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https://www.readbyqxmd.com/read/27858108/effects-of-ranitidine-antacid-food-and-formulation-on-the-pharmacokinetics-of-fostamatinib-results-from-five-phase-i-clinical-studies
#1
Talia Flanagan, Paul Martin, Michael Gillen, David Mathews, Eleanor Lisbon, Martin Kruusmägi
PURPOSE: Fostamatinib is an orally dosed phosphate prodrug that is cleaved by intestinal alkaline phosphatase to the active metabolite R406. Clinical studies were performed to assess the effect of food and ranitidine on exposure, to support in vitro-in vivo relationships (IVIVR) understanding and formulation transitions and to investigate absolute oral bioavailability. METHODS: A series of in vitro dissolution and clinical pharmacokinetic studies were performed to support the design and introduction of a new formulation, understand the impact of changes in in vitro dissolution on in vivo performance for two fostamatinib formulations, to characterize the effects of food and ranitidine on exposure, and determine the absolute oral bioavailability...
November 17, 2016: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27476075/spleen-tyrosine-kinase-a-crucial-player-and-potential-therapeutic-target-in-renal-disease
#2
Terry King-Wing Ma, Stephen P McAdoo, Frederick Wai-Keung Tam
Spleen tyrosine kinase (Syk), a 72 kDa cytoplasmic non-receptor protein-tyrosine kinase, plays an important role in signal transduction in a variety of cell types. Ever since its discovery in the early 1990s, there has been accumulating evidence to suggest a pathogenic role of Syk in various allergic disorders, autoimmune diseases and malignancies. Additionally, there is emerging data from both pre-clinical and clinical studies that Syk is implicated in the pathogenesis of proliferative glomerulonephritis (GN), including anti-glomerular basement membrane disease, anti-neutrophil cytoplasmic antibody-associated GN, lupus nephritis and immunoglobulin A nephropathy (IgAN)...
2016: Nephron
https://www.readbyqxmd.com/read/27163495/effects-of-fostamatinib-on-the-pharmacokinetics-of-the-cyp2c8-substrate-pioglitazone-results-from-in-vitro-and-phase-1-clinical-studies
#3
Paul Martin, Michael Gillen, David Millson, Stuart Oliver, Clive Brealey, Dominic Surry, David Sweeny, David Lau, Philip Leese
Fostamatinib is a prodrug that undergoes gastrointestinal tract dephosphorylation to form the active metabolite, R406. Here we report its cytochrome P450-inducing potential. In vitro, R406 3 and 10 μM induced CYP2C8 to levels representing 53% and 75%, respectively, of the level achieved by the positive control, rifampicin. Induction of other enzymes was minor. The effect of fostamatinib (100 mg twice daily) on the pharmacokinetics of a single oral 30-mg dose of the CYP2C8 substrate pioglitazone and its metabolite, hydroxy pioglitazone, was then investigated (open-label, nonrandomized, 2-period phase I study [n = 15])...
May 2016: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/27113955/fostamatinib-an-oral-spleen-tyrosine-kinase-inhibitor-in-the-treatment-of-rheumatoid-arthritis-a-meta-analysis-of-randomized-controlled-trials
#4
Sumit Kunwar, Ashok Raj Devkota, Dipesh K C Ghimire
Fostamatinib is a selective inhibitor of spleen tyrosine kinase which has a role in the pathogenesis of RA. Multiple RCTs have been performed to study the effects of fostamatinib. The objective of this study was to perform a meta-analysis to analyze the efficacy and safety of fostamatinib in the management of RA. We searched PubMed, EMBASE and Cochrane CENTRAL through 11/9/15. Random effect model was used to estimate odds ratio (OR) and 95 % confidence interval. We measured outcomes with efficacy analysis using ACR20/50/70 response criteria and safety with adverse events...
August 2016: Rheumatology International
https://www.readbyqxmd.com/read/27044884/linear-extrapolation-of-missing-radiographic-change-scores-in-clinical-trials-does-not-spuriously-overestimate-group-radiographic-changes-in-rheumatoid-arthritis
#5
Iris M Markusse, Robert Landewé, Ron Wolterbeek, Meilien Ho, Martin Jenkins, Désirée van der Heijde
OBJECTIVE: To assess linear extrapolation (LE) and last observation carried forward (LOCF) as imputation methods for radiographic change in patients with RA. METHODS: The OSKIRA-1 trial enrolled 918 patients with active RA for studying the efficacy of fostamatinib. Radiographs were scheduled for all patients at baseline and week 12, regardless of early escape, and at weeks 24 and 52 for patients who remained in the study. Complete radiographic data for the 24-week follow-up were available for 623 patients and were assessed according to the Sharp/van der Heijde score...
July 2016: Rheumatology
https://www.readbyqxmd.com/read/26891724/atheroprotection-through-syk-inhibition-fails-in-established-disease-when-local-macrophage-proliferation-dominates-lesion-progression
#6
COMPARATIVE STUDY
Alexandra Lindau, Carmen Härdtner, Sonja P Hergeth, Kelly Daryll Blanz, Bianca Dufner, Natalie Hoppe, Nathaly Anto-Michel, Jan Kornemann, Jiadai Zou, Louisa M S Gerhardt, Timo Heidt, Florian Willecke, Serjosha Geis, Peter Stachon, Dennis Wolf, Peter Libby, Filip K Swirski, Clinton S Robbins, William McPheat, Shaun Hawley, Martin Braddock, Ralf Gilsbach, Lutz Hein, Constantin von zur Mühlen, Christoph Bode, Andreas Zirlik, Ingo Hilgendorf
Macrophages in the arterial intima sustain chronic inflammation during atherogenesis. Under hypercholesterolemic conditions murine Ly6C(high) monocytes surge in the blood and spleen, infiltrate nascent atherosclerotic plaques, and differentiate into macrophages that proliferate locally as disease progresses. Spleen tyrosine kinase (SYK) may participate in downstream signaling of various receptors that mediate these processes. We tested the effect of the SYK inhibitor fostamatinib on hypercholesterolemia-associated myelopoiesis and plaque formation in Apoe(-/-) mice during early and established atherosclerosis...
March 2016: Basic Research in Cardiology
https://www.readbyqxmd.com/read/26748647/effects-of-fostamatinib-on-the-pharmacokinetics-of-oral-contraceptive-warfarin-and-the-statins-rosuvastatin-and-simvastatin-results-from-phase-i-clinical-studies
#7
P Martin, M Gillen, J Ritter, D Mathews, C Brealey, D Surry, S Oliver, V Holmes, P Severin, R Elsby
BACKGROUND AND OBJECTIVES: Fostamatinib is a spleen tyrosine kinase inhibitor that has been investigated as therapy for rheumatoid arthritis and immune thrombocytopenic purpura. The present studies assessed the potential for pharmacokinetic interaction between fostamatinib and the commonly prescribed medications oral contraceptive (OC), warfarin, and statins (rosuvastatin, simvastatin) in healthy subjects. METHODS: The OC study was a crossover study over two 28-day treatment periods (Microgynon(®) 30 plus placebo or fostamatinib)...
March 2016: Drugs in R&D
https://www.readbyqxmd.com/read/26739683/effects-of-cyp3a4-inhibitors-ketoconazole-and-verapamil-and-the-cyp3a4-inducer-rifampicin-on-the-pharmacokinetic-parameters-of-fostamatinib-results-from-in-vitro-and-phase-i-clinical-studies
#8
Paul Martin, Michael Gillen, David Millson, Stuart Oliver, Clive Brealey, Elliott B Grossbard, Muhammad Baluom, David Lau, David Sweeny, Tim Mant, Kelli Craven
BACKGROUND: Fostamatinib (R788) is a spleen tyrosine kinase (SYK) inhibitor. The active metabolite of fostamatinib, R406, is primarily metabolized by CYP3A4. OBJECTIVES: The aim of this study was to characterize hepatic microsomal metabolism of R406 and confirm the role of CYP3A4 in R406 metabolism, determining whether co-administration of CYP3A4 inhibitors (ketoconazole, verapamil) or inducers (rifampicin) affects R406 pharmacokinetics. METHODS: R406 stability was determined using human hepatic microsomes...
March 2016: Drugs in R&D
https://www.readbyqxmd.com/read/26707592/a-phase-ii-trial-to-evaluate-the-efficacy-of-fostamatinib-in-patients-with-relapsed-or-refractory-diffuse-large-b-cell-lymphoma-dlbcl
#9
RANDOMIZED CONTROLLED TRIAL
Ian W Flinn, Nancy L Bartlett, Kristie A Blum, Kirit M Ardeshna, Ann S LaCasce, Christopher R Flowers, Andrei R Shustov, Kenneth S Thress, Patrick Mitchell, Fred Zheng, Jeffrey M Skolnik, Jonathan W Friedberg
PURPOSE: To assess the safety and efficacy of fostamatinib in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). EXPERIMENTAL DESIGN: Relapsed or refractory DLBCL patients originally received the oral spleen tyrosine kinase inhibitor, fostamatinib in a two-arm, randomised, double-blinded manner at either 100 mg twice a day (BID) or 200 mg BID until disease progression or unacceptable toxicity. The primary objective was to assess the overall response rate (ORR)...
February 2016: European Journal of Cancer
https://www.readbyqxmd.com/read/26700956/solitary-inhibition-of-the-breast-cancer-resistance-protein-efflux-transporter-results-in-a-clinically-significant-drug-drug-interaction-with-rosuvastatin-by-causing-up-to-a-2-fold-increase-in-statin-exposure
#10
Robert Elsby, Paul Martin, Dominic Surry, Pradeep Sharma, Katherine Fenner
The intestinal efflux transporter breast cancer resistance protein (BCRP) restricts the absorption of rosuvastatin. Of the transporters important to rosuvastatin disposition, fostamatinib inhibited BCRP (IC50 = 50 nM) and organic anion-transporting polypeptide 1B1 (OATP1B1; IC50 > 10 μM), but not organic anion transporter 3, in vitro, predicting a drug-drug interaction (DDI) in vivo through inhibition of BCRP only. Consequently, a clinical interaction study between fostamatinib and rosuvastatin was performed (and reported elsewhere)...
March 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/26621482/how-comparable-are-rates-of-malignancies-in-patients-with-rheumatoid-arthritis-across-the-world-a-comparison-of-cancer-rates-and-means-to-optimise-their-comparability-in-five-ra-registries
#11
Johan Askling, Niklas Berglind, Stefan Franzen, Thomas Frisell, Christopher Garwood, Jeffrey D Greenberg, Meilien Ho, Marie Holmqvist, Laura Horne, Eisuke Inoue, Kaleb Michaud, Fredrik Nyberg, Dimitrios A Pappas, George Reed, Eiichi Tanaka, Trung N Tran, Suzanne M M Verstappen, Hisashi Yamanaka, Eveline Wesby-van Swaay, Deborah Symmons
BACKGROUND: The overall incidence of cancer in patients with rheumatoid arthritis (RA) is modestly elevated. The extent to which cancer rates in RA vary across clinical cohorts and patient subsets, as defined by disease activity or treatment is less known but critical for understanding the safety of existing and new antirheumatic therapies. We investigated comparability of, and means to harmonise, malignancy rates in five RA registries from four continents. METHODS: Participating RA registries were Consortium of Rheumatology Researchers of North America (CORRONA) (USA), Swedish Rheumatology Quality of Care Register (SRR) (Sweden), Norfolk Arthritis Register (NOAR) (UK), CORRONA International (several countries) and Institute of Rheumatology, Rheumatoid Arthritis (IORRA) (Japan)...
October 2016: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/26519231/pharmacokinetic-properties-of-fostamatinib-in-patients-with-renal-or-hepatic-impairment-results-from-2-phase-i-clinical-studies
#12
Paul Martin, Stuart Oliver, Michael Gillen, Thomas Marbury, David Millson
PURPOSE: Phase III trials of fostamatinib, an oral spleen tyrosine kinase inhibitor, in the treatment of rheumatoid arthritis have been completed. Herein, we report the effects of renal and hepatic impairment on the pharmacokinetic (PK) properties of the active metabolite of fostamatinib, R406, in plasma, and on the urinary excretion of R406 and its metabolite N-glucuronide. METHODS: Two Phase I, single-center, open-label clinical trials determined the PK properties and tolerability of fostamatinib in subjects with normal or impaired renal or hepatic function...
December 1, 2015: Clinical Therapeutics
https://www.readbyqxmd.com/read/26516588/prevention-of-fostamatinib-induced-blood-pressure-elevation-by-antihypertensive-agents
#13
Dave Lengel, Eva Lamm Bergström, Herb Barthlow, Karen Oldman, Helen Musgrove, Alex Harmer, Jean-Pierre Valentin, Paul Duffy, Martin Braddock, Jon Curwen
Fostamatinib is a tyrosine kinase inhibitor with activity against spleen tyrosine kinase which has completed clinical trials for patients with rheumatoid arthritis. In clinical studies fostamatinib treatment was associated with a small elevation of systemic arterial blood pressure (BP), a similar finding to that seen with other kinase inhibitors, especially those that inhibit VEGFR2 signaling. We have investigated the link between fostamatinib-induced blood pressure elevation and plasma levels of the fostamatinib-active metabolite R940406 in conscious rats and found the time course of the BP effect correlated closely with changes in R940406 plasma concentration, indicating a direct pharmacological relationship...
October 2015: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/26516587/in-vitro-pharmacological-profiling-of-r406-identifies-molecular-targets-underlying-the-clinical-effects-of-fostamatinib
#14
Michael G Rolf, Jon O Curwen, Margaret Veldman-Jones, Cath Eberlein, Jianyan Wang, Alex Harmer, Caroline J Hellawell, Martin Braddock
Off-target pharmacology may contribute to both adverse and beneficial effects of a new drug. In vitro pharmacological profiling is often applied early in drug discovery; there are fewer reports addressing the relevance of broad profiles to clinical adverse effects. Here, we have characterized the pharmacological profile of the active metabolite of fostamatinib, R406, linking an understanding of drug selectivity to the increase in blood pressure observed in clinical studies. R406 was profiled in a broad range of in vitro assays to generate a comprehensive pharmacological profile and key targets were further investigated using functional and cellular assay systems...
October 2015: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/26514315/effects-of-fostamatinib-on-the-pharmacokinetics-of-digoxin-a-p-glycoprotein-substrate-results-from-in-vitro-and-phase-i-clinical-studies
#15
Paul Martin, Michael Gillen, David Millson, Stuart Oliver, Clive Brealey, Robert Elsby, Muhammad Baluom, David Lau, Tim Mant
PURPOSE: Fostamatinib, a spleen tyrosine kinase inhibitor and prodrug of the active metabolite R406, is being developed as an anti-inflammatory drug for several indications for which polypharmacy is likely. Digoxin, indicated for congestive cardiac failure, may be used for certain supraventricular dysrhythmias. The studies reported herein examined whether fostamatinib and R406 are inhibitors of P-glycoprotein (P-gp) in vitro and evaluated the effect of fostamatinib on the pharmacokinetic parameters of digoxin to understand drug-drug interaction (DDI) potential in the clinic...
December 1, 2015: Clinical Therapeutics
https://www.readbyqxmd.com/read/26490353/characterization-of-the-disposition-of-fostamatinib-in-japanese-subjects-including-pharmacokinetic-assessment-in-dry-blood-spots-results-from-two-phase-i-clinical-studies
#16
RANDOMIZED CONTROLLED TRIAL
Paul Martin, S Y Amy Cheung, Mark Yen, David Han, Michael Gillen
PURPOSE: The aims of the present study were to characterize the pharmacokinetics of fostamatinib in two phase I studies in healthy Japanese subjects after single- and multiple-dose administration, and to evaluate the utility of dried blood spot (DBS) sampling. METHODS: In study A, 40 Japanese and 16 white subjects were randomized in a double-blind parallel group study consisting of seven cohorts, which received either placebo or a fostamatinib dose between 50 and 200 mg after single and multiple dosing...
January 2016: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/26148346/spleen-tyrosine-kinase-syk-inhibitor-fostamatinib-limits-tissue-damage-and-fibrosis-in-a-bleomycin-induced-scleroderma-mouse-model
#17
Omer Nuri Pamuk, Guray Can, Suleyman Ayvaz, Turan Karaca, Gulsum Emel Pamuk, Selim Demirtas, George C Tsokos
OBJECTIVES: The pathogenesis of fibrosis in scleroderma (SSc) is unknown. TGF-β and platelet-derived growth factor are important in the development of fibrosis and tyrosine kinases are involved in these pathways. The possible antifibrotic effects of various kinase inhibitors in SSc have been studied before. Spleen tyro-sine kinase (Syk) is a protein tyrosine kinase which activates intracellular signal transduction pathways; and has been claimed to be involved in the pathogenesis of systemic autoimmune diseases...
July 2015: Clinical and Experimental Rheumatology
https://www.readbyqxmd.com/read/26116555/the-syk-inhibitor-fostamatinib-decreases-the-severity-of-colonic-mucosal-damage-in-a-rodent-model-of-colitis
#18
Guray Can, Suleyman Ayvaz, Hatice Can, Selim Demirtas, Hasan Aksit, Bulent Yilmaz, Ugur Korkmaz, Mevlut Kurt, Turan Karaca
BACKGROUND AND AIMS: Inflammatory bowel disease is a chronic inflammatory disease of the gastrointestinal system. In some cases, current medications used for inflammatory bowel disease may not be enough for remission, creating a need for more potent and reliable medications. There is no study showing the efficacy of fostamatinib, with proven effects on some inflammatory diseases, on ulcerative colitis. In our study we planned to research the efficacy of fostamatinib, a spleen tyrosine kinase inhibitor, on acetic acid-induced colitis...
October 2015: Journal of Crohn's & Colitis
https://www.readbyqxmd.com/read/25852057/targeting-syk-activated-b-cells-in-murine-and-human-chronic-graft-versus-host-disease
#19
Ryan Flynn, Jessica L Allen, Leo Luznik, Kelli P MacDonald, Katelyn Paz, Kylie A Alexander, Ante Vulic, Jing Du, Angela Panoskaltsis-Mortari, Patricia A Taylor, Jonathan C Poe, Jonathan S Serody, William J Murphy, Geoffrey R Hill, Ivan Maillard, John Koreth, Corey S Cutler, Robert J Soiffer, Joseph H Antin, Jerome Ritz, Nelson J Chao, Raphael A Clynes, Stefanie Sarantopoulos, Bruce R Blazar
Novel therapies for chronic graft-versus-host disease (cGVHD) are needed. Aberrant B-cell activation has been demonstrated in mice and humans with cGVHD. Having previously found that human cGVHD B cells are activated and primed for survival, we sought to further evaluate the role of the spleen tyrosine kinase (Syk) in cGVHD in multiple murine models and human peripheral blood cells. In a murine model of multiorgan system, nonsclerodermatous disease with bronchiolitis obliterans where cGVHD is dependent on antibody and germinal center (GC) B cells, we found that activation of Syk was necessary in donor B cells, but not T cells, for disease progression...
June 25, 2015: Blood
https://www.readbyqxmd.com/read/25748087/targeting-the-spleen-tyrosine-kinase-with-fostamatinib-as-a-strategy-against-waldenstr%C3%A3-m-macroglobulinemia
#20
Isere Kuiatse, Veerabhadran Baladandayuthapani, Heather Y Lin, Sheeba K Thomas, Chad C Bjorklund, Donna M Weber, Michael Wang, Jatin J Shah, Xing-Ding Zhang, Richard J Jones, Stephen M Ansell, Guang Yang, Steven P Treon, Robert Z Orlowski
PURPOSE: Waldenström macroglobulinemia (WMG) is a lymphoproliferative disorder characterized by good initial responses to standard therapeutics, but only a minority of patients achieve complete remissions, and most inevitably relapse, indicating a need for novel agents. B-cell receptor signaling has been linked to clonal evolution in WMG, and Spleen tyrosine kinase (Syk) is overexpressed in primary cells, suggesting that it could be a novel and rational target. EXPERIMENTAL DESIGN: We studied the impact of the Syk inhibitor fostamatinib on BCWM...
June 1, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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