of the disease and limited efficacy of available treatments.
PATIENT CONCERNS
We reported an HCC patient who developed lung metastases 1 year after HCC resection. Sorafenib was then initiated; however, disease progression was noted 3 months later. Sorafenib therapy was initially maintained due to lack of effective alternatives, but disease progression continued.
DIAGNOSES
HCC patient with lung metastases, and pulmonary portal, and mediastinal lymph node metastases (stage IVB).
INTERVENTIONS
Brivanib alaninate was used alone as second-line therapy.
OUTCOMES
All metastases showed increased size on radiographic imaging approximately 3 months after brivanib alaninate was initiated. However, 2.5 months later, the lung metastases significantly decreased in size or disappeared. The pulmonary portal, and mediastinal lymph node metastases also significantly decreased in size. At 9.5 months after brivanib alaninate initiation, the pulmonary portal, and mediastinal lymph node metastases nearly disappeared, and the lung metastases continued to decrease in size. Alpha fetoprotein (AFP) level showed the same change pattern as the tumor-response observed on radiographic imaging. The total duration of brivanib alaninate treatment was 11 months, which was stopped due to repeated grade 2 thrombocytopenia. The other side effects were tolerable. Fifteen months after initiation of brivanib alaninate, the patient remained in very good condition without evidence of disease progression.
LESSONS
Brivanib alaninate alone as second-line therapy showed excellent antitumor efficacy for an HCC patient with numerous lung and lymph node metastases. It may exert its antitumor effects in a delayed-onset fashion. We suggest that patients receive brivanib alaninate for a long duration to fully determine its efficacy.
Topics: Alanine; Antineoplastic Agents; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Male; Middle Aged; Retreatment; Sorafenib; Treatment Failure; Triazines
PubMed: 30855507
DOI: 10.1097/MD.0000000000014823 -
Drug Metabolism and Disposition: the... Dec 2012Brivanib alaninate is an orally administered alanine prodrug of brivanib, a dual inhibitor of the vascular endothelial growth factor (VEGF) and fibroblast growth factor...
Brivanib alaninate is an orally administered alanine prodrug of brivanib, a dual inhibitor of the vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) signaling pathways. It is currently in clinical trials for the treatment of hepatocellular carcinoma and colorectal cancer. Brivanib has a single asymmetric center derived from a secondary alcohol. The potential for chiral inversion was investigated in incubations with liver subcellular fractions and in animals and humans after oral doses of brivanib alaninate. Incubations of [¹⁴C]brivanib alaninate with liver microsomes and cytosols from rats, monkeys, and humans followed by chiral chromatography resulted in two radioactive peaks, corresponding to brivanib and its enantiomer. The percentage of the enantiomeric metabolite relative to brivanib in microsomal and cytosolic incubations of different species in the presence of NADPH ranged from 11.6 to 15.8 and 0.8 to 3.1%, respectively. The proposed mechanism of inversion involves the oxidation of brivanib to a ketone metabolite, which is subsequently reduced to brivanib and its enantiomer. After oral doses of brivanib alaninate to rats and monkeys, the enantiomeric metabolite was a prominent drug-related component in plasma, with the percentages of area under the curve (AUC) at 94.7 and 39.7%, respectively, relative to brivanib. In humans, the enantiomeric metabolite was a minor circulating component, with the AUC <3% of brivanib. Pharmacological studies indicated that brivanib and its enantiomer had similar potency toward the inhibition of VEGF receptor-2 and FGF receptor-1 kinases. Because of low plasma concentration in humans, the enantiomeric metabolite was not expected to contribute significantly to target-related pharmacology of brivanib. Moreover, adequate exposure in the toxicology species suggested no specific safety concerns with respect to exposure to the enantiomeric metabolite.
Topics: Administration, Oral; Adolescent; Adult; Alanine; Animals; Area Under Curve; Cytosol; Female; Humans; Ketones; Macaca fascicularis; Male; Microsomes, Liver; Middle Aged; NADP; Oxidation-Reduction; Rats; Rats, Sprague-Dawley; Receptor, Fibroblast Growth Factor, Type 1; Triazines; Vascular Endothelial Growth Factor Receptor-2; Young Adult
PubMed: 22983304
DOI: 10.1124/dmd.112.047340 -
Future Oncology (London, England) Sep 2012The development of new agents in oncology has focused on disrupting key pathways in oncogenesis. Both malignant angiogenesis and peptide growth factor signaling have... (Review)
Review
The development of new agents in oncology has focused on disrupting key pathways in oncogenesis. Both malignant angiogenesis and peptide growth factor signaling have been studied extensively and have been validated for cancer treatment. While antibody-directed therapeutics offer increased specificity, small-molecule tyrosine kinase inhibitors often have the ability to hit multiple targets. Brivanib alaninate (BMS582664) is an oral, potent selective inhibitor of both the FGF and VEGF family of receptors. It is a first-in-class FGF/VEGF inhibitor now in late-phase clinical trials. Besides its antiangiogenic activity from blocking VEGF receptor 1-3, its ability to disrupt FGF receptors 1-3 has been suggested to add additional antiangiogenic activity, overcome resistance from VEGF blockade, and block FGF-dependent tumor proliferation. In this review, we will discuss the preclinical science driving brivanib's development and the clinical data generated to date.
Topics: Alanine; Angiogenesis Inhibitors; Animals; Clinical Trials as Topic; Drug Screening Assays, Antitumor; Humans; Neoplasms; Treatment Outcome; Triazines
PubMed: 23030483
DOI: 10.2217/fon.12.104 -
Journal of Clinical Pharmacology Jun 2012Brivanib alaninate is the orally available prodrug of brivanib, a dual inhibitor of fibroblast growth factor and vascular endothelial growth factor signaling pathways... (Clinical Trial)
Clinical Trial
Brivanib alaninate is the orally available prodrug of brivanib, a dual inhibitor of fibroblast growth factor and vascular endothelial growth factor signaling pathways that is under therapeutic investigation for various malignancies. Brivanib alaninate inhibits CYP3A4 in vitro, and thus there is potential for drug-drug interaction with CYP3A4 substrates, such as midazolam. The present study evaluated pharmacokinetic parameters and safety/tolerability upon coadministration of brivanib alaninate and midazolam. Healthy participants received intravenous (IV) or oral midazolam with and without oral brivanib alaninate. Blood samples for pharmacokinetic analysis were collected up to 12 hours after midazolam and up to 48 hours after brivanib alaninate. Twenty-four participants were administered study drugs; 21 completed the trial. No clinically relevant effect of brivanib alaninate on the overall exposure to midazolam following IV or oral administration was observed. Orally administered brivanib alaninate was generally well tolerated in the presence of IV or oral midazolam. The lack of a pharmacokinetic interaction between brivanib and midazolam indicates that brivanib alaninate does not influence either intestinal or hepatic CYP3A4 and confirms that brivanib alaninate may be safely coadministered with midazolam and other CYP3A4 substrates.
Topics: Administration, Oral; Adult; Alanine; Antineoplastic Agents; Cross-Over Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Female; Fibroblast Growth Factors; Half-Life; Humans; Injections, Intravenous; Intestines; Liver; Male; Metabolic Detoxication, Phase I; Midazolam; Middle Aged; Patient Dropouts; Prodrugs; Receptors, Vascular Endothelial Growth Factor; Triazines
PubMed: 21659627
DOI: 10.1177/0091270011407495 -
Cancer Chemotherapy and Pharmacology Dec 2009Brivanib alaninate is a prodrug of brivanib (BMS-540215), a potent oral VEGFR-2 inhibitor and is currently in development for the treatment of hepatocellular and colon...
PURPOSE
Brivanib alaninate is a prodrug of brivanib (BMS-540215), a potent oral VEGFR-2 inhibitor and is currently in development for the treatment of hepatocellular and colon carcinomas. In vitro and in vivo studies were conducted to characterize the preclinical pharmacokinetics and disposition of brivanib and brivanib alaninate, and antitumor efficacy in mice bearing human xenografts.
METHODS
In vitro studies were conducted in liver and intestinal fractions, plasma and Caco-2 cells to assess the metabolic stability. Pharmacokinetics of brivanib were determined in preclinical species after administration of single intravenous or oral doses of both brivanib and brivanib alaninate. The antitumor efficacy was assessed at equimolar doses in nude mice bearing human tumor xenografts. Human efficacious dose was predicted based on projected human pharmacokinetic parameters and exposure at efficacious doses in the mouse efficacy models.
RESULTS
In vitro and in vivo studies indicated that brivanib alaninate was efficiently converted to brivanib. Brivanib showed good brain penetration in rats consistent with its high intrinsic permeability and lack of active efflux in Caco-2 cells. The oral bioavailability of brivanib varied among species (22-88%) and showed dissolution rate-limited absorption even when combined with organic co-solvents. Administration of brivanib as brivanib alaninate allowed completely aqueous vehicles, and an improvement in the oral bioavailability (55-97%) was observed. The clearance of brivanib in humans is anticipated to be low to intermediate (hepatic extraction ratio < 0.7), while its volume of distribution is expected to be high. The minimum efficacious dose of brivanib alaninate was determined to be 60 mg/kg per day.
CONCLUSIONS
Brivanib alaninate is rapidly and efficiently converted to the parent, brivanib, as demonstrated both in vitro and in vivo and offers an excellent mode to deliver brivanib orally.
Topics: Administration, Oral; Alanine; Animals; Antineoplastic Agents; Biological Availability; Brain; Caco-2 Cells; Dogs; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Humans; Injections, Intravenous; Macaca fascicularis; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Prodrugs; Pyrroles; Rats; Solubility; Tissue Distribution; Triazines; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays
PubMed: 19396600
DOI: 10.1007/s00280-009-1002-0 -
Drug Metabolism and Disposition: the... May 2011Brivanib [(R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[1,2,4]triazin-6-yloxy)propan-2-ol, BMS-540215] is a potent and selective dual inhibitor of...
Brivanib [(R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[1,2,4]triazin-6-yloxy)propan-2-ol, BMS-540215] is a potent and selective dual inhibitor of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) signaling pathways. Its alanine prodrug, brivanib alaninate [(1R,2S)-2-aminopropionic acid 2-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy]-1-methylethyl ester, BMS-582664], is currently under development as an oral agent for the treatment of cancer. This study describes the in vivo biotransformation of brivanib after a single oral dose of [(14)C]brivanib alaninate to intact rats, bile duct-cannulated (BDC) rats, intact monkeys, BDC monkeys, and humans. Fecal excretion was the primary route of elimination of drug-derived radioactivity in animals and humans. In BDC rats and monkeys, the majority of radioactivity was excreted in bile. Brivanib alaninate was rapidly and completely converted via hydrolysis to brivanib in vivo. The area under the curve from zero to infinity of brivanib accounted for 14.2 to 54.3% of circulating radioactivity in plasma in animals and humans, suggesting that metabolites contributed significantly to the total drug-related radioactivity. In plasma from animals and humans, brivanib was a prominent circulating component. All the metabolites that humans were exposed to were also present in toxicological species. On the basis of metabolite exposure and activity against VEGF and FGF receptors of the prominent human circulating metabolites, only brivanib is expected to contribute to the pharmacological effects in humans. Unchanged brivanib was not detected in urine or bile samples, suggesting that metabolic clearance was the primary route of elimination. The primary metabolic pathways were oxidative and conjugative metabolism of brivanib.
Topics: Administration, Oral; Alanine; Animals; Antineoplastic Agents; Bile; Biotransformation; Feces; Humans; Macaca fascicularis; Male; Neoplasms; Radioligand Assay; Rats; Rats, Sprague-Dawley; Triazines; Vascular Endothelial Growth Factor Receptor-2
PubMed: 21289073
DOI: 10.1124/dmd.110.037341 -
Journal of Cellular Physiology Feb 2020In age-related macular degeneration (AMD), choroidal neovascularization (CNV), a major pathologic feature of neovascular AMD (nAMD), affects 10% of patients, potentially...
In age-related macular degeneration (AMD), choroidal neovascularization (CNV), a major pathologic feature of neovascular AMD (nAMD), affects 10% of patients, potentially causing serious complications, including vision loss. Vascular endothelial growth factor receptor 2 (VEGFR2) and fibroblast growth factor receptor 1 (FGFR1) contribute to the pathogenesis of CNV. Brivanib is an oral selective dual receptor tyrosine kinase (RTK) inhibitor of FGFRs and VEGFRs, especially VEGFR2 and FGFR1. In this study, brivanib inhibited zebrafish embryonic angiogenesis without impairing neurodevelopment. In a mouse CNV model, brivanib intravitreal injection blocked phosphorylation of FGFR1 and VEGFR2 and reduced CNV leakage, area, and formation without causing intraocular toxicity. Moreover, brivanib oral gavage reduced CNV leakage and area. Accordingly, brivanib remained at high concentrations (above 14,000 ng/ml) in retinal/choroidal/scleral tissues following intravitreal injection. Similarly, brivanib remained at high concentrations (over 10,000 ng/ml) in retinal/choroidal/scleral tissues following oral gavage. Finally, in vitro cell experiments demonstrated that brivanib inhibited the proliferation, migration and tube formation of microvascular endothelial cells. In conclusion, our study suggested that brivanib treatment could be a novel therapeutic strategy for nAMD.
Topics: Alanine; Angiogenesis Inhibitors; Animals; Cell Movement; Cell Proliferation; Choroidal Neovascularization; Disease Models, Animal; Endothelial Cells; Lasers; Male; Mice; Mice, Inbred C57BL; Protein Kinase Inhibitors; Triazines; Wet Macular Degeneration; Zebrafish
PubMed: 31270802
DOI: 10.1002/jcp.29041