title: Population Pharmacokinetics of ABT-806, an Investigational Anti-Epidermal Growth Factor Receptor (EGFR) Monoclonal Antibody, in Advanced Solid Tumor Types Likely to Either Over-Express Wild-Type EGFR or Express Variant III Mutant EGFR.
abstract: OBJECTIVE
  ABT-806 is a veneered 'humanized' recombinant IgG1κ antibody that is specific for a unique epitope of human epidermal growth factor receptor (EGFR) expressed only on tumor cells with the EGFRde2-7 (EGFRvIII) deletion mutant as well as tumors with wild-type amplified receptors. We aimed to develop a population pharmacokinetic model of ABT-806 in cancer patients, and to evaluate fixed versus body weight-based dosing regimens.
  
  
  METHODS
  The pharmacokinetics of ABT-806 were evaluated in a phase I, open-label study in cancer patients following intravenous infusion of ABT-806 every other week. A total of 587 serum concentrations of ABT-806 from 61 patients were analyzed using non-linear mixed-effects modeling. The impact of body weight-based and fixed dosing of ABT-806 was evaluated using a simulation approach.
  
  
  RESULTS
  A two-compartment model with linear elimination was used to describe the serum concentration-time data of ABT-806. The population estimates of the apparent clearance from the central (CLc) and peripheral (CLp) compartments were 0.011 and 0.025 L/h, respectively. The apparent volume of distribution estimates of the central (V 1) and peripheral (V 2) compartments were 3.5 and 3.3 L, respectively. The estimates of inter-subject variability (percentage coefficient of variation) in CLc, CLp, V 1, and V 2 were 38, 37, 20, and 48 %, respectively. Albumin on CLc and body weight on V 1 were statistically significant covariates; however, they explained 18 and 30 % of the inter-individual variability of clearance and V 1, respectively. Simulation results indicated that fixed and body weight-based dosing regimens yield similar steady-state concentrations and overall variability.
  
  
  CONCLUSIONS
  ABT-806 demonstrated a unique pharmacokinetic profile compared to the marketed monoclonal antibodies against EGFR. The analysis indicates it is feasible to switch to fixed doses in subsequent clinical trials of ABT-806.
authors.affiliation: Department of Clinical Pharmacology and Pharmacometrics, AbbVie Inc., One North Waukegan Road, AP13A, North Chicago, IL, 60064, USA.
authors.forename: Shringi
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Clinical Pharmacology and Pharmacometrics, AbbVie Inc., One North Waukegan Road, AP13A, North Chicago, IL, 60064, USA. rajendar.mittapalli@abbvie.com.
authors.forename: Rajendar K
authors.initials: RK
authors.lastname: Mittapalli
authors.affiliation: Oncology Development, AbbVie Inc., North Chicago, IL, USA.
authors.forename: Kyle D
authors.initials: KD
authors.lastname: Holen
authors.affiliation: Department of Clinical Pharmacology and Pharmacometrics, AbbVie Inc., One North Waukegan Road, AP13A, North Chicago, IL, 60064, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Xiong
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics*; D001835:Body Weight; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C410723:epidermal growth factor receptor VIII; C512478:EGFR protein, human; D066246:ErbB Receptors; C000604456:depatuxizumab