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Quantifying the relationship between inhibition of VEGF receptor 2, drug‐induced blood pressure elevation and hypertension
Author(s) -
Collins Teresa,
Gray Kelly,
Bista Michal,
Skinner Matt,
Hardy Christopher,
Wang Haiyun,
Mettetal Jerome T,
Harmer Alexander R
Publication year - 2018
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14103
Subject(s) - blood pressure , medicine , pharmacology , pharmacokinetics , endocrinology
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.