title: Pharmacokinetics and pharmacodynamics of tocilizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, following single-dose administration by subcutaneous and intravenous routes to healthy subjects.
abstract: OBJECTIVE
  Tocilizumab, a humanized anti-interleukin-6 receptor (IL-6R) monoclonal antibody, given by intravenous (i.v.) infusion every 4 weeks has been approved for treatment of patients with rheumatoid arthritis. The objective of the study was to determine pharmacokinetics (PK) and pharmacodynamics (PD) of tocilizumab including absolute PK and PD bioavailabilities following subcutaneous (s.c.) administration.
  
  
  METHODS
  The PK and PD of tocilizumab 162 mg or 81 mg after single s.c. and i.v. administration were evaluated in an open-label, 4-parallel group study involving 48 healthy subjects (n = 12/group).
  
  
  RESULTS
  Following single-dose s.c. administration of tocilizumab, area under the serum concentration-time curve (AUC∞) increased by 6.4-fold, and maximum serum concentration (Cmax) increased by 4-fold, as the dose was doubled from 81 mg to 162 mg. Tocilizumab absolute PK bioavailability (AUC∞ ratio (s.c./i.v.)) was higher at 162 mg (48.8%) than at 81 mg (22.7%). Tocilizumab PD bioavailability for soluble IL-6R (sIL-6R) (AUClast ratio (s.c./i.v.)) was 109% at 162 mg and 80.9% at 81 mg. Tocilizumab PD bioavailability for C-reactive protein (CRP) effect was 98.2% (CRP AUC480h ratio) at 162 mg and 80.4% (AUC240h ratio (s.c./i.v.)) at 81 mg. Tocilizumab was well tolerated at both doses after s.c. and i.v. administration.
  
  
  CONCLUSIONS
  Tocilizumab absolute PK bioavailability for s.c. vs. i.v. administration was low; however, the PD effects for sIL-6R and CRP levels were comparable after 162-mg s.c. and i.v. administration. Therefore, 162 mg s.c. dose is a comparable dose for 162 mg i.v. dose based on PD bioavailability.
authors.affiliation: Department of Clinical Pharmacology, Hoffmann-La Roche Inc., Nutley, NJ, USA. zhangxiaoping@aol.com
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.forename: Angela
authors.initials: A
authors.lastname: Georgy
authors.forename: Lucy
authors.initials: L
authors.lastname: Rowell
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001682:Biological Availability; D002097:C-Reactive Protein / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D015850:Interleukin-6 / Q000097:blood*; D008297:Male; D008875:Middle Aged; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors*; D013997:Time Factors; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D002097:C-Reactive Protein; C502936:tocilizumab