title: Population pharmacokinetics of bevacizumab in cancer patients with external validation.
abstract: BACKGROUND
  Bevacizumab is approved for various cancers. This analysis aimed to comprehensively evaluate bevacizumab pharmacokinetics and the influence of patient variables on bevacizumab pharmacokinetics.
  
  
  METHODS
  Rich and sparse bevacizumab serum concentrations were collected from Phase I through IV studies in early and metastatic cancers. Bevacizumab was given intravenously as single agent or in combination with chemotherapy for single- and multiple-dose schedules.
  
  
  RESULTS
  Model-building used 8943 bevacizumab concentrations from 1792 patients with colon/colorectal, non-small cell lung, kidney, pancreatic, breast, prostate and brain cancer. Bevacizumab doses ranged from 1 to 20 mg/kg given once every 1, 2 or 3 weeks. A two-compartment model best described the data. The population estimates of clearance (CL), central volume of distribution (V1) and half-life for a typical 70-kg patient were 9.01 mL/h, 2.88 L and 19.6 days. CL and V1 increased with body weight and were higher in males than females by 14 and 18 %, respectively. CL decreased with increasing albumin and decreasing alkaline phosphatase. The final model was externally validated using 1670 concentrations from 146 Japanese patients that were not used for model-building. Mean prediction errors were -2.1, 3.1 and 1.0 % for concentrations, CL and V1, respectively, confirming adequate predictive performance.
  
  
  CONCLUSIONS
  A robust bevacizumab pharmacokinetic model was developed and externally validated, which may be used to simulate bevacizumab exposure to optimize dosing strategies. Asian and non-Asian patients exhibited similar bevacizumab pharmacokinetics. Given the similarity in pharmacokinetics among monoclonal antibodies, this may inform pharmacokinetic studies in different ethnic groups for other therapeutic antibodies.
authors.affiliation: Clinical Pharmacology, Genentech Inc, 1 DNA Way, South San Francisco, CA, 94080, USA. kelong.x.han@gsk.com.|GlaxoSmithKline, 709 Swedeland Rd, King of Prussia, PA, 19406, USA. kelong.x.han@gsk.com.
authors.forename: Kelong
authors.initials: K
authors.lastname: Han
authors.affiliation: Pharsight Consulting Services, Montreal, QC, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Peyret
authors.affiliation: Pharsight Consulting Services, Marseille, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Marchand
authors.affiliation: Clinical Pharmacology, Genentech Inc, 1 DNA Way, South San Francisco, CA, 94080, USA.
authors.forename: Angelica
authors.initials: A
authors.lastname: Quartino
authors.affiliation: Pharsight Consulting Services, Montreal, QC, Canada.
authors.forename: Nathalie H
authors.initials: NH
authors.lastname: Gosselin
authors.affiliation: Clinical Pharmacology, Genentech Inc, 1 DNA Way, South San Francisco, CA, 94080, USA.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Girish
authors.affiliation: Clinical Pharmacology, Genentech Inc, 1 DNA Way, South San Francisco, CA, 94080, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Allison
authors.affiliation: Clinical Pharmacology, Genentech Inc, 1 DNA Way, South San Francisco, CA, 94080, USA. jin.jin@gene.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Jin
mesh_terms: D000328:Adult; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D044466:Asian People; D000068258:Bevacizumab / Q000008:administration & dosage* / Q000493:pharmacokinetics; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D017327:Clinical Trials, Phase IV as Topic; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012737:Sex Factors; D014018:Tissue Distribution
chemical_list: D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab
keywords: Adult; Asian; Bevacizumab; Cancer; External validation; Japan; Population pharmacokinetics