title: Population pharmacokinetics of bevacizumab in children with osteosarcoma: implications for dosing.
abstract: OBJECTIVE
  To describe sources of interindividual variability in bevacizumab disposition in pediatric patients and explore associations among bevacizumab pharmacokinetics and clinical wound healing outcomes.
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: David C
authors.initials: DC
authors.lastname: Turner
authors.affiliation: 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, MarylandAuthors' 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.
authors.forename: Fariba
authors.initials: F
authors.lastname: Navid
authors.affiliation: 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.
authors.forename: Najat C
authors.initials: NC
authors.lastname: Daw
authors.affiliation: 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.
authors.forename: Shenghua
authors.initials: S
authors.lastname: Mao
authors.affiliation: 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.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Wu
authors.affiliation: 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, MarylandAuthors' 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.
authors.forename: Victor M
authors.initials: VM
authors.lastname: Santana
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Neel
authors.affiliation: 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.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Rao
authors.affiliation: 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.
authors.forename: Jennifer Reikes
authors.initials: JR
authors.lastname: Willert
authors.affiliation: 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.
authors.forename: David M
authors.initials: DM
authors.lastname: Loeb
authors.affiliation: 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.
authors.forename: K Elaine
authors.initials: KE
authors.lastname: Harstead
authors.affiliation: 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.
authors.forename: Stacy L
authors.initials: SL
authors.lastname: Throm
authors.affiliation: 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.
authors.forename: Burgess B
authors.initials: BB
authors.lastname: Freeman
authors.affiliation: 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 clinton.stewart@stjude.org.
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
mesh_terms: D000293:Adolescent; D000465:Algorithms; D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics*; D019540:Area Under Curve; D000068258:Bevacizumab; D015992:Body Mass Index; D001835:Body Weight; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002648:Child; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D008954:Models, Biological; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism; D013997:Time Factors
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab