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Ian Walters - One of the best experts on this subject based on the ideXlab platform.
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Brivanib decreases the transcription of growth factors and their receptors in carbon tetrachloride.
2014Co-Authors: Ikuo Nakamura, Kais Zakharia, Bubu A. Banini, Dalia S. Mikhail, Tae Hyo Kim, Ju Dong Yang, Catherine D. Moser, Hassan M. Shaleh, Sarah R. Thornburgh, Ian WaltersAbstract:Hepatic levels of growth factors and growth factor receptor mRNA were measured by real time PCR in sham and CCl4 mice treated with no Brivanib or with Brivanib 25 mg/kg, 50 mg/kg, or 100 mg/kg. In all of the sham experiments, higher concentrations of Brivanib decreased the mRNA levels of the growth factors and their receptors. (A) mRNA levels of PDGFB are not affected by Brivanib treatment in CCl4. (B) mRNA levels of PDGFRB decrease as the concentration of Brivanib increases in CCl4. (C) mRNA levels of TGFB1 decrease as the concentration of Brivanib increases in CCl4. (D) mRNA levels of TGFBR2 are lower in Brivanib-treated CCl4 mice compared to no Brivanib. (E) mRNA levels of FGF2 are not affected by Brivanib treatment in CCl4. (F) mRNA levels of FGFR2 are lower in Brivanib-treated CCl4 mice compared to no Brivanib. (G, H) mRNA levels of VEGFA and VEGFR2 decrease as the concentration of Brivanib increases in CCl4 mice.
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Brivanib inhibits unstimulated and PDGF, VEGF, or FGF2-stimulated LX-2 cell proliferation.
2014Co-Authors: Ikuo Nakamura, Kais Zakharia, Bubu A. Banini, Dalia S. Mikhail, Tae Hyo Kim, Ju Dong Yang, Catherine D. Moser, Hassan M. Shaleh, Sarah R. Thornburgh, Ian WaltersAbstract:The effect of Brivanib on cell proliferation of LX-2 HSCs without growth factor (A). The effect of Brivanib on LX-2 cell proliferation induced by 50 ng/ml PDGF (B); 1 ng/ml VEGF (C); or 10 ng/ml FGF (D). LX-2 HSCs were starved for 24 hours, Brivanib was added at the indicated concentrations, and 2 hours later, the respective growth factor was added. BrdU incorporation was measured at 72 hours after the administration of growth factor. Data shown are representative of four samples per treatment group and are presented as mean ± SEM. ∞,P
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Brivanib does not inhibit TGF-β1-induced α-SMA expression in human LX-2 hepatic stellate cells.
2014Co-Authors: Ikuo Nakamura, Kais Zakharia, Bubu A. Banini, Dalia S. Mikhail, Tae Hyo Kim, Ju Dong Yang, Catherine D. Moser, Hassan M. Shaleh, Sarah R. Thornburgh, Ian WaltersAbstract:(A) The expression of α-SMA in LX-2 HSCs after TGF-β1 treatment was assessed by Western immunoblotting. HSCs were incubated with 10% or 1% FBS for 24 hours, and TGF-β1 was added at different concentrations. The lysate was extracted 24 hours after addition of TGF-β1. Peak α-SMA expression was seen after treatment with 2 ng/ml of TGF-β1. (B) To determine the effect of Brivanib on TGF-β1-induced activation of HSCs as assessed by α-SMA expression, LX-2 HSCs were partially serum-starved by incubation with 1% FBS for 24 hours. Brivanib was then added at increasing concentrations 2 hours before addition of 2 ng/ml TGF-β1. Cell lysates were prepared 24 hours after adding TGF-β1 and analyzed by Western immunoblotting.
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Brivanib decreases viability of PDGF-BB treated LX-2 cells.
2014Co-Authors: Ikuo Nakamura, Kais Zakharia, Bubu A. Banini, Dalia S. Mikhail, Tae Hyo Kim, Ju Dong Yang, Catherine D. Moser, Hassan M. Shaleh, Sarah R. Thornburgh, Ian WaltersAbstract:(A) The effect of increasing concentrations of Brivanib on the viability of LX-2 HSCs cultured in DMEM/10% FBS was assessed using Cell Counting Kit-8 (CCK-8). Cells showed a Brivanib dose-dependent decrease in viability, with half maximal inhibitory concentration (IC50) of 16.98 µM (95% CI 13.95 µM–20.67 µM). (B) Cells stimulated with 5 ng/ml PDGF-BB in serum-free medium showed a similar trend albeit more pronounced decrease in viability compared to cells cultured in 10% FBS. The IC50 of LX-2 cells cultured in serum-free media supplemented with PDGF-BB was 8.79 µM (95% CI 7.80 µM–9.99 µM).
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Brivanib inhibits PDGF-BB induced phosphorylation of PDGFRβ in human LX-2 hepatic stellate cells.
2014Co-Authors: Ikuo Nakamura, Kais Zakharia, Bubu A. Banini, Dalia S. Mikhail, Tae Hyo Kim, Ju Dong Yang, Catherine D. Moser, Hassan M. Shaleh, Sarah R. Thornburgh, Ian WaltersAbstract:(A) The expression of phosphorylated (P-PDGFRβ) and total PDGFRβ (T-PDGFRβ) in HSCs after PDGF-BB treatment was assessed by Western immunoblotting. HSCs were incubated in 10% FBS-supplemented DMEM for 24 hours, followed by starvation in serum-free medium for 24 hours. PDGF-BB was added at 5 or 10 ng/ml, followed by extraction of protein lysate 1 or 5 minutes after induction with PDGF-BB. Both time- and dose-dependent increase in phosphorylated PDGFRβ were seen, with minimal change in total PDGFRβ. β-actin was used as a loading control. (B) To determine the effect of Brivanib on PDGF-BB induced phosphorylation of PDGFRβ, LX-2 cells were serum starved, followed by treatment with 5, 10 or 20 µM of Brivanib. Two hours after Brivanib treatment, 5 ng/ml PDGF-BB was added, and protein lysates prepared after 5 minutes of PDGF-BB exposure. All doses of Brivanib tested inhibited PDGF-BB induced phosphorylation of PDGFRβ. (C) Ratio of phosphorylated PDGFRβ relative to total PDGFRβ. Prior to calculation of the P-PDGFRβ/T-PDGFRβ ratio, protein levels were first normalized to β-actin, and then to the P-PDGFRβ or T-PDGFRβ level in their respective control studies. Data represents the mean of four replicate studies ± SEM.
Eric Masson - One of the best experts on this subject based on the ideXlab platform.
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The effects of liver impairment on the pharmacokinetics of Brivanib, a dual inhibitor of fibroblast growth factor receptor and vascular endothelial growth factor receptor tyrosine kinases
Cancer Chemotherapy and Pharmacology, 2013Co-Authors: Anthony El-khoueiry, Ian Walters, Shariq Syed, Georgia Kollia, Bruce S. Fischer, James A. Posey, Juan Ramón Castillo Ferrando, Smitha S. Krishnamurthi, Eric MassonAbstract:Purpose Hepatic impairment may impede tyrosine kinase inhibitor metabolism. This phase I study compared the pharmacokinetics of Brivanib in patients with hepatocellular carcinoma (HCC) and varying levels of hepatic impairment with those with non-HCC malignancies and normal liver function. Methods Patients were assigned to the following groups: Groups A, B, and C (HCC plus mild, moderate, or severe hepatic impairment, respectively) and Group D (non-HCC malignancy and normal hepatic function). Brivanib alaninate (Brivanib prodrug) doses were 400 mg in Groups A, B, and D and 200 mg in Group C. Brivanib exposure was determined on day 1 (single dose) and day 28 (multiple doses). Results Twenty-four patients participated in the study. After a single Brivanib alaninate dose, Brivanib exposure was comparable between Groups A, B, and D. Area under the concentration–time curve was 50 % higher in Group C versus Group D. There were not enough data to draw conclusions on multiple doses. Safety profile in Groups A, B, and D was consistent with previous Brivanib monotherapy experience. Tolerability could not be assessed in Group C because of dose interruptions and discontinuations, generally due to the disease natural history. Conclusions Brivanib exposure was similar in patients with HCC and mild or moderate hepatic impairment (Child-Pugh [CP] A or B status) and those with non-HCC malignancies and normal hepatic function, suggesting dose adjustment is unnecessary with CP A or B status. Experience with HCC and severe hepatic impairment (CP C status) is insufficient to recommend Brivanib use in this population.
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The effects of liver impairment on the pharmacokinetics of Brivanib, a dual inhibitor of fibroblast growth factor receptor and vascular endothelial growth factor receptor tyrosine kinases
Cancer chemotherapy and pharmacology, 2013Co-Authors: Anthony B. El-khoueiry, Ian Walters, Shariq Syed, Georgia Kollia, Bruce S. Fischer, Smitha S. Krishnamurthi, James Posey, Juan Ramón Castillo Ferrando, Eric MassonAbstract:Purpose Hepatic impairment may impede tyrosine kinase inhibitor metabolism. This phase I study compared the pharmacokinetics of Brivanib in patients with hepatocellular carcinoma (HCC) and varying levels of hepatic impairment with those with non-HCC malignancies and normal liver function.
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Metabolic Chiral Inversion of Brivanib and Its Relevance to Safety and Pharmacology
Drug metabolism and disposition: the biological fate of chemicals, 2012Co-Authors: Jiachang Gong, Shariq Syed, Eric Masson, Jinping Gan, Yuan-qing Xia, Daphne Williams, Janice Pursley, Mohammed Jemal, W. Griff Humphreys, Ramaswamy A. IyerAbstract: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
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Lack of food effect on single-dose pharmacokinetics of Brivanib, and safety and efficacy following multiple doses in subjects with advanced or metastatic solid tumors
Cancer Chemotherapy and Pharmacology, 2011Co-Authors: Patricia Lorusso, Shariq Syed, Georgia Kollia, Geoffrey I. Shapiro, Herbert Hurwitz, Mary Jo Pilat, Janice Chemidlin, Bruce Fischer, Eric MassonAbstract:Purpose Brivanib alaninate, an orally available prodrug of Brivanib, is currently under evaluation for the treatment of several malignancies. This study aimed to (1) investigate effects of a high-fat meal on single-dose pharmacokinetics of Brivanib in subjects with advanced/metastatic solid tumors and (2) assess the safety and preliminary efficacy of single and multiple doses of Brivanib alaninate in this population. Methods A two-part study was conducted consisting of a single-dose phase (Part A) and a multiple-dose phase (Part B). In Part A, subjects received a single dose of Brivanib alaninate (800 mg) either in a fasting state or following ingestion of a high-fat meal (approximately 951 kcal [15% protein, 33% carbohydrate, 52% fat]); serial blood samples were collected for pharmacokinetic analysis up to 48 h post-dosing. In Part B, subjects received Brivanib alaninate (800 mg) once daily until discontinuation. Throughout both phases, subjects were evaluated for adverse events (AEs) and best clinical response. Results No clinically significant differences in Brivanib exposure were observed between fed and fasting subjects in Part A; C _max was unchanged and AUC_INF decreased marginally when administered in a fed versus fasted state. In Part A, the incidence of treatment-emergent AEs was broadly similar in a fed or fasted state. Brivanib alaninate was generally well tolerated throughout the study and showed preliminary evidence of antitumor activity. Conclusions Consumption of a high-fat meal had no significant effect on Brivanib pharmacokinetics. The study further demonstrates the acceptable safety/tolerability profile and antitumor potential of Brivanib in patients with advanced malignancies.
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Lack of Effect of Brivanib on the Pharmacokinetics of Midazolam, a CYP3A4 Substrate, Administered Intravenously and Orally in Healthy Participants
Journal of clinical pharmacology, 2011Co-Authors: Shariq Syed, Ian Walters, Pamela L. Clemens, Deanne Lathers, Georgia Kollia, Arindam Dhar, Eric MassonAbstract: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.
Joseph Fargnoli - One of the best experts on this subject based on the ideXlab platform.
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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.
European journal of cancer (Oxford England : 1990), 2010Co-Authors: Roshani R. Patel, Surojeet Sengupta, Helen Kim, Andres J. Klein-szanto, Jennifer R. Pyle, Fang Zhu, Eric A. Ross, Salewa Oseni, Joseph FargnoliAbstract:Abstract 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 μg 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.
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Abstract B12: The antitumor and antiangiogenic activity of Brivanib, a dual inhibitor of VEGFR‐2 and FGFR‐1 kinases
Angiogenesis and Antiangiogenesis Agents, 2009Co-Authors: Joseph Fargnoli, Robert Jeyaseelan, Barri Wautlet, Anne Lewin, Benjamin Henley, John T. HuntAbstract:Angiogenesis plays a central supporting role in tumorigenesis in a wide variety of different cancer types. This complex and highly regulated process has been shown to be driven by various proangiogenic factors. The vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) family of growth factors in conjunction with their associated tyrosine kinase receptors exert a major influence on tumor growth and dissemination, and potentially work synergistically to promote angiogenesis. Brivanib alaninate (BMS‐582664) which is currently in phase III clinical trails is the orally active prodrug of Brivanib (BMS‐540215), a selective dual inhibitor of VEGF and FGF signaling. We demonstrate here that in vivo Brivanib provides antitumor activity in a broad range of xenograft models over multiple dose levels, and that Brivanib alaninate demonstrates dose‐dependent efficacy equivalent to Brivanib. Brivanib alaninate also reduces tumor cell proliferation as determined by a significant reduction in Ki‐67 staining as well as a decrease in tumor vascular density as reflected by a reduction in CD34 staining, a cellsurface marker of endothelial cells. Additionally, using Matrigel™ plug assays in athymic mice we demonstrated that Brivanib alaninate inhibits angiogenesis driven by VEGF or bFGF alone as well as when both of these cytokines are combined to drive angiogenesis in this model. Moreover, Brivanib was more effective in inhibiting angiogenesis in this model system under all these conditions when compared to either bevacizumab, an antibody directed at the human VEGF cytokine or DC101, an antibody directed at the murine form of VEGF receptor‐2. Dynamic contrast‐enhanced magnetic resonance imaging, used to assess the effects of Brivanib alaninate on tumor microcirculation, demonstrated a marked decrease in contrast agent uptake at an efficacious dose level, with a reduction in area under the plasma concentration‐time curve from time 0 to 60 min (AUC60) at 24 h and 48 h of 54% and 64%, respectively. These results demonstrate that Brivanib alaninate is an effective antitumor agent in preclinical tumor and angiogenesis models across a range of doses, and that efficacy is accompanied by changes in cellular and vascular activities. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B12.
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abstract b12 the antitumor and antiangiogenic activity of Brivanib a dual inhibitor of vegfr 2 and fgfr 1 kinases
Molecular Cancer Therapeutics, 2009Co-Authors: Joseph Fargnoli, Robert Jeyaseelan, Barri Wautlet, Anne Lewin, Benjamin Henley, John T. HuntAbstract:Angiogenesis plays a central supporting role in tumorigenesis in a wide variety of different cancer types. This complex and highly regulated process has been shown to be driven by various proangiogenic factors. The vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) family of growth factors in conjunction with their associated tyrosine kinase receptors exert a major influence on tumor growth and dissemination, and potentially work synergistically to promote angiogenesis. Brivanib alaninate (BMS‐582664) which is currently in phase III clinical trails is the orally active prodrug of Brivanib (BMS‐540215), a selective dual inhibitor of VEGF and FGF signaling. We demonstrate here that in vivo Brivanib provides antitumor activity in a broad range of xenograft models over multiple dose levels, and that Brivanib alaninate demonstrates dose‐dependent efficacy equivalent to Brivanib. Brivanib alaninate also reduces tumor cell proliferation as determined by a significant reduction in Ki‐67 staining as well as a decrease in tumor vascular density as reflected by a reduction in CD34 staining, a cellsurface marker of endothelial cells. Additionally, using Matrigel™ plug assays in athymic mice we demonstrated that Brivanib alaninate inhibits angiogenesis driven by VEGF or bFGF alone as well as when both of these cytokines are combined to drive angiogenesis in this model. Moreover, Brivanib was more effective in inhibiting angiogenesis in this model system under all these conditions when compared to either bevacizumab, an antibody directed at the human VEGF cytokine or DC101, an antibody directed at the murine form of VEGF receptor‐2. Dynamic contrast‐enhanced magnetic resonance imaging, used to assess the effects of Brivanib alaninate on tumor microcirculation, demonstrated a marked decrease in contrast agent uptake at an efficacious dose level, with a reduction in area under the plasma concentration‐time curve from time 0 to 60 min (AUC60) at 24 h and 48 h of 54% and 64%, respectively. These results demonstrate that Brivanib alaninate is an effective antitumor agent in preclinical tumor and angiogenesis models across a range of doses, and that efficacy is accompanied by changes in cellular and vascular activities. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B12.
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Preclinical pharmacokinetics and in vitro metabolism of Brivanib (BMS-540215), a potent VEGFR2 inhibitor and its alanine ester prodrug Brivanib alaninate
Cancer chemotherapy and pharmacology, 2009Co-Authors: Punit Marathe, Amrita Kamath, Yueping Zhang, Celia D’arienzo, Rajeev S. Bhide, Joseph FargnoliAbstract: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.
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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
Clinical cancer research : an official journal of the American Association for Cancer Research, 2008Co-Authors: Hung Huynh, Joseph Fargnoli, Van Chanh Ngo, Mark Ayers, Khee Chee Soo, Heng Nung Koong, Choon Hua Thng, Hock Soo Ong, Alexander Y. F. Chung, Pierce K. H. ChowAbstract: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.
Georgia Kollia - One of the best experts on this subject based on the ideXlab platform.
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The effects of liver impairment on the pharmacokinetics of Brivanib, a dual inhibitor of fibroblast growth factor receptor and vascular endothelial growth factor receptor tyrosine kinases
Cancer Chemotherapy and Pharmacology, 2013Co-Authors: Anthony El-khoueiry, Ian Walters, Shariq Syed, Georgia Kollia, Bruce S. Fischer, James A. Posey, Juan Ramón Castillo Ferrando, Smitha S. Krishnamurthi, Eric MassonAbstract:Purpose Hepatic impairment may impede tyrosine kinase inhibitor metabolism. This phase I study compared the pharmacokinetics of Brivanib in patients with hepatocellular carcinoma (HCC) and varying levels of hepatic impairment with those with non-HCC malignancies and normal liver function. Methods Patients were assigned to the following groups: Groups A, B, and C (HCC plus mild, moderate, or severe hepatic impairment, respectively) and Group D (non-HCC malignancy and normal hepatic function). Brivanib alaninate (Brivanib prodrug) doses were 400 mg in Groups A, B, and D and 200 mg in Group C. Brivanib exposure was determined on day 1 (single dose) and day 28 (multiple doses). Results Twenty-four patients participated in the study. After a single Brivanib alaninate dose, Brivanib exposure was comparable between Groups A, B, and D. Area under the concentration–time curve was 50 % higher in Group C versus Group D. There were not enough data to draw conclusions on multiple doses. Safety profile in Groups A, B, and D was consistent with previous Brivanib monotherapy experience. Tolerability could not be assessed in Group C because of dose interruptions and discontinuations, generally due to the disease natural history. Conclusions Brivanib exposure was similar in patients with HCC and mild or moderate hepatic impairment (Child-Pugh [CP] A or B status) and those with non-HCC malignancies and normal hepatic function, suggesting dose adjustment is unnecessary with CP A or B status. Experience with HCC and severe hepatic impairment (CP C status) is insufficient to recommend Brivanib use in this population.
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The effects of liver impairment on the pharmacokinetics of Brivanib, a dual inhibitor of fibroblast growth factor receptor and vascular endothelial growth factor receptor tyrosine kinases
Cancer chemotherapy and pharmacology, 2013Co-Authors: Anthony B. El-khoueiry, Ian Walters, Shariq Syed, Georgia Kollia, Bruce S. Fischer, Smitha S. Krishnamurthi, James Posey, Juan Ramón Castillo Ferrando, Eric MassonAbstract:Purpose Hepatic impairment may impede tyrosine kinase inhibitor metabolism. This phase I study compared the pharmacokinetics of Brivanib in patients with hepatocellular carcinoma (HCC) and varying levels of hepatic impairment with those with non-HCC malignancies and normal liver function.
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p06 04a phase 1b study of Brivanib in combination with 5fu lv and folfiri in patients with advanced or metastatic gastro intestinal malignancies
Annals of Oncology, 2013Co-Authors: Antoine Hollebecque, Georgia Kollia, Derek J. Jonker, Michael B. Sawyer, J. M. Chemidlin, L. Wong, Carlos Becerra, J-c. Soria, Anthony B Elkhoueiry, D. S. A. NuytenAbstract:grades: nausea 82%, diarrhea 68%, vomiting 61%, decreased appetite 52%, fatigue 57%, mucositis 46%, hypertension 36%, hand-foot syndrome 30%). A higher than expected rate of bleeding events was observed ((n = 45) grade 1:38%, grade 3/ 4:7%, grade 5:2%). An interim analysis did not show higher than expected TREs (n = 3/45, 1 arterial), which was consistent with data from other Brivanib studies. Therefore, the protocol was amended and aspirin treatment was stopped. Discontinuations were mostly due to progression (61%) followed by related AEs (13%). Conclusion: The safety profile of Brivanib in GI-malignancy patients is manageable and consistent with monotherapy toxicities; there does not seem to be an increase in TREs, however, with aspirin co-treatment, the bleeding rate was higher than expected. The MTD is 800mg with 5FU/LV and 600mg with FOLFIRI.
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P06.04A PHASE 1B STUDY OF Brivanib IN COMBINATION WITH 5FU/LV AND FOLFIRI IN PATIENTS WITH ADVANCED OR METASTATIC GASTRO-INTESTINAL MALIGNANCIES
Annals of Oncology, 2013Co-Authors: Antoine Hollebecque, Georgia Kollia, Derek J. Jonker, Michael B. Sawyer, Anthony B. El-khoueiry, J. M. Chemidlin, L. Wong, Carlos Becerra, J-c. Soria, D. S. A. NuytenAbstract:grades: nausea 82%, diarrhea 68%, vomiting 61%, decreased appetite 52%, fatigue 57%, mucositis 46%, hypertension 36%, hand-foot syndrome 30%). A higher than expected rate of bleeding events was observed ((n = 45) grade 1:38%, grade 3/ 4:7%, grade 5:2%). An interim analysis did not show higher than expected TREs (n = 3/45, 1 arterial), which was consistent with data from other Brivanib studies. Therefore, the protocol was amended and aspirin treatment was stopped. Discontinuations were mostly due to progression (61%) followed by related AEs (13%). Conclusion: The safety profile of Brivanib in GI-malignancy patients is manageable and consistent with monotherapy toxicities; there does not seem to be an increase in TREs, however, with aspirin co-treatment, the bleeding rate was higher than expected. The MTD is 800mg with 5FU/LV and 600mg with FOLFIRI.
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Lack of food effect on single-dose pharmacokinetics of Brivanib, and safety and efficacy following multiple doses in subjects with advanced or metastatic solid tumors
Cancer Chemotherapy and Pharmacology, 2011Co-Authors: Patricia Lorusso, Shariq Syed, Georgia Kollia, Geoffrey I. Shapiro, Herbert Hurwitz, Mary Jo Pilat, Janice Chemidlin, Bruce Fischer, Eric MassonAbstract:Purpose Brivanib alaninate, an orally available prodrug of Brivanib, is currently under evaluation for the treatment of several malignancies. This study aimed to (1) investigate effects of a high-fat meal on single-dose pharmacokinetics of Brivanib in subjects with advanced/metastatic solid tumors and (2) assess the safety and preliminary efficacy of single and multiple doses of Brivanib alaninate in this population. Methods A two-part study was conducted consisting of a single-dose phase (Part A) and a multiple-dose phase (Part B). In Part A, subjects received a single dose of Brivanib alaninate (800 mg) either in a fasting state or following ingestion of a high-fat meal (approximately 951 kcal [15% protein, 33% carbohydrate, 52% fat]); serial blood samples were collected for pharmacokinetic analysis up to 48 h post-dosing. In Part B, subjects received Brivanib alaninate (800 mg) once daily until discontinuation. Throughout both phases, subjects were evaluated for adverse events (AEs) and best clinical response. Results No clinically significant differences in Brivanib exposure were observed between fed and fasting subjects in Part A; C _max was unchanged and AUC_INF decreased marginally when administered in a fed versus fasted state. In Part A, the incidence of treatment-emergent AEs was broadly similar in a fed or fasted state. Brivanib alaninate was generally well tolerated throughout the study and showed preliminary evidence of antitumor activity. Conclusions Consumption of a high-fat meal had no significant effect on Brivanib pharmacokinetics. The study further demonstrates the acceptable safety/tolerability profile and antitumor potential of Brivanib in patients with advanced malignancies.
Shariq Syed - One of the best experts on this subject based on the ideXlab platform.
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The effects of liver impairment on the pharmacokinetics of Brivanib, a dual inhibitor of fibroblast growth factor receptor and vascular endothelial growth factor receptor tyrosine kinases
Cancer Chemotherapy and Pharmacology, 2013Co-Authors: Anthony El-khoueiry, Ian Walters, Shariq Syed, Georgia Kollia, Bruce S. Fischer, James A. Posey, Juan Ramón Castillo Ferrando, Smitha S. Krishnamurthi, Eric MassonAbstract:Purpose Hepatic impairment may impede tyrosine kinase inhibitor metabolism. This phase I study compared the pharmacokinetics of Brivanib in patients with hepatocellular carcinoma (HCC) and varying levels of hepatic impairment with those with non-HCC malignancies and normal liver function. Methods Patients were assigned to the following groups: Groups A, B, and C (HCC plus mild, moderate, or severe hepatic impairment, respectively) and Group D (non-HCC malignancy and normal hepatic function). Brivanib alaninate (Brivanib prodrug) doses were 400 mg in Groups A, B, and D and 200 mg in Group C. Brivanib exposure was determined on day 1 (single dose) and day 28 (multiple doses). Results Twenty-four patients participated in the study. After a single Brivanib alaninate dose, Brivanib exposure was comparable between Groups A, B, and D. Area under the concentration–time curve was 50 % higher in Group C versus Group D. There were not enough data to draw conclusions on multiple doses. Safety profile in Groups A, B, and D was consistent with previous Brivanib monotherapy experience. Tolerability could not be assessed in Group C because of dose interruptions and discontinuations, generally due to the disease natural history. Conclusions Brivanib exposure was similar in patients with HCC and mild or moderate hepatic impairment (Child-Pugh [CP] A or B status) and those with non-HCC malignancies and normal hepatic function, suggesting dose adjustment is unnecessary with CP A or B status. Experience with HCC and severe hepatic impairment (CP C status) is insufficient to recommend Brivanib use in this population.
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The effects of liver impairment on the pharmacokinetics of Brivanib, a dual inhibitor of fibroblast growth factor receptor and vascular endothelial growth factor receptor tyrosine kinases
Cancer chemotherapy and pharmacology, 2013Co-Authors: Anthony B. El-khoueiry, Ian Walters, Shariq Syed, Georgia Kollia, Bruce S. Fischer, Smitha S. Krishnamurthi, James Posey, Juan Ramón Castillo Ferrando, Eric MassonAbstract:Purpose Hepatic impairment may impede tyrosine kinase inhibitor metabolism. This phase I study compared the pharmacokinetics of Brivanib in patients with hepatocellular carcinoma (HCC) and varying levels of hepatic impairment with those with non-HCC malignancies and normal liver function.
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Metabolic Chiral Inversion of Brivanib and Its Relevance to Safety and Pharmacology
Drug metabolism and disposition: the biological fate of chemicals, 2012Co-Authors: Jiachang Gong, Shariq Syed, Eric Masson, Jinping Gan, Yuan-qing Xia, Daphne Williams, Janice Pursley, Mohammed Jemal, W. Griff Humphreys, Ramaswamy A. IyerAbstract: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
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Lack of food effect on single-dose pharmacokinetics of Brivanib, and safety and efficacy following multiple doses in subjects with advanced or metastatic solid tumors
Cancer Chemotherapy and Pharmacology, 2011Co-Authors: Patricia Lorusso, Shariq Syed, Georgia Kollia, Geoffrey I. Shapiro, Herbert Hurwitz, Mary Jo Pilat, Janice Chemidlin, Bruce Fischer, Eric MassonAbstract:Purpose Brivanib alaninate, an orally available prodrug of Brivanib, is currently under evaluation for the treatment of several malignancies. This study aimed to (1) investigate effects of a high-fat meal on single-dose pharmacokinetics of Brivanib in subjects with advanced/metastatic solid tumors and (2) assess the safety and preliminary efficacy of single and multiple doses of Brivanib alaninate in this population. Methods A two-part study was conducted consisting of a single-dose phase (Part A) and a multiple-dose phase (Part B). In Part A, subjects received a single dose of Brivanib alaninate (800 mg) either in a fasting state or following ingestion of a high-fat meal (approximately 951 kcal [15% protein, 33% carbohydrate, 52% fat]); serial blood samples were collected for pharmacokinetic analysis up to 48 h post-dosing. In Part B, subjects received Brivanib alaninate (800 mg) once daily until discontinuation. Throughout both phases, subjects were evaluated for adverse events (AEs) and best clinical response. Results No clinically significant differences in Brivanib exposure were observed between fed and fasting subjects in Part A; C _max was unchanged and AUC_INF decreased marginally when administered in a fed versus fasted state. In Part A, the incidence of treatment-emergent AEs was broadly similar in a fed or fasted state. Brivanib alaninate was generally well tolerated throughout the study and showed preliminary evidence of antitumor activity. Conclusions Consumption of a high-fat meal had no significant effect on Brivanib pharmacokinetics. The study further demonstrates the acceptable safety/tolerability profile and antitumor potential of Brivanib in patients with advanced malignancies.
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Lack of Effect of Brivanib on the Pharmacokinetics of Midazolam, a CYP3A4 Substrate, Administered Intravenously and Orally in Healthy Participants
Journal of clinical pharmacology, 2011Co-Authors: Shariq Syed, Ian Walters, Pamela L. Clemens, Deanne Lathers, Georgia Kollia, Arindam Dhar, Eric MassonAbstract: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.