title: Population pharmacokinetic and covariate analysis of pertuzumab, a HER2-targeted monoclonal antibody, and evaluation of a fixed, non-weight-based dose in patients with a variety of solid tumors.
abstract: OBJECTIVE
  To characterize the population pharmacokinetics (PK) of pertuzumab across clinical trials in a variety of solid tumors, evaluate the potential impact of patient characteristics on PK, and confirm the appropriateness of the fixed (non-weight-based) dose.
  
  
  METHODS
  Pertuzumab concentration data collected following intravenous administration during eleven phase I/II studies and the pivotal phase III trial CLEOPATRA were analyzed using nonlinear mixed-effects modeling. The potential impact of patient and laboratory characteristics and HER2 target-related variables on pertuzumab PK were investigated in a covariate analysis. The final model was used to confirm selection of fixed, non-weight-based dosing of pertuzumab, and to compare pertuzumab PK in CLEOPATRA with the other studies.
  
  
  RESULTS
  The analysis included 4,525 serum concentration measurements from 481 patients with solid tumors. Pertuzumab PK in the 2-25 mg/kg dose range was described by a two-compartment linear model with first-order elimination. The elimination clearance and central compartment volume were 0.235 L/day, and 3.11 L, respectively, and the terminal elimination half-life was 18.0 days. Baseline serum albumin and lean body weight had statistically significant effects on pertuzumab clearance; however, simulations showed that the magnitude of their effects on pertuzumab exposure was minimal compared with overall variability and was not clinically relevant. Thus, variations in these factors do not require dose adjustments.
  
  
  CONCLUSIONS
  The fixed, non-weight-based dosing of pertuzumab, 840 mg loading dose followed by a 420 mg maintenance dose every 3 weeks, in patients with the solid tumors in this analysis is well supported by the population pharmacokinetic modeling and simulation results.
authors.affiliation: Clinical Pharmacology, MS 463a, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Garg
authors.forename: Angelica
authors.initials: A
authors.lastname: Quartino
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Jin
authors.initials: J
authors.lastname: Jin
authors.forename: D Russell
authors.initials: DR
authors.lastname: Wada
authors.forename: Hanbin
authors.initials: H
authors.lastname: Li
authors.forename: Javier
authors.initials: J
authors.lastname: Cortés
authors.forename: Virginia
authors.initials: V
authors.lastname: McNally
authors.forename: Graham
authors.initials: G
authors.lastname: Ross
authors.forename: Jennifer
authors.initials: J
authors.lastname: Visich
authors.forename: Bert
authors.initials: B
authors.lastname: Lum
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D001835:Body Weight; D002986:Clinical Trials as Topic; D003661:Decision Support Techniques; D004305:Dose-Response Relationship, Drug; D005260:Female; D018734:Genes, erbB-2 / Q000502:physiology*; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017711:Nonlinear Dynamics; D012709:Serum Albumin
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D012709:Serum Albumin; C485206:pertuzumab