title: Population pharmacokinetics and exposure-response relationship of amatuximab, an anti-mesothelin monoclonal antibody, in patients with malignant pleural mesothelioma and its application in dose selection.
abstract: OBJECTIVE
  To characterize amatuximab pharmacokinetics (PK) and the relationship of amatuximab exposure with response in patients with unresectable malignant pleural mesothelioma (MPM) receiving amatuximab with pemetrexed and cisplatin.
  
  
  METHODS
  A nonlinear mixed effects PK model was built using data from all of the amatuximab studies conducted to date. Patients received amatuximab alone or in combination with chemotherapy. The influence of demographic, laboratory and disease characteristics on PK parameters was assessed. Exposure-response analyses explored relationships between amatuximab exposure and overall survival (OS), progression-free survival (PFS) and safety. Alternative amatuximab dosing regimens were explored with simulations using population PK and parametric survival models.
  
  
  RESULTS
  Amatuximab PK was best described by a two-compartment model with parallel linear and nonlinear elimination pathways. Body weight and an antidrug antibodies reaction with the titer >64 affected volume of distribution and clearance, respectively. Exposure-response analyses demonstrated that the amatuximab exposure (C min) showed a significant effect on OS (log-rank test, P = 0.0202). For patients with amatuximab C min above the median (38.2 μg/mL), the median OS was 583 days (90 % CI 418 -NE). For patients with C min ≤ 38.2 μg/mL, the median OS was 375 days (90 % CI 325-486). The amatuximab exposure showed similar significant effect on PFS. Exposure-response analysis for adverse events did not reveal any relationship.
  
  
  CONCLUSIONS
  In patients with MPM, higher amatuximab exposure in combination with chemotherapy was shown to be associated with longer OS, supporting evaluation of more frequent dosing in future trials to achieve higher exposure and subsequently longer OS.
authors.affiliation: Clinical Pharmacology, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire, AL10 9SN, UK.
authors.forename: Anubha
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Clinical Pharmacology, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire, AL10 9SN, UK. ziad_hussein@eisai.net.
authors.forename: Ziad
authors.initials: Z
authors.lastname: Hussein
authors.affiliation: Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Raffit
authors.initials: R
authors.lastname: Hassan
authors.affiliation: Morphotek, Inc., Exton, PA, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Wustner
authors.affiliation: Former Employee of Morphotek, Inc., Exton, PA, USA.
authors.forename: Julia D
authors.initials: JD
authors.lastname: Maltzman
authors.affiliation: Morphotek, Inc., Exton, PA, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Wallin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000401:mortality; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D008954:Models, Biological; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000401:mortality
chemical_list: D000911:Antibodies, Monoclonal; C526187:amatuximab
keywords: Amatuximab; Malignant pleural mesothelioma; Monoclonal antibody; Population pharmacokinetic/pharmacodynamic modeling