• David C Turner, Fariba Navid, Najat C Daw, Shenghua Mao, Jianrong Wu, Victor M Santana, Michael Neel, Bhaskar Rao, Jennifer Reikes Willert, David M Loeb, K Elaine Harstead, Stacy L Throm, Burgess B Freeman, and Clinton F Stewart.
• Authors' Affiliations: Departments of Pharmaceutical Sciences, Oncology, Biostatistics, and Surgery; Preclinical Pharmacokinetic Shared Resource, St. Jude Children's Research Hospital; Department of Pediatrics, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee; Division of Pediatrics, MD Anderson Cancer Center, Houston, Texas; Department of Pediatrics, Stanford School of Medicine, Palo Alto, California; and Department of Oncology, Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
• Clin Cancer Res. 2014 May 15; 20 (10): 2783-92.

PurposeTo describe sources of interindividual variability in bevacizumab disposition in pediatric patients and explore associations among bevacizumab pharmacokinetics and clinical wound healing outcomes.Experimental DesignBefore 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.ResultsBevacizumab 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).ConclusionA 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.©2014 American Association for Cancer Research.

28 keywords...

hide…