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

Background and PurposeSeveral 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 ApproachPorcine aortic endothelial cells overexpressing VEGFR-2 (PAE) were used to determine IC50 for VEGFR-2 phosphorylation. These IC50 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,C-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 ResultsAll-grade hypertension was predominantly observed when the C-av,C-u was >0.1-fold of the VEGFR-2 (PAE) IC50. Furthermore, based on the PKPD analysis, an exposure-dependent blood pressure elevation >1mmHg was observed only when the C-av,C-u was >0.1-fold of the VEGFR-2 (PAE) IC50. Conclusions and ImplicationsTaken 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 C-av,C-u appears to confer a minimal risk of hypertension.