Population Pharmacokinetic Analysis of Tocilizumab in Patients With Rheumatoid Arthritis

Tocilizumab is a humanized anti‐interleukin‐6 (IL‐6) receptor monoclonal antibody that has demonstrated efficacy in the treatment of rheumatoid arthritis (RA). A population pharmacokinetic (PK) model was developed using nonlinear mixed effect modeling to describe the PK profile of tocilizumab and used to estimate interindividual variability and assess the influence of covariates on PK parameters. The model was constructed based on data collected from 1793 patients with moderate to severe RA who received tocilizumab (4 or 8 mg/kg), via intravenous infusion every 4 weeks, during 4 phase III clinical trials. Serum concentration‐time profiles of tocilizumab were adequately described by a 2‐compartment disposition model with parallel linear and nonlinear elimination kinetics. The 8‐mg/kg dose of tocilizumab, compared with the 4‐mg/kg dose, resulted in a more pronounced saturation of the nonlinear clearance pathway over the dosing interval, and this nonlinear clearance was representative of target‐mediated elimination due to tocilizumab binding to the IL‐6 receptor.

[1]  M. Genovese,et al.  Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. , 2008, Arthritis and rheumatism.

[2]  J. Kremer,et al.  IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial , 2008, Annals of the rheumatic diseases.

[3]  J. Smolen,et al.  Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial , 2008, The Lancet.

[4]  T. Kishimoto,et al.  Humanized antihuman IL-6 receptor antibody, tocilizumab. , 2008, Handbook of experimental pharmacology.

[5]  D. Mould,et al.  Modeling and Simulation of Abatacept Exposure and Interleukin‐6 Response in Support of Recommended Doses for Rheumatoid Arthritis 1 , 2007 .

[6]  Y. Ohsugi.  Recent advances in immunopathophysiology of interleukin-6: an innovative therapeutic drug, tocilizumab (recombinant humanized anti-human interleukin-6 receptor antibody), unveils the mysterious etiology of immune-mediated inflammatory diseases. , 2007, Biological & pharmaceutical bulletin.

[7]  J. Scheller,et al.  The IL-6/sIL-6R complex as a novel target for therapeutic approaches , 2007, Expert opinion on therapeutic targets.

[8]  Ulrich Klotz,et al.  Clinical Pharmacokinetics and Use of Infliximab , 2007, Clinical pharmacokinetics.

[9]  D. Mould,et al.  Modeling and simulation of abatacept exposure and interleukin-6 response in support of recommended doses for rheumatoid arthritis. , 2007, Journal of clinical pharmacology.

[10]  T. Kishimoto,et al.  Interleukin 6: from bench to bedside , 2006, Nature Clinical Practice Rheumatology.

[11]  P. Emery,et al.  Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. , 2006, Arthritis and rheumatism.

[12]  P. Lipsky.  Interleukin-6 and rheumatic diseases , 2006, Arthritis research & therapy.

[13]  C. Gabay,et al.  Interleukin-6 and chronic inflammation , 2006, Arthritis research & therapy.

[14]  M. H. Ensom,et al.  Pharmacokinetics of Intravenous Immunoglobulin: A Systematic Review , 2006, Pharmacotherapy.

[15]  N. Nishimoto.  Interleukin-6 in rheumatoid arthritis , 2006, Current opinion in rheumatology.

[16]  M. Tabrizi,et al.  Elimination mechanisms of therapeutic monoclonal antibodies. , 2006, Drug discovery today.

[17]  Y. Ohsugi,et al.  Tocilizumab inhibits signal transduction mediated by both mIL-6R and sIL-6R, but not by the receptors of other members of IL-6 cytokine family. , 2005, International immunopharmacology.

[18]  D. Combs,et al.  Population Pharmacokinetics of Rituximab (Anti‐CD20 Monoclonal Antibody) in Rheumatoid Arthritis Patients During a Phase II Clinical Trial , 2005, Journal of clinical pharmacology.

[19]  N. Miyasaka,et al.  Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. , 2004, Arthritis and rheumatism.

[20]  Mats O. Karlsson,et al.  Assessment of Actual Significance Levels for Covariate Effects in NONMEM , 2001, Journal of Pharmacokinetics and Pharmacodynamics.

[21]  T. Kishimoto,et al.  Toxicity, pharmacokinetics, and dose-finding study of repetitive treatment with the humanized anti-interleukin 6 receptor antibody MRA in rheumatoid arthritis. Phase I/II clinical study. , 2003, The Journal of rheumatology.

[22]  R. Price,et al.  Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: a randomized, double-blind, placebo-controlled, dose-escalation trial. , 2002, Arthritis and rheumatism.

[23]  E N Jonsson,et al.  Xpose--an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. , 1999, Computer methods and programs in biomedicine.

[24]  M. Błasińska-Morawiec,et al.  Serum levels of IL-6 type cytokines and soluble IL-6 receptors in active B-cell chronic lymphocytic leukemia and in cladribine induced remission. , 1999, Mediators of inflammation.

[25]  A. Davidson,et al.  Rheumatoid factor specificity of a VH3-encoded antibody is dependent on the heavy chain CDR3 region and is independent of protein A binding. , 1998, Journal of immunology.

[26]  U. Müller-Ladner,et al.  Decrease of interleukin 6 during the first 12 months is a prognostic marker for clinical outcome during 36 months treatment with disease-modifying anti-rheumatic drugs. , 1997, British journal of rheumatology.

[27]  R. Madhok,et al.  Serum interleukin 6 levels in rheumatoid arthritis: correlations with clinical and laboratory indices of disease activity. , 1993, Annals of the rheumatic diseases.

[28]  S. Akira,et al.  Interleukin-6 in biology and medicine. , 1993, Advances in immunology.

[29]  B. Kirkham,et al.  Serial estimation of interleukin 6 as a measure of systemic disease in rheumatoid arthritis. , 1992, The Journal of rheumatology.

[30]  R. Cooper,et al.  Relationships between local inflammation, interleukin‐6 concentration and the acute phase protein response in arthritis patients , 1991, European journal of clinical investigation.

[31]  J. Snick,et al.  Interleukin-6: an overview. , 1990, Annual review of immunology.

[32]  J. Van Snick.  Interleukin-6: an overview. , 1990, Annual review of immunology.

[33]  F. Houssiau,et al.  Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides. , 1988, Arthritis and rheumatism.

[34]  W. Colburn,et al.  Specific antibodies and Fab fragments to alter the pharmacokinetics and reverse the pharmacologic/toxicologic effects of drugs. , 1980, Drug metabolism reviews.

[35]  T. Waldmann,et al.  Metabolism of immunoglobulins. , 1969, Progress in allergy.