Ambulatory monitoring detects sorafenib-induced blood pressure elevations on the first day of treatment

Abstract

Purpose: Hypertension is a mechanism-based toxicity of sorafenib and other cancer therapeutics that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. This prospective, single-center, cohort study characterized ambulatory blood pressure monitoring as an early pharmacodynamic biomarker of VEGF signaling pathway inhibition by sorafenib.

Experimental design: Fifty-four normotensive advanced cancer patients underwent 24-hour ambulatory blood pressure monitoring before and between days 6 and 10 of sorafenib therapy. After blood pressure changes were detected among the first cohort within 10 days, ambulatory blood pressure monitoring was done during the first 24 hours of treatment for the second cohort.

Results: For the entire patient population, the blood pressure increase [mean systolic, +10.8 mm Hg; 95% confidence interval (95% CI), 8.6-13.0; range, -5.2 to +28.7 mm Hg; mean diastolic, +8.0 mm Hg; 95% CI, 6.3-9.7; range, -4.4 to +27.1 mm Hg] was detected between days 6 and 10 (P < 0.0001 for both) and plateaued thereafter. Variability in blood pressure change did not associate with: age, body size, sex, self-reported race, baseline blood pressure, or steady-state sorafenib plasma concentrations. In the second cohort, the blood pressure elevation was detected during the first 24 hours (mean systolic, +8.2 mm Hg; 95% CI, 5.0-11.3; mean diastolic, +6.5 mm Hg; 95% CI, 4.7-8.3; P < 0.0001 for both).

Conclusions: Ambulatory blood pressure monitoring detects the blood pressure response to VEGF signaling pathway inhibition by sorafenib during the first 24 hours of treatment. The magnitude of blood pressure elevation is highly variable and unpredictable but could be important in optimizing the therapeutic index of VEGF signaling pathway inhibitor therapy.

Figure 1. Time course and distribution of Ambulatory Blood Pressure measurements

Box-plots display the population distribution of 24-hr mean systolic (A) and diastolic (B) BP measured by ambulatory monitoring. The median for the population is represented by the horizontal line, the interquartile range (IQR) by the edges of the boxes and values no more than 1.5 x IQR away from the upper or lower quartile by the ends of the bars, with dots representing those more than 1.5x IQR: prior to sorafenib administration (BL), over the course of the first 24 hours of sorafenib administration (day 1), when steady state plasma concentrations are first reached (day 6–10) and at a subsequent time-point (wk 5–7) typically 35–49 days of sorafenib therapy.

Figure 2. Change (day 6–10 measurement - baseline measurement) in mean arterial pressure measured by ambulatory monitoring for each patient

The grey bars demarcate 14 subjects with measurements less than twice the limit of detection for change (4.3 mmHg) in mean arterial blood pressure. The 8 subjects identified by dark bars had changes in mean arterial blood pressure more than twice the observed average change (16.7 mmHg).

Figure 3. Correlation between baseline blood pressure and change in blood pressure with exposure to sorafenib

For the 54 patients with complete ambulatory measurements on both sessions at steady state sorafenib dosing, the magnitude of change in blood pressure does not positively correlate with the absolute baseline value for systolic blood pressure (r = −0.17 [−0.42, 0.10] P = 0.22) (A) or diastolic blood pressure (r = −0.27 [95% CI −0.50, 0.002] P = 0.05) (B).

Figure 4. Absence of correlation between total sorafenib plasma concentrations/exposure and change in blood pressure

The magnitude of change in systolic blood pressure (A) and diastolic blood pressure (B) does not correlate with observed minimum total sorafenib plasma concentrations. For SBP, OR = 1.29 [95% CI = 0.63, 2.61], P = 0.49 and for DBP, OR = 1.22 [95% CI = 0.62, 2.43], P = 0.57.