British journal of pharmacology 2017 11 21() doi 10.1111/bph.14103
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.
We sought to quantify the relationship between VEGFR-2 inhibition and blood pressure elevation for a range of kinase inhibitors. A porcine aortic endothelial (PAE) assay was used to determine the VEGFR-2 phosphorylation IC50 . These potency values were compared to published reports of exposure attained during clinical use and the corresponding incidence of all-grade hypertension. Unbound average plasma concentration (Cav,u ) was selected to be the most appropriate pharmacokinetic parameter. The PKPD relationship for blood pressure elevation was investigated for selected kinase inhibitors derived either from the clinical literature data or from rat telemetry experimental data.
The data showed that all-grade hypertension was predominantly observed when the Cav,u was >0.1-fold of the VEGFR-2 (PAE) IC50 . Furthermore, based on the PKPD analysis, an exposure-dependent blood pressure elevation >1 mm Hg was only observed when the Cav,u was >0.1-fold of the VEGFR-2 (PAE) IC50 .
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 IC50 and Cav,u appears to confer a minimal risk of hypertension.