A pharmacokinetic binding model for bevacizumab and VEGF(165) in colorectal cancer patients

PURPOSE: To characterize the population pharmacokinetics of bevacizumab, its binding properties to VEGF(165) and the effect of demographic data and VEGF-A polymorphisms on the interplay between bevacizumab serum pharmacokinetics and VEGF(165) serum concentrations in patients with colorectal cancer stage IV. METHODS: Bevacizumab and VEGF(165) 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 VEGF(165). The estimated clearance of bevacizumab was 0.18 L/day, the free VEGF(165) levels at baseline were 212 ng/L, and the elimination rate constant of free VEGF(165) 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 VEGF(165) 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00280-015-2701-3) contains supplementary material, which is available to authorized users.