Axitinib, sold under the brand name Inlyta, is a small molecule tyrosine kinase inhibitor developed by Pfizer. It has been shown to significantly inhibit growth of breast cancer in animal (xenograft) models[3] and has shown partial responses in clinical trials with renal cell carcinoma (RCC)[4] and several other tumour types.[5]
It was approved to treat renal cell carcinoma by the U.S. Food and Drug Administration after showing a modest increase in progression-free survival,[6] though there have been reports of fatal adverse effects.[7]
A Phase II clinical trial showed good response in combination chemotherapy with gemcitabine for advanced pancreatic cancer.[11] However, Pfizer reported on January 30, 2009, that Phase III clinical trials of the drug when used in combination with gemcitabine showed no evidence of improved survival rates over treatments using gemcitabine alone for advanced pancreatic cancer and halted the trial.[12]
In 2010, a Phase III trial for previously treated metastatic renal cell carcinoma (mRCC) showed significantly extended progression-free survival when compared to sorafenib.[13] In December 2011, the Oncologic Drugs Advisory Committee (ODAC) voted unanimously to recommend that US FDA approve axitinib for the second-line treatment of patients with advanced renal cell carcinoma (RCC), based on the results of the Phase III trial comparing axitinib and sorafenib.[14]
It has also been studied in combination with the ALK1 inhibitor dalantercept.[15]
Diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, hand-foot syndrome, weight decreased, vomiting, asthenia, and constipation are the most common side effects occurring in more than 20% of patients.[17]
Interactions
Coadministration with strong CYP3A4/CYP3A5 inhibitors should be avoided where possible as they may reduce plasma clearance of axitinib.[2]
It was also proposed that it might act by inducing autophagy, as some other tyrosine kinase inhibitors, like sorafenib.[19]
It has also been shown[16] to bind (in a different conformation from the VEGF binding) to the BCR-ABL fusion protein, specifically inhibiting the drug-resistant T315I mutant isoform.
In Germany, Switzerland and other European countries it is available under the trade name Inlyta.[20][21]
References
^ ab"Inlyta- axitinib tablet, film coated". DailyMed. Pfizer Inc. Retrieved 25 January 2014.
^ abcdefg"Inlyta (axitinib) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 25 January 2014.
^Wilmes LJ, Pallavicini MG, Fleming LM, Gibbs J, Wang D, Li KL, et al. (April 2007). "AG-013736, a novel inhibitor of VEGF receptor tyrosine kinases, inhibits breast cancer growth and decreases vascular permeability as detected by dynamic contrast-enhanced magnetic resonance imaging". Magnetic Resonance Imaging. 25 (3): 319–27. doi:10.1016/j.mri.2006.09.041. PMID 17371720.
^Rini B, Rixe O, Bukowski R, Michaelson MD, Wilding G, Hudes G, et al. (June 2005). "AG-013736, a multi-target tyrosine kinase receptor inhibitor, demonstrates anti-tumor activity in a Phase 2 study of cytokine-refractory, metastatic renal cell cancer (RCC)". Journal of Clinical Oncology ASCO Annual Meeting Proceedings. 23 (16S): 4509. Archived from the original on 2014-01-26.
^Rugo HS, Herbst RS, Liu G, Park JW, Kies MS, Steinfeldt HM, et al. (August 2005). "Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results". Journal of Clinical Oncology. 23 (24): 5474–83. doi:10.1200/JCO.2005.04.192. PMID 16027439.
^"FDA Approves Inlyta for Advanced Renal Cell Carcinoma". Drugs.com. January 27, 2012.
^Fauber J, Chu E (October 27, 2014). "The Slippery Slope: Is a Surrogate Endpoint Evidence of Efficacy?". MedPage Today.
^"Inlyta : EPAR - Product Information" (PDF). European Medicines Agency. Pfizer Ltd. 17 December 2013. Retrieved 25 January 2014.
^. electronic Medicines Compendium. Pfizer Limited. 5 December 2013. Archived from the original on 2014-02-22. Retrieved 25 January 2014.
^"PRODUCT INFORMATION INLYTA (axitinib)" (PDF). TGA eBusiness Services. Pfizer Australia Pty Ltd. 5 July 2013. Retrieved 25 January 2014.
^Spano JP, Chodkiewicz C, Maurel J, Wong R, Wasan H, Barone C, et al. (June 2008). "Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomised phase II study". Lancet. 371 (9630): 2101–8. doi:10.1016/S0140-6736(08)60661-3. PMID 18514303. S2CID 11062859.
^"Pfizer pancreatic cancer drug fails, trial halted". Reuters. January 30, 2009.
^"Pfizer's Phase III Trial in mRCC Turns Up Positive Results". 19 Nov 2010.
^"ODAC Unanimously Supports Axitinib for Renal Cell Carcinoma". 7 Dec 2011.
^ abPemovska T, Johnson E, Kontro M, Repasky GA, Chen J, Wells P, et al. (March 2015). "Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation". Nature. 519 (7541): 102–5. Bibcode:2015Natur.519..102P. doi:10.1038/nature14119. PMID 25686603. S2CID 4389086.
^"FDA Prescribing Information" (PDF). 30 Jan 2012.
^Escudier B, Gore M (2011). "Axitinib for the management of metastatic renal cell carcinoma". Drugs in R&D. 11 (2): 113–26. doi:10.2165/11591240-000000000-00000. PMC3585900. PMID 21679004.
^Zhang Y, Xue D, Wang X, Lu M, Gao B, Qiao X (January 2014). "Screening of kinase inhibitors targeting BRAF for regulating autophagy based on kinase pathways". Molecular Medicine Reports. 9 (1): 83–90. doi:10.3892/mmr.2013.1781. PMID 24213221.
^AHFS Patient Medication Information [Internet]. Bethesda (MD): American Society of Health-System Pharmacists, Inc.; c2022. Axitinib; [last revised 2020 August 15; cited 2022 March 28]; [about 5 p.]. Available from: https://medlineplus.gov/druginfo/meds/a612017.html
axitinib, sold, under, brand, name, inlyta, small, molecule, tyrosine, kinase, inhibitor, developed, pfizer, been, shown, significantly, inhibit, growth, breast, cancer, animal, xenograft, models, shown, partial, responses, clinical, trials, with, renal, cell,. Axitinib sold under the brand name Inlyta is a small molecule tyrosine kinase inhibitor developed by Pfizer It has been shown to significantly inhibit growth of breast cancer in animal xenograft models 3 and has shown partial responses in clinical trials with renal cell carcinoma RCC 4 and several other tumour types 5 AxitinibClinical dataTrade namesInlyta AxinixOther namesAG013736AHFS Drugs comMonographMedlinePlusa612017License dataEU EMA by INN US DailyMed AxitinibPregnancycategoryAU DRoutes ofadministrationBy mouthATC codeL01EK01 WHO Legal statusLegal statusAU S4 Prescription only CA only UK POM Prescription only US only 1 Pharmacokinetic dataBioavailability58 2 Protein binding gt 99 2 MetabolismLiver mostly CYP3A4 CYP3A5 mediated but with some contributions from CYP1A2 CYP2C19 UGT1A1 2 Elimination half life2 5 6 1 hours 2 ExcretionFeces 41 12 as unchanged drug urine 23 2 IdentifiersIUPAC name N Methyl 2 3 E 2 pyridin 2 ylethenyl 1H indazol 6 yl sulfanyl benzamideCAS Number319460 85 0 YPubChem CID6450551IUPHAR BPS5659DrugBankDB06626 YChemSpider4953153 YUNIIC9LVQ0YUXGKEGGD03218 YChEBICHEBI 66910 NChEMBLChEMBL1289926 NPDB ligandAXI PDBe RCSB PDB CompTox Dashboard EPA DTXSID3049049ECHA InfoCard100 166 384Chemical and physical dataFormulaC 22H 18N 4O SMolar mass386 47 g mol 13D model JSmol Interactive imageSMILES CNC O c1ccccc1Sc4ccc3c C Cc2ccccn2 n nH c3c4InChI InChI 1S C22H18N4OS c1 23 22 27 18 7 2 3 8 21 18 28 16 10 11 17 19 25 26 20 17 14 16 12 9 15 6 4 5 13 24 15 h2 14H 1H3 H 23 27 H 25 26 b12 9 YKey RITAVMQDGBJQJZ FMIVXFBMSA N Y N Y what is this verify It was approved to treat renal cell carcinoma by the U S Food and Drug Administration after showing a modest increase in progression free survival 6 though there have been reports of fatal adverse effects 7 Contents 1 Approvals and indications 1 1 Renal cell carcinoma 2 Clinical trials 3 Adverse effects 4 Interactions 5 Mechanism of action 6 Pharmacokinetics 7 Society and culture 7 1 Brand names 8 References 9 External linksApprovals and indications EditRenal cell carcinoma Edit It has received approval for use as a treatment for renal cell carcinoma from the US Food and Drug Administration FDA 27 January 2012 the European Medicines Agency EMA 13 September 2012 the UK Medicines and Healthcare products Regulatory Agency MHRA 3 September 2012 and the Australian Therapeutic Goods Administration TGA 26 July 2012 1 8 9 10 Clinical trials EditA Phase II clinical trial showed good response in combination chemotherapy with gemcitabine for advanced pancreatic cancer 11 However Pfizer reported on January 30 2009 that Phase III clinical trials of the drug when used in combination with gemcitabine showed no evidence of improved survival rates over treatments using gemcitabine alone for advanced pancreatic cancer and halted the trial 12 In 2010 a Phase III trial for previously treated metastatic renal cell carcinoma mRCC showed significantly extended progression free survival when compared to sorafenib 13 In December 2011 the Oncologic Drugs Advisory Committee ODAC voted unanimously to recommend that US FDA approve axitinib for the second line treatment of patients with advanced renal cell carcinoma RCC based on the results of the Phase III trial comparing axitinib and sorafenib 14 It has also been studied in combination with the ALK1 inhibitor dalantercept 15 A study published in 2015 16 showed that axitinib effectively inhibits a mutated gene BCR ABL1 T315I that is common in chronic myeloid leukemias and adult acute lymphoblastic leukemias which have become resistant to other tyrosine kinase inhibitors like imatinib This is one of the first examples of a new indication for an existing drug being discovered by screening known drugs using a patient s own cells Adverse effects EditSee also List of adverse effects of axitinib Diarrhea hypertension fatigue decreased appetite nausea dysphonia hand foot syndrome weight decreased vomiting asthenia and constipation are the most common side effects occurring in more than 20 of patients 17 Interactions EditCoadministration with strong CYP3A4 CYP3A5 inhibitors should be avoided where possible as they may reduce plasma clearance of axitinib 2 Mechanism of action EditIts primary mechanism of action is thought to be vascular endothelial growth factor receptor 1 3 c KIT and PDGFR inhibition this in turn enables it to inhibit angiogenesis the formation of new blood vessels by tumours 18 It was also proposed that it might act by inducing autophagy as some other tyrosine kinase inhibitors like sorafenib 19 It has also been shown 16 to bind in a different conformation from the VEGF binding to the BCR ABL fusion protein specifically inhibiting the drug resistant T315I mutant isoform The effect of axitinib on tyrosine kinases Protein IC50 nM VEGFR1 0 1VEGFR2 0 2VEGFR3 0 1 0 3PDGFR 1 6c KIT 1 7Pharmacokinetics EditPharmacokinetic parameters of Axitinib 2 Bioavailability Tmax Cmax AUC Vd Plasma protein binding Metabolising enzymes t1 2 Excretion routes58 2 5 4 1 hr 27 8 ng mL 265 ng h mL 160 L gt 99 Mostly CYP3A4 and CYP3A5 Lesser contributions from CYP1A2 CYP2C19 UGT1A1 2 5 6 1 hr Faeces 41 urine 23 Society and culture EditBrand names Edit In Bangladesh it is under the trade name Axinix citation needed In Germany Switzerland and other European countries it is available under the trade name Inlyta 20 21 References Edit a b Inlyta axitinib tablet film coated DailyMed Pfizer Inc Retrieved 25 January 2014 a b c d e f g Inlyta axitinib dosing indications interactions adverse effects and more Medscape Reference WebMD Retrieved 25 January 2014 Wilmes LJ Pallavicini MG Fleming LM Gibbs J Wang D Li KL et al April 2007 AG 013736 a novel inhibitor of VEGF receptor tyrosine kinases inhibits breast cancer growth and decreases vascular permeability as detected by dynamic contrast enhanced magnetic resonance imaging Magnetic Resonance Imaging 25 3 319 27 doi 10 1016 j mri 2006 09 041 PMID 17371720 Rini B Rixe O Bukowski R Michaelson MD Wilding G Hudes G et al June 2005 AG 013736 a multi target tyrosine kinase receptor inhibitor demonstrates anti tumor activity in a Phase 2 study of cytokine refractory metastatic renal cell cancer RCC Journal of Clinical Oncology ASCO Annual Meeting Proceedings 23 16S 4509 Archived from the original on 2014 01 26 Rugo HS Herbst RS Liu G Park JW Kies MS Steinfeldt HM et al August 2005 Phase I trial of the oral antiangiogenesis agent AG 013736 in patients with advanced solid tumors pharmacokinetic and clinical results Journal of Clinical Oncology 23 24 5474 83 doi 10 1200 JCO 2005 04 192 PMID 16027439 FDA Approves Inlyta for Advanced Renal Cell Carcinoma Drugs com January 27 2012 Fauber J Chu E October 27 2014 The Slippery Slope Is a Surrogate Endpoint Evidence of Efficacy MedPage Today Inlyta EPAR Product Information PDF European Medicines Agency Pfizer Ltd 17 December 2013 Retrieved 25 January 2014 Inlyta 1 mg 3mg 5 mg amp 7mg film coated tablets Summary of Product Characteristics SPC electronic Medicines Compendium Pfizer Limited 5 December 2013 Archived from the original on 2014 02 22 Retrieved 25 January 2014 PRODUCT INFORMATION INLYTA axitinib PDF TGA eBusiness Services Pfizer Australia Pty Ltd 5 July 2013 Retrieved 25 January 2014 Spano JP Chodkiewicz C Maurel J Wong R Wasan H Barone C et al June 2008 Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer an open label randomised phase II study Lancet 371 9630 2101 8 doi 10 1016 S0140 6736 08 60661 3 PMID 18514303 S2CID 11062859 Pfizer pancreatic cancer drug fails trial halted Reuters January 30 2009 Pfizer s Phase III Trial in mRCC Turns Up Positive Results 19 Nov 2010 ODAC Unanimously Supports Axitinib for Renal Cell Carcinoma 7 Dec 2011 ALK1 VEGF Combo Active in Advanced RCC Jan 2017 a b Pemovska T Johnson E Kontro M Repasky GA Chen J Wells P et al March 2015 Axitinib effectively inhibits BCR ABL1 T315I with a distinct binding conformation Nature 519 7541 102 5 Bibcode 2015Natur 519 102P doi 10 1038 nature14119 PMID 25686603 S2CID 4389086 FDA Prescribing Information PDF 30 Jan 2012 Escudier B Gore M 2011 Axitinib for the management of metastatic renal cell carcinoma Drugs in R amp D 11 2 113 26 doi 10 2165 11591240 000000000 00000 PMC 3585900 PMID 21679004 Zhang Y Xue D Wang X Lu M Gao B Qiao X January 2014 Screening of kinase inhibitors targeting BRAF for regulating autophagy based on kinase pathways Molecular Medicine Reports 9 1 83 90 doi 10 3892 mmr 2013 1781 PMID 24213221 AHFS Patient Medication Information Internet Bethesda MD American Society of Health System Pharmacists Inc c2022 Axitinib last revised 2020 August 15 cited 2022 March 28 about 5 p Available from https medlineplus gov druginfo meds a612017 html PubChem Axitinib pubchem ncbi nlm nih gov Retrieved 2022 03 28 External links Edit Axitinib Drug Information Portal U S National Library of Medicine Portal Medicine Retrieved from https en wikipedia org w index php title Axitinib amp oldid 1120545038, wikipedia, wiki, book, books, library,
