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: Before tumor resection, three doses of bevacizumab (15 mg/kg) were administered to patients (median age, 12.2 years) enrolled in 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 before 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.
Subject(s)
Antibodies, Monoclonal, Humanized/pharmacokinetics , Bone Neoplasms/drug therapy , Models, Biological , Osteosarcoma/drug therapy , Adolescent , Algorithms , Angiogenesis Inhibitors/pharmacokinetics , Area Under Curve , Bevacizumab , Body Mass Index , Body Weight , Bone Neoplasms/metabolism , Child , Computer Simulation , Dose-Response Relationship, Drug , Female , Humans , Logistic Models , Male , Osteosarcoma/metabolism , Time FactorsABSTRACT
BACKGROUND: The combination of gemcitabine and docetaxel has demonstrated promise in sarcomas diagnosed in adults. In the current study, the toxicity and efficacy of this combination were evaluated in pediatric sarcomas. METHODS: A retrospective case review of 22 patients with recurrent or refractory bone or soft-tissue sarcomas who received gemcitabine (at a dose of 675 mg/m(2) intravenously on Days 1 and 8) and docetaxel (at a dose of 75-100 mg/m(2) intravenously on Day 8) was undertaken. RESULTS: The patients (ages 8-23 years) received a total of 109 courses of chemotherapy (median, 4 courses; range, 1-13 courses). Seventeen patients had osteosarcoma, 2 patients had Ewing sarcoma family of tumors (ESFT), 1 patient had a malignant fibrous histiocytoma (MFH), 1 patient had a chondrosarcoma, and 1 patient had an undifferentiated sarcoma. Of the 14 patients evaluable for response, the patient with an MFH achieved a complete response (CR), 3 patients with osteosarcoma achieved a partial response (PR), and 2 patients (1 with ESFT and 1 with osteosarcoma) had stable disease (SD). The overall objective response (CR + PR) rate was 29%. Median duration of response (CR + PR + SD) was 4.8 months (range, 1.6-13 months). The toxicity was manageable and consisted primarily of thrombocytopenia and neutropenia. CONCLUSIONS: In the current study, gemcitabine in combination with docetaxel was found to be well tolerated and demonstrated antitumor activity in children and adolescents with recurrent or refractory osteosarcoma and MFH. Further evaluation of this drug combination is warranted in these patients.
