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

Teresa Collins1, Kelly Gray1, Michal Bista1

  • 1AstraZeneca, Darwin Building, Cambridge Science Park, Milton Road, Cambridge, CB4, 0WG, UK.

British Journal of Pharmacology
|November 22, 2017
PubMed
Abstract

Insights

Hypertension risk from cancer drugs is linked to VEGFR-2 inhibition. A 10-fold safety margin between drug exposure and VEGFR-2 IC50 minimizes blood pressure elevation risk.

Area of Science:

  • Pharmacology
  • Oncology
  • Cardiovascular Research

Background:

  • Anti-angiogenic cancer drugs targeting VEGF receptor (VEGFR) signaling often cause hypertension (15-60% incidence).
  • Tyrosine kinase inhibitors (TKIs) with off-target VEGFR-2 activity can also elevate blood pressure.
  • Quantifying the link between VEGFR-2 inhibition and hypertension is crucial for novel TKI development.

Purpose of the Study:

  • To quantify the relationship between VEGFR-2 inhibition and blood pressure elevation.
  • To establish a predictive model for hypertension risk in TKI development.
  • To identify a safety margin for VEGFR-2 inhibition to minimize hypertension.

Main Methods:

  • Used porcine aortic endothelial cells (PAE) overexpressing VEGFR-2 to determine IC50 for phosphorylation.
  • Compared IC50 values with clinical exposure data (unbound average plasma concentration, C_av,u) and hypertension incidence.
  • Investigated pharmacokinetic-pharmacodynamic (PKPD) relationships using clinical data and rat telemetry.

Main Results:

  • Hypertension was observed when C_av,u exceeded 0.1-fold of the VEGFR-2 (PAE) IC50.
  • Exposure-dependent blood pressure elevation (>1 mmHg) occurred only when C_av,u was >0.1-fold of the VEGFR-2 (PAE) IC50.
  • Risk of blood pressure elevation is proportional to the degree of VEGFR-2 inhibition.

Conclusions:

  • A margin of >10-fold between VEGFR-2 IC50 and C_av,u appears to confer minimal hypertension risk.
  • VEGFR-2 inhibition potency can be translated into blood pressure elevation risk for TKI development.
  • This PKPD model aids in designing safer TKIs with reduced cardiovascular side effects.

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