title: Rationale for fixed dosing of pertuzumab in cancer patients based on population pharmacokinetic analysis.
abstract: OBJECTIVE
  Our objectives were to develop the population pharmacokinetic (PK) for pertuzumab and examine the variability of steady-state trough serum concentrations (C(SS,trough)) and exposure after fixed, body-weight-based, or body-surface area (BSA)-based dosing methods in cancer patients.
  
  
  METHODS
  Pertuzumab was administered by i.v. infusion (every 3 weeks) either as a weight-based dose (0.5-15 mg/kg) or a fixed dose (420 or 1050 mg). Data from three clinical studies, comprising 153 patients and 1458 concentration-time points, were pooled for this analysis using NONMEM.
  
  
  RESULTS
  A linear two-compartment model best described the data. Body weight and BSA were significant covariates affecting clearance (CL) and distribution volume (Vc), respectively. However, weight and BSA only explained small percentage of interpatient variability for CL and Vc, respectively. Simulation results indicated that PK profiles were very similar after the three dosing methods. Compared to fixed dosing, weight- and BSA-based dosing only reduced the population variability of C(SS,trough) moderately.
  
  
  CONCLUSIONS
  A population PK model was developed for pertuzumab, the first monoclonal IgG1 antibody in a new class of agents known as HER dimerization inhibitors. In addition, our analyses demonstrate the feasibility of administering pertuzumab using a fixed dose in women with ovarian and breast cancers.
authors.affiliation: Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech Inc., 1 DNA Way MS70, South San Francisco, California 94080-4990, USA. cheeng@gene.com
authors.forename: Chee M
authors.initials: CM
authors.lastname: Ng
authors.forename: Bert L
authors.initials: BL
authors.lastname: Lum
authors.forename: Veronica
authors.initials: V
authors.lastname: Gimenez
authors.forename: Steve
authors.initials: S
authors.lastname: Kelsey
authors.forename: David
authors.initials: D
authors.lastname: Allison
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D001830:Body Surface Area; D001835:Body Weight; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D008954:Models, Biological; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C485206:pertuzumab