title: Characterization of the relationship between dose and blood eosinophil response following subcutaneous administration of mepolizumab.
abstract: OBJECTIVE
  Mepolizumab is a humanized IgG1 monoclonal antibody that blocks human IL-5 from binding to the IL-5 receptor, which is mainly expressed on eosinophils. Eosinophils are key cells in the inflammatory cascade of various diseases, including asthma. This study investigated the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between exposure of mepolizumab subcutaneous (SC) administration and blood eosinophil reduction compared with intravenous (IV) administration in adult subjects with asthma.
  
  
  METHODS
  In this multi-center, randomized, open-label, parallel-group, repeat-dose study, 70 adult subjects received one of four possible treatment regimens: mepolizumab 12.5, 125, or 250 mg SC or 75 mg IV. In addition to analyzing the dose and PK/PD relationship, absolute bioavailability, safety, tolerability, and incidence of anti-mepolizumab antibodies were evaluated.
  
  
  RESULTS
  Blood eosinophil levels decreased in a dose-dependent manner with the lowest (12.5 mg) dose clearly differentiating from the other doses. A non-linear inhibition Imax model based on blood eosinophil levels at week 12 identified that the SC doses providing 50% and 90% of maximal blood eosinophil inhibition were 11 mg (95% confidence interval (CI): 5.19 - 16.85) and 99 mg (95% CI: 47 - 152), respectively. The route of administration did not affect the exposure-response relationship. The estimated mepolizumab SC absolute bioavailability (arm) was 74% (90% CI: 54 - 102%). The safety profile of mepolizumab was favorable.
  
  
  CONCLUSIONS
  A dose-dependent reduction in blood eosinophils across all mepolizumab doses investigated was observed. The subcutaneous absolute bioavailability was 74%. The route of administration did not affect the mepolizumab exposure eosinophil response relationship.
authors.forename: Isabelle J
authors.initials: IJ
authors.lastname: Pouliquen
authors.forename: Oliver
authors.initials: O
authors.lastname: Kornmann
authors.forename: Sharon V
authors.initials: SV
authors.lastname: Barton
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Price
authors.forename: Hector G
authors.initials: HG
authors.lastname: Ortega
mesh_terms: D000293:Adolescent; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000187:drug effects*; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D015848:Interleukin-5 / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D013183:Sputum / Q000166:cytology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015848:Interleukin-5; C434107:mepolizumab