title: Serum tocilizumab trough concentration can be used to monitor systemic IL-6 receptor blockade in patients with rheumatoid arthritis: a prospective observational cohort study.
abstract: OBJECTIVE
  To investigate the pharmacokinetics (PK) and dynamics of tocilizumab (TCZ) in daily practice.
  
  
  METHODS
  An observational study of 66 consecutive RA patients treated with TCZ 8 mg/kg once every 4 weeks intravenously, monitored for 24 weeks. Spearman's rank test was used to investigate the correlation between TCZ concentration and C-reactive protein (CRP). Clinical improvement was assessed at week 24 using the Disease Activity Score in 28 joints (DAS28) compared to baseline, and its relationship with TCZ concentration was investigated using linear regression analyses. TCZ trough concentrations and anti-drug antibodies were measured using an enzyme-linked immunosorbent assay (ELISA) and antigen binding test, respectively.
  
  
  RESULTS
  At baseline, 26 patients (39.4%) had a CRP level above 10 mg/L with a median (interquartile range, IQR) of 37.7 (21.9-49.7) mg/L. A TCZ concentration above 1 mg/L was sufficient to normalize CRP levels. Spearman's rank test showed a correlation coefficient of -0.460 (p < 0.0001). The TCZ concentration varied widely, with concentrations < 1 mg/L in 17-31% of patients, depending on the time point of measurement. Anti-TCZ antibodies were detected in one sample. Linear regression analyses showed a coefficient of 0.080 with a 95% confidence interval (CI) of 0.039-0.113 (p < 0.001) for the association between TCZ concentration and ΔDAS28. No confounders were identified.
  
  
  CONCLUSIONS
  The TCZ standard regimen results in a wide variety of serum TCZ trough concentrations; this is mostly due to target binding and to a lesser extent to immunogenicity. The majority of patients obtained TCZ concentrations > 1 mg/L, which is sufficient for CRP normalization. Therefore, dose taper strategies might be possible in a substantial proportion of patients.
authors.affiliation: a Department of Rheumatology , Amsterdam Rheumatology and immunology Centre, location Reade , Amsterdam , The Netherlands.
authors.forename: E L
authors.initials: EL
authors.lastname: Kneepkens
authors.affiliation: a Department of Rheumatology , Amsterdam Rheumatology and immunology Centre, location Reade , Amsterdam , The Netherlands.
authors.forename: Iam
authors.initials: I
authors.lastname: van den Oever
authors.affiliation: b Department of Rheumatology , La Paz hospital Madrid , Spain.
authors.forename: C H
authors.initials: CH
authors.lastname: Plasencia
authors.affiliation: c Immunology Unit , La Paz Hospital Madrid , Spain.
authors.forename: D
authors.initials: D
authors.lastname: Pascual-Salcedo
authors.affiliation: d Sanquin Diagnostic Services Amsterdam , The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: de Vries
authors.affiliation: e Department of Immunopathology , Sanquin Research and Landsteiner Laboratory, Academic Medical Centre Amsterdam , The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Hart
authors.affiliation: a Department of Rheumatology , Amsterdam Rheumatology and immunology Centre, location Reade , Amsterdam , The Netherlands.|f Department of Rheumatology , Amsterdam Rheumatology and immunology Centre, VU Medical Centre , Amsterdam , The Netherlands.
authors.forename: M T
authors.initials: MT
authors.lastname: Nurmohamed
authors.affiliation: b Department of Rheumatology , La Paz hospital Madrid , Spain.
authors.forename: A
authors.initials: A
authors.lastname: Balsa
authors.affiliation: e Department of Immunopathology , Sanquin Research and Landsteiner Laboratory, Academic Medical Centre Amsterdam , The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Rispens
authors.affiliation: a Department of Rheumatology , Amsterdam Rheumatology and immunology Centre, location Reade , Amsterdam , The Netherlands.|e Department of Immunopathology , Sanquin Research and Landsteiner Laboratory, Academic Medical Centre Amsterdam , The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Wolbink
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000097:blood* / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D019947:Receptors, Interleukin-6; C502936:tocilizumab