Population Pharmacokinetics of Bevacizumab in Children with Osteosarcoma: Implications for Dosing

Abstract

Purpose To describe sources of interindividual variability in bevacizumab disposition in pediatric patients and explore associations among bevacizumab pharmacokinetics and clinical wound healing outcomes. Experimental Design Prior to tumor resection, three doses of bevacizumab (15 mg/kg) were administered to patients (median age 12.2 years) enrolled on a multi-institutional osteosarcoma trial. Serial sampling for bevacizumab pharmacokinetics was obtained from 27 patients. A population pharmacokinetic model was fit to the data, and patient demographics and clinical chemistry values were systematically tested as predictive covariates on model parameters. Associations between bevacizumab exposure and wound healing status were evaluated by logistic regression. Results Bevacizumab concentration-time data were adequately described by a two-compartment model. Pharmacokinetic parameter estimates were similar to those previously reported in adults with a long median (range) terminal half-life of 12.2 days (8.6 to 32.4 days) and a volume of distribution indicating confinement primarily to the vascular space,49.1 mL/kg (27.1 to 68.3 mL/kg). Body composition was a key determinant of bevacizumab exposure as body mass index percentile was significantly (p<0.05) correlated to body-weight normalized clearance and volume of distribution. Furthermore, bevacizumab exposure prior to primary tumor resection was associated with increased risk of major wound healing complications after surgery (p<0.05). Conclusion A population pharmacokinetic model for bevacizumab was developed which demonstrated that variability in bevacizumab exposure using weight-based dosing is related to body composition. Bevacizumab dosage scaling using ideal body weight would provide an improved dosing approach in children by minimizing pharmacokinetic variability and reducing likelihood of major wound healing complications.

A phase II trial evaluating the feasibility of adding bevacizumab to standard osteosarcoma therapy

“…A novel finding from the present study that we previously reported is that bevacizumab exposure (i.e., area under the concentration-time curve, AUC) prior to surgery was associated with increased risk of major wound healing complications after surgery. 22 …”

“…The sampling strategy, sample analysis, and development of the population pharmacokinetic model for bevacizumab have been previously described. 22 Bevacizumab concentration-time data were fit to a two-compartment model with first order elimination from the central compartment. Bevacizumab exposure [area under curve (AUC)] from the first dose (week 0) to time of methotrexate administration was estimated for each patient using a nonlinear mixed effects model in NONMEM (version 7.3; ICON solutions, Hanover, MD), a software package utilized for population pharmacokinetic modeling.…”

Serum C-reactive protein and overall survival of patients with osteosarcoma

“…In the present retrospective cohort, the prognostic significance of serum CRP level in patients with osteosarcoma was successfully identified. For those osteosarcoma patients with high serum CRP level, more adjuvant treatments may be necessary and can be added to improve the survival [4,5,14].…”

“…A study from Norway showed that there was no improvement in the overall survival for osteosarcoma since the 1990s, and the survival rates were still poor for elderly people or patients with metastatic diseases [2]. Previous studies have suggested that patients with poor histological response to chemotherapy or advanced stages usually have worse prognosis [4][5][6]. It is no doubt that identification of prognostic factors to choose starting and reasonable therapy is very helpful to improve patients' survival.…”

Influence of Antigen Mass on the Pharmacokinetics of Therapeutic Antibodies in Humans

“…Notably, FcRn expression was suggested to be increased with inflammation, which would lead to an decrease in mAb intrinsic clearance. [4] Elimination half-life (T½R) estimates of bevacizumab was 21 days in teleangiectasia [147] , 17-20 days in various solid tumours [148,149] , 15-17 days in child sarcoma [144,150] , and 19 days in colorectal cancer (CRC) and, surprisingly, 44 days in multi-metastatic CRC. [130] For trastuzumab, T½R was 28 days in metastatic breast cancer (BC), but highly controversial in early BC, 12 days [94] or 40 days.…”