A pharmacokinetic binding model for bevacizumab and VEGF165 in colorectal cancer patients

Abstract

Purpose: To characterize the population pharmacokinetics of bevacizumab, its binding properties to VEGF165 and the effect of demographic data and VEGF-A polymorphisms on the interplay between bevacizumab serum pharmacokinetics and VEGF165 serum concentrations in patients with colorectal cancer stage IV.

Methods: Bevacizumab and VEGF165 data were collected from 19 adult patients with metastatic colorectal cancer enrolled in an observational clinical study. Bevacizumab was administered with one of the following combinations: 5-FU/Leucovorin/Irinotecan, 5-FU/Leucovorin/Oxaliplatin, Capecitabine/Irinotecan at doses ranging from 5 to 10 mg/kg every 2 or 3 weeks. Data analysis was performed using nonlinear mixed-effects modeling implemented in NONMEM 7.3.

Results: A target-mediated drug disposition model adequately described bevacizumab concentration changes over time and its binding characteristics to VEGF165. The estimated clearance of bevacizumab was 0.18 L/day, the free VEGF165 levels at baseline were 212 ng/L, and the elimination rate constant of free VEGF165 was 0.401 day(-1). Body weight was allometrically included in all PK parameters.

Conclusion: The final model adequately described the pre- and post-dose concentrations of total bevacizumab and free VEGF165 in patients with colorectal cancer. Model parameters were consistent with those previously reported for patients with solid tumors. Correlations between the binding affinity of bevacizumab and the VEGF-2578C/A and VEGF-634G/C polymorphisms were noticed.

Fig. 1

Structure of the binding model for bevacizumab–VEGF₁₆₅ interaction. The approximation CL_RC = CL was used for purposes of model fitting

Fig. 2

Prediction-corrected visual predictive checks of the binding model based on 1000 simulations (panel a total bevacizumab, panel b free VEGF₁₆₅). Median (solid line), 10th and 90th percentiles (dashed lines) of the observed data (circles) are compared to the 95 % confidence intervals (shaded areas) for the median, 10th and 90th percentiles of the simulated data

Fig. 3

Model-predicted concentrations of total bevacizumab, total and free VEGF₁₆₅ for a typical patient of 70 kg. Panels a, b show the total bevacizumab and free VEGF₁₆₅ concentration profiles at doses of 5 and 7.5 mg/kg, respectively. Panel c depicts the total VEGF₁₆₅ profiles over time for the two dosing regimens