-
Drug Metabolism and Disposition: the... Nov 2010The goal of this study was to evaluate the pharmacokinetics, mass balance, metabolism, routes and extent of elimination, and safety of a single oral dose of... (Clinical Trial)
Clinical Trial
The goal of this study was to evaluate the pharmacokinetics, mass balance, metabolism, routes and extent of elimination, and safety of a single oral dose of (14)C-labeled brivanib alaninate and the safety and tolerability of brivanib after multiple doses in patients with advanced or metastatic solid tumors. This was a two-part, single-center, open-label, single oral-dose (part A) followed by multiple-dose (part B) study in patients with advanced or metastatic solid tumors. In part A, patients received a single dose of [(14)C]brivanib alaninate and in part B patients received 800 mg of nonradiolabeled brivanib alaninate every day. Four patients (two white, two black: two with non-small-cell lung cancer, one with ovarian cancer, and one with renal cell carcinoma) were treated in both parts. The median time to reach the maximal plasma concentration of brivanib was 1 h, geometric mean maximal plasma concentration was 6146 ng/ml, mean terminal half-life was 13.8 h, and geometric mean apparent oral clearance was 14.7 l/h. After a single oral dose of [(14)C]brivanib alaninate, 12.2 and 81.5% of administered radioactivity was recovered in urine and feces, respectively. Brivanib alaninate was completely converted to the active moiety, brivanib, and the predominant route of elimination was fecal. Renal excretion of unchanged brivanib was minimal. Brivanib was well tolerated; fatigue was the most frequent adverse event occurring in all patients and the most frequent treatment-related adverse event in three (75%). The best clinical response in one patient was stable disease; the other three had progressive disease. Brivanib alaninate was rapidly absorbed and extensively metabolized after a single 800-mg oral dose; the majority of drug-related radioactivity was excreted in feces.
Topics: Administration, Oral; Aged; Alanine; Antineoplastic Agents; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Feces; Female; Humans; Male; Metabolic Clearance Rate; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Pyrroles; Triazines
PubMed: 20671097
DOI: 10.1124/dmd.110.033951 -
European Journal of Cancer (Oxford,... Jun 2010Tamoxifen, a selective oestrogen receptor modulator (SERM), and brivanib alaninate, a vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor, are two target...
Experimental treatment of oestrogen receptor (ER) positive breast cancer with tamoxifen and brivanib alaninate, a VEGFR-2/FGFR-1 kinase inhibitor: a potential clinical application of angiogenesis inhibitors.
PURPOSE
Tamoxifen, a selective oestrogen receptor modulator (SERM), and brivanib alaninate, a vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor, are two target specific agents that result in a substantial decrease in tumour growth when given alone. Tamoxifen activates SERM stimulated breast and endometrial tumour growth. Tamoxifen and brivanib alaninate have side-effects that can affect therapeutic outcomes. The primary goal of the current study was to evaluate the therapeutic effects of lower doses of both agents when given in combination to mice with SERM sensitive, oestrogen stimulated tumour xenografts (MCF-7 E2 tumours). Experiments were conducted to evaluate the response of SERM stimulated breast (MCF-7 Tam, MCF-7 Ral) and endometrial tumours (EnCa 101) to demonstrate the activity of brivanib alaninate in SERM resistant models.
EXPERIMENTAL DESIGN
In the current study, tumour xenografts were minced and bi-transplanted into the mammary fat pads of athymic, ovariectomised mice. Preliminary experiments were conducted to determine an effective oral dose of tamoxifen and brivanib alaninate that had minimal effect on tumour growth. Doses of 125 microg of tamoxifen and 0.05 mg/g of brivanib alaninate were evaluated. An experiment was designed to evaluate the effect of the two agents together when started at the time of tumour implantation. An additional experiment was done in which tumours were already established and then treated, to obtain enough tumour tissue for molecular analysis.
RESULTS
Brivanib alaninate was effective at inhibiting tumour growth in SERM sensitive (MCF-7 E2) and SERM stimulated (EnCa 101, MCF-7 Ral, MCF-7 Tam) models. The effect of the low dose drug combination as an anti-tumour strategy for SERM sensitive (MCF-7 E2) in early treatment was as effective as higher doses of either drug used alone. In established tumours, the combination is successful at decreasing tumour growth, while neither agent alone is effective. Molecular analysis revealed a decreased phosphorylation of VEGFR-2 in tumours that were treated with brivanib alaninate and an increase in VEGFA transcription to compensate for the blockade of VEGFR-2 by increasing the transcription of VEGFA. Tamoxifen increases the phosphorylation of VEGFR-2 and this effect is abrogated by brivanib alaninate. There was also increased necrosis in tumours treated with brivanib alaninate.
CONCLUSION
Historically, tamoxifen has a role in blocking angiogenesis as well as the blockade of the ER. Tamoxifen and a low dose of an angiogenesis inhibitor, brivanib alaninate, can potentially be combined not only to maximise therapeutic efficacy but also to retard SERM resistant tumour growth.
Topics: Alanine; Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Dose-Response Relationship, Drug; Female; Humans; Immunohistochemistry; Mice; Mice, Nude; Neoplasm Transplantation; Pyrroles; Random Allocation; Receptor, Fibroblast Growth Factor, Type 1; Reverse Transcriptase Polymerase Chain Reaction; Tamoxifen; Transplantation, Heterologous; Triazines; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2
PubMed: 20303261
DOI: 10.1016/j.ejca.2010.02.018 -
Best Practice & Research. Clinical... Oct 2014In the last years the management of patients with liver cancer has been improved. The BCLC staging/treatment strategy identifies the optimal candidates for each... (Review)
Review
In the last years the management of patients with liver cancer has been improved. The BCLC staging/treatment strategy identifies the optimal candidates for each treatment option and sorafenib is the only effective systemic treatment. Others (sunitinib, brivanib, linifanib, everolimus, ramucirumab) have failed in terms of safety/survival benefit. Some patients at intermediate/early stage, may be considered for systemic therapy when options of higher priority may have failed or not be feasible. The 800 mg/day is the recommended starting dose. Close follow-up and easy access for the patients so that they can report any adverse event and implement dose adjustments is the key point in the management of them. Development of early dermatologic adverse events has been correlated with better outcome and the pattern of radiologic progression characterizes better the prognosis/outcome of these patients. Treatment beyond progression may be considered if there is no option for a second line research trial.
Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Niacinamide; Patient Selection; Phenylurea Compounds; Sorafenib; Treatment Outcome
PubMed: 25260318
DOI: 10.1016/j.bpg.2014.08.003 -
European Journal of Cancer (Oxford,... Oct 2019Brivanib is a selective inhibitor of vascular endothelial growth factor and fibroblast growth factor (FGF) signalling. We performed a phase II randomised discontinuation... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Brivanib is a selective inhibitor of vascular endothelial growth factor and fibroblast growth factor (FGF) signalling. We performed a phase II randomised discontinuation trial of brivanib in 7 tumour types (soft-tissue sarcomas [STS], ovarian cancer, breast cancer, pancreatic cancer, non-small-cell lung cancer [NSCLC], gastric/esophageal cancer and transitional cell carcinoma [TCC]).
PATIENTS AND METHODS
During a 12-week open-label lead-in period, patients received brivanib 800 mg daily and were evaluated for FGF2 status by immunohistochemistry. Patients with stable disease at week 12 were randomised to brivanib or placebo. A study steering committee evaluated week 12 response to determine if enrolment in a tumour type would continue. The primary objective was progression-free survival (PFS) for brivanib versus placebo in patients with FGF2-positive tumours.
RESULTS
A total of 595 patients were treated, and stable disease was observed at the week 12 randomisation point in all tumour types. Closure decisions were made for breast cancer, pancreatic cancer, NSCLC, gastric cancer and TCC. Criteria for expansion were met for STS and ovarian cancer. In 53 randomised patients with STS and FGF2-positive tumours, the median PFS was 2.8 months for brivanib and 1.4 months for placebo (hazard ratio [HR]: 0.58, p = 0.08). For all randomised patients with sarcomas, the median PFS was 2.8 months (95% confidence interval [CI]: 1.4-4.0) for those treated with brivanib compared with 1.4 months (95% CI: 1.3-1.6) for placebo (HR = 0.64, 95% CI: 0.38-1.07; p = 0.09). In the 36 randomised patients with ovarian cancer and FGF2-positive tumours, the median PFS was 4.0 (95% CI: 2.6-4.2) months for brivanib and 2.0 months (95% CI: 1.2-2.7) for placebo (HR: 0.56, 95% CI: 0.26-1.22). For all randomised patients with ovarian cancer, the median PFS in those randomised to brivanib was 4.0 months (95% CI: 2.6-4.2) and was 2.0 months (95% CI: 1.2-2.7) in those randomised to placebo (HR = 0.54, 95% CI: 0.25-1.17; p = 0.11).
CONCLUSION
Brivanib demonstrated activity in STS and ovarian cancer with an acceptable safety profile. FGF2 expression, as defined in the protocol, is not a predictive biomarker of the efficacy of brivanib.
Topics: Aged; Alanine; Antineoplastic Agents; Biomarkers, Tumor; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasms; Prognosis; Survival Rate; Triazines; Withholding Treatment
PubMed: 31522033
DOI: 10.1016/j.ejca.2019.07.024 -
International Journal of Pharmaceutics Jul 2014A quality by design approach was applied to the development of brivanib alaninate tablets. Brivanib alaninate, an ester pro-drug, undergoes hydrolysis to its parent...
A quality by design approach was applied to the development of brivanib alaninate tablets. Brivanib alaninate, an ester pro-drug, undergoes hydrolysis to its parent compound, BMS-540215. The shelf-life of the tablets is determined by the rate of the hydrolysis reaction. Hydrolysis kinetics in the tablets was studied to understand its dependence on temperature and humidity. The BMS-540215 amount versus time profile was simulated using a kinetic model for the formation of BMS-540215 as function of relative humidity in the environment and a sorption-desorptiom moisture transfer model for the relative humidity inside the package. The combined model was used to study the effect of initial tablet water content on the rate of degradation and to identify a limit for initial tablet water content that results in acceptable level of the degradant at the end of shelf-life. A strategy was established for the moisture and degradant control in the tablet based on the understanding of its stability behavior and mathematical models. The control strategy includes a specification limit on the tablet water content and manufacturing process controls that achieve this limit at the time of tablet release testing.
Topics: Alanine; Angiogenesis Inhibitors; Chemistry, Pharmaceutical; Computer Simulation; Drug Stability; Humidity; Hydrolysis; Kinetics; Models, Chemical; Prodrugs; Quality Control; Solubility; Tablets; Technology, Pharmaceutical; Temperature; Triazines; Water
PubMed: 24780101
DOI: 10.1016/j.ijpharm.2014.04.059 -
Journal of Clinical Oncology : Official... Oct 2013
Topics: Alanine; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Drug Resistance, Neoplasm; Female; Humans; Liver Neoplasms; Male; Niacinamide; Palliative Care; Phenylurea Compounds; Protein Kinase Inhibitors; Salvage Therapy; Sorafenib; Triazines
PubMed: 23980088
DOI: 10.1200/JCO.2013.49.7941 -
Journal of Gastroenterology and... May 2014Vascular endothelial (VEGF) and fibroblast growth factor (FGF)-induced hepatic stellate (HSCs) and liver endothelial cells (LECs) activation accelerates hepatic...
Beneficial effects of dual vascular endothelial growth factor receptor/fibroblast growth factor receptor inhibitor brivanib alaninate in cirrhotic portal hypertensive rats.
BACKGROUND AND AIM
Vascular endothelial (VEGF) and fibroblast growth factor (FGF)-induced hepatic stellate (HSCs) and liver endothelial cells (LECs) activation accelerates hepatic fibrogenesis and angiogenesis, and hemodynamic dysarrangements in cirrhosis. VEGF targeting agents had been reported as potential drugs for cirrhosis. However, the evaluation of effects of dual VEGF/FGF targeting agent in cirrhosis is still limited.
METHODS
Using hemodynamic parameters, blood chemistry, primary isolated HSCs and LECs, histology, and digital imaging, we assess the effects of 2-week brivanib alaninate, a dual VEGFR/FGFR inhibitor, treatment in the pathophysiology of bile duct-ligated-cirrhotic rats.
RESULTS
Fibrogenic and angiogenic markers in the serum and liver of bile duct-ligated-cirrhotic rats, including hydroxyproline, transforming growth factor-β1, angiopoietin-1, VEGF, FGF-2, endocan and phosphorylated-VEGFR2/VEGFR2, and phosphorylated-FGFR/FGFR together with hepatic CD31/angiopoietin-1 expressions (immunohistochemistry staining), angiogenesis (micro-computed tomography scan), microcirculatory dysfunction (in vivo miscroscopy and in situ liver perfusion study), portal hypertension, and hyperdynamic circulations (colored microsphere methods) were markedly suppressed and ameliorated by brivanib alaninate treatment. In in vitro study, acute brivanib alaninate incubation inhibited the transforming growth factor-β1-induced HSCs contraction/migration and VEGF-induced LECs angiogenesis. Concomitantly, the overexpression of various fibrogenic and angiogenic markers in HSCs and LECs, and in their culture media, was increased in parallel and these changes were suppressed by acute brivanib alaninate incubation.
CONCLUSIONS
This study demonstrated that brivanib alaninate targeting multiple mechanisms and working in the different pathogenic steps of the complications of cirrhotic rats with portal hypertension.
Topics: Alanine; Animals; Cell Proliferation; Cells, Cultured; Hepatic Stellate Cells; Hypertension, Portal; Liver Cirrhosis; Male; Molecular Targeted Therapy; Rats; Rats, Sprague-Dawley; Receptors, Fibroblast Growth Factor; Receptors, Vascular Endothelial Growth Factor; Triazines
PubMed: 24325631
DOI: 10.1111/jgh.12480 -
Molecular Pharmaceutics Nov 2019Brivanib, a promising tyrosine kinase inhibitor, is currently undergoing advanced stages of clinical evaluation for solid tumor therapy. In this work, we investigated...
Brivanib Exhibits Potential for Pharmacokinetic Drug-Drug Interactions and the Modulation of Multidrug Resistance through the Inhibition of Human ABCG2 Drug Efflux Transporter and CYP450 Biotransformation Enzymes.
Brivanib, a promising tyrosine kinase inhibitor, is currently undergoing advanced stages of clinical evaluation for solid tumor therapy. In this work, we investigated possible interactions of this novel drug candidate with ABC drug efflux transporters and cytochrome P450 (CYP450) drug-metabolizing enzymes that participate in cancer multidrug resistance (MDR) and pharmacokinetic drug-drug interactions (DDIs). First, in accumulation experiments with various model substrates, we identified brivanib as an inhibitor of the ABCB1, ABCG2, and ABCC1 transporters. However, in subsequent combination studies employing 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-tetrazolium bromide proliferation assays in both Madin-Darby canine kidney II (MDCKII) and A431 cellular models, only ABCG2 inhibition was revealed to be able to synergistically potentiate mitoxantrone effects. Advantageous to its possible use as MDR antagonist, brivanib's chemosensitizing properties were not impaired by activity of any of the MDR-associated ABC transporters, as observed in comparative viability assay in the MDCKII cell sublines. In incubation experiments with eight recombinant CYP450s, we found that brivanib potently inhibited CYP2C subfamily members and the CYP2B6 isoform. Finally, in induction studies, we demonstrated that brivanib upregulated and messenger RNA levels in systemic cell models, although this interaction was not significantly manifested at a functional level. In conclusion, brivanib exhibits potential to cause clinically relevant pharmacokinetic DDIs and act as a modulator of ABCG2-mediated MDR. Our findings might be used as an important background for subsequent in vivo investigations and pave the way for the safe and effective use of brivanib in oncological patients.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; Alanine; Animals; Biotransformation; Cell Line; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dogs; Drug Interactions; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Madin Darby Canine Kidney Cells; Neoplasm Proteins; Triazines
PubMed: 31633365
DOI: 10.1021/acs.molpharmaceut.9b00361 -
Drug Metabolism and Disposition: the... Jan 2012Brivanib alaninate, the L-alanine ester prodrug of brivanib, is currently being developed as an anticancer agent. In humans, brivanib alaninate is rapidly hydrolyzed to... (Comparative Study)
Comparative Study
Brivanib alaninate, the L-alanine ester prodrug of brivanib, is currently being developed as an anticancer agent. In humans, brivanib alaninate is rapidly hydrolyzed to brivanib. Prominent biotransformation pathways of brivanib included oxidation and direct sulfate conjugation. A series of in vitro studies were conducted to identify the human esterases involved in the prodrug hydrolysis and to identify the primary human cytochrome P450 and sulfotransferase (SULT) enzymes involved in the metabolism of brivanib. Brivanib alaninate was efficiently converted to brivanib in the presence of either human carboxylesterase 1 or carboxylesterase 2. Because esterases are ubiquitous, it is likely that multiple esterases are involved in the hydrolysis. Oxidation of brivanib in human liver microsomes (HLM) primarily formed a hydroxylated metabolite (M7). Incubation of brivanib with human cDNA-expressed P450 enzymes and with HLM in the presence of selective chemical inhibitors and monoclonal P450 antibodies demonstrated that CYP1A2 and CYP3A4 were the major contributors for the formation of M7. Direct sulfation of brivanib was catalyzed by multiple SULT enzymes, including SULT1A1, SULT1B1, SULT2A1, SULT1A3, and SULT1E1. Because the primary in vitro oxidative metabolite (M7) was not detected in humans after oral doses of brivanib alaninate, further metabolism studies of M7 in HLM and human liver cytosol were performed. The data demonstrated that M7 was metabolized to the prominent metabolites observed in humans. Overall, multiple enzymes are involved in the metabolism of brivanib, suggesting a low potential for drug-drug interactions either through polymorphism or through inhibition of a particular drug-metabolizing enzyme.
Topics: Alanine; Biotransformation; Cytochrome P-450 Enzyme System; Cytosol; Humans; Oxidation-Reduction; Sulfotransferases; Triazines
PubMed: 21989950
DOI: 10.1124/dmd.111.042457 -
PloS One 2014Brivanib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR) tyrosine kinases, which are both...
BACKGROUND AND AIMS
Brivanib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR) tyrosine kinases, which are both involved in mechanisms of liver fibrosis. We hypothesized that inhibition of VEGFR and FGFR by brivanib would inhibit liver fibrosis. We therefore examined the effect of brivanib on liver fibrosis in three mouse models of fibrosis.
METHODS
In vivo, we induced liver fibrosis by bile duct ligation (BDL), chronic carbon tetrachloride (CCl4), and chronic thioacetamide (TAA) administration. Liver fibrosis was examined by immunohistochemistry and Western immunoblotting. In vitro, we used LX-2 human hepatic stellate cells (HSCs) to assess the effect of brivanib on stellate cell proliferation and activation.
RESULTS
After in vivo induction with BDL, CCl4, and TAA, mice treated with brivanib showed reduced liver fibrosis and decreased expression of collagen Iα1 and α-smooth muscle actin in the liver. In vitro, brivanib decreased proliferation of HSCs induced by platelet-derived growth factor (PDGF), VEGF, and FGF. Brivanib also decreased stellate cell viability and inhibited PDGFBB-induced phosphorylation of its cognate receptor.
CONCLUSION
Brivanib reduces liver fibrosis in three different animal models and decreases human hepatic stellate cell activation. Brivanib may represent a novel therapeutic approach to treatment of liver fibrosis and prevention of liver cancer.
Topics: Alanine; Animals; Carbon Tetrachloride Poisoning; Cell Line; Cell Proliferation; Cell Survival; Collagen Type I; Collagen Type I, alpha 1 Chain; Fibroblast Growth Factors; Hepatic Stellate Cells; Humans; Immunohistochemistry; Liver Cirrhosis; Liver Neoplasms; Mice; Platelet-Derived Growth Factor; Protein Kinase Inhibitors; Signal Transduction; Triazines; Vascular Endothelial Growth Factor A
PubMed: 24710173
DOI: 10.1371/journal.pone.0092273