Quantifying the relationship between inhibition of VEGF receptor 2, drug-induced blood pressure elevation and hypertension.

Publisher: Wiley Country of Publication: England NLM ID: 7502536 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5381 (Electronic) Linking ISSN: 00071188 NLM ISO Abbreviation: Br J Pharmacol Subsets: MEDLINE

Publication: London : Wiley
Original Publication: London, Macmillian Journals Ltd.

Angiogenesis Inhibitors/*toxicity ; Blood Pressure/*physiology ; Hypertension/*chemically induced ; Protein Kinase Inhibitors/*toxicity ; Vascular Endothelial Growth Factor Receptor-2/*antagonists & inhibitors; Animals ; Axitinib ; Blood Pressure/drug effects ; Dose-Response Relationship, Drug ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Human Umbilical Vein Endothelial Cells/drug effects ; Human Umbilical Vein Endothelial Cells/metabolism ; Humans ; Hypertension/metabolism ; Imidazoles/toxicity ; Indazoles/toxicity ; Rats ; Swine ; Vascular Endothelial Growth Factor Receptor-2/metabolism

Background and Purpose: Several anti-angiogenic cancer drugs that inhibit VEGF receptor (VEGFR) signalling for efficacy are associated with a 15-60% incidence of hypertension. Tyrosine kinase inhibitors (TKIs) that have off-target activity at VEGFR-2 may also cause blood pressure elevation as an undesirable side effect. Therefore, the ability to translate VEGFR-2 off-target potency into blood pressure elevation would be useful in development of novel TKIs. Here, we have sought to quantify the relationship between VEGFR-2 inhibition and blood pressure elevation for a range of kinase inhibitors.
Experimental Approach: Porcine aortic endothelial cells overexpressing VEGFR-2 (PAE) were used to determine IC 50 for VEGFR-2 phosphorylation. These IC 50 values were compared with published reports of exposure attained during clinical use and the corresponding incidence of all-grade hypertension. Unbound average plasma concentration (C av,u ) was selected to be the most appropriate pharmacokinetic parameter. The pharmacokinetic-pharmacodynamic (PKPD) relationship for blood pressure elevation was investigated for selected kinase inhibitors, using data derived either from clinical papers or from rat telemetry experiments.
Key Results: All-grade hypertension was predominantly observed when the C av,u was >0.1-fold of the VEGFR-2 (PAE) IC 50 . Furthermore, based on the PKPD analysis, an exposure-dependent blood pressure elevation >1 mmHg was observed only when the C av,u was >0.1-fold of the VEGFR-2 (PAE) IC 50 .
Conclusions and Implications: Taken together, these data show that the risk of blood pressure elevation is proportional to the amount of VEGFR-2 inhibition, and a margin of >10-fold between VEGFR-2 IC 50 and C av,u appears to confer a minimal risk of hypertension.
(© 2017 The British Pharmacological Society.)

J Natl Cancer Inst. 2009 May 20;101(10):708-20. (PMID: 19436029)
Clin Cancer Res. 2014 Sep 1;20(17):4449-58. (PMID: 24958809)
Am Heart J. 2012 Feb;163(2):156-63. (PMID: 22305831)
Drug Metab Pharmacokinet. 2011;26(6):612-20. (PMID: 21897052)
Clin Cancer Res. 2006 Dec 1;12(23):7180-6. (PMID: 17145844)
Am J Med. 2012 Jan;125(1):14-22. (PMID: 22195528)
Toxicol Sci. 2016 Feb;149(2):458-72. (PMID: 26609138)
Br J Pharmacol. 2015 Jul;172(13):3189-93. (PMID: 25964986)
Methods Mol Biol. 2010;627:91-100. (PMID: 20217615)
Clin Cancer Res. 2005 Aug 1;11(15):5558-65. (PMID: 16061873)
Clin Pharmacol Ther. 2010 May;87(5):601-8. (PMID: 20376000)
Nat Rev Drug Discov. 2012 Oct;11(10):751-61. (PMID: 22935759)
Regul Toxicol Pharmacol. 2010 Jun;57(1):70-3. (PMID: 20074607)
Nat Rev Drug Discov. 2012 Dec;11(12):909-22. (PMID: 23197038)
CPT Pharmacometrics Syst Pharmacol. 2015 Jan;4(1):e00016. (PMID: 26225225)
Cancer Chemother Pharmacol. 2016 Mar;77(3):527-38. (PMID: 26791870)
Oncologist. 2011;16(4):432-44. (PMID: 21441297)
J Toxicol Sci. 2014 Apr;39(2):237-42. (PMID: 24646704)
Curr Oncol Rep. 2016 Jun;18(6):33. (PMID: 27099141)
Drug Saf. 2013 Jun;36(6):413-26. (PMID: 23620170)
J Pharmacol Toxicol Methods. 2014 Jul-Aug;70(1):73-85. (PMID: 24879942)
J Clin Pharmacol. 2014 Apr;54(4):415-21. (PMID: 24165976)
PLoS Biol. 2010 Jun 29;8(6):e1000412. (PMID: 20613859)
Br J Pharmacol. 2015 Jul;172(14):3461-71. (PMID: 26114403)
Drug Metab Dispos. 2012 Mar;40(3):539-55. (PMID: 22180047)
Br J Pharmacol. 2018 Feb;175(4):618-630. (PMID: 29161763)
Pharm Res. 2013 Jun;30(6):1513-24. (PMID: 23568527)
Clin Pharmacokinet. 2016 Oct;55(10):1251-1269. (PMID: 27154065)
Proc Natl Acad Sci U S A. 2012 Nov 6;109(45):18281-9. (PMID: 22988103)
Clin Pharmacokinet. 2015 Apr;54(4):397-407. (PMID: 25343945)
Cardiovasc Res. 2003 Apr 1;58(1):32-45. (PMID: 12667944)
Methods Enzymol. 1998;295:268-94. (PMID: 9750223)
Nat Biotechnol. 2011 Oct 30;29(11):1046-51. (PMID: 22037378)
Int J Cancer. 2011 Jul 1;129(1):245-55. (PMID: 21170960)
Br J Pharmacol. 2011 Sep;164(2):260-73. (PMID: 21480866)
Cancer Chemother Pharmacol. 2010 Jul;66(2):357-71. (PMID: 19967539)
Br J Pharmacol. 2014 May;171(9):2308-20. (PMID: 24329544)
Biometrics. 1997 Sep;53(3):983-97. (PMID: 9333350)
Bioorg Med Chem Lett. 2015 Mar 1;25(5):998-1008. (PMID: 25630223)
Semin Nephrol. 2010 Nov;30(6):591-601. (PMID: 21146124)
Semin Cancer Biol. 2015 Dec;35 Suppl:S224-S243. (PMID: 25600295)
FASEB J. 2017 Mar;31(3):1193-1203. (PMID: 27986807)
Nucleic Acids Res. 2016 Jan 4;44(D1):D1054-68. (PMID: 26464438)
Br J Pharmacol. 2014 Nov;171(22):5076-92. (PMID: 24962208)
J Cardiovasc Pharmacol. 2009 Feb;53(2):173-8. (PMID: 19188829)
Br J Pharmacol. 2017 Dec;174 Suppl 1:S225-S271. (PMID: 29055036)

0 (Angiogenesis Inhibitors)
0 (Imidazoles)
0 (Indazoles)
0 (Protein Kinase Inhibitors)
C9LVQ0YUXG (Axitinib)
EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2)

Date Created: 20171122 Date Completed: 20180815 Latest Revision: 20210109

20231215

PMC5786461

10.1111/bph.14103

29161763