PharmacotherapyOriginal researchGolimumab Pharmacokinetics After Repeated Subcutaneous and Intravenous Administrations in Patients with Rheumatoid Arthritis and the Effect of Concomitant Methotrexate: An Open-Label, Randomized Study
Introduction
Rheumatoid arthritis (RA) is a chronic inflammatory disorder of the joints that affects approximately 0.5% to 1% of the population.1 Tumor necrosis factor α (TNFα), a proinflammatory cytokine, is overproduced in the joints of patients with RA and is a key mediator in RA.2, 3, 4 Golimumab is a human anti-TNFα immunoglobulin G1κ monoclonal antibody (mAb) that binds to TNFα with high affinity5 and thus inhibits TNFα bioactivity. In Phase III clinical trials, golimumab, as monotherapy and with concomitant methotrexate (MTX), significantly reduced the signs and symptoms of RA and had a safety profile consistent with other approved anti-TNFα biologic agents.6, 7, 8, 9
The pharmacokinetic characteristics of golimumab have been evaluated after a single intravenous (IV) administration in patients with RA10 and a single subcutaneous (SC) administration in healthy subjects.11 In the IV study, both the Cmax and the AUC increased in a dose-proportional manner over the dose range of 0.1 to 10 mg/kg. Mean clearance (CL) was estimated to be 4.9 to 6.7 mL/d/kg, and the t½ ranged from 8 to 20 days.10 After a single SC administration of golimumab 100 mg in healthy subjects, golimumab was absorbed slowly into the blood with a median Tmax of 4.0 days.11 The median t½ after SC administration was 10.9 days, which was consistent with that observed after IV administration.11
Concomitant use of MTX has been previously reported to affect the pharmacokinetics of anti-TNF therapies in some patient populations.12, 13 Because golimumab is an anti-TNFα agent and is approved for use with concomitant MTX,14 it is important to understand the potential interaction between concomitant MTX use and golimumab pharmacokinetics. This drug interaction has been evaluated in previous studies that reported various findings. In patients with psoriatic arthritis, a population pharmacokinetic analysis that was based on sparse pharmacokinetic data from a Phase III study reported that concomitant use of MTX did not significantly influence the apparent CL/F of golimumab.15 In patients with RA, concomitant use of MTX was identified as a significant covariate for golimumab CL/F in a population pharmacokinetic analysis.16
The primary objective of this Phase I study was to determine the pharmacokinetics of golimumab after repeated SC or IV administrations. We also performed a post hoc analysis to assess the extent of the effect of concomitant MTX on golimumab pharmacokinetics after repeated SC administrations in patients with RA. In addition, because limited clinical data indicate a weak correlation between baseline levels of C-reactive protein (CRP), an acute-phase reactant that correlates well with disease activity in RA,17, 18 and apparent CL/F of anti-TNFα mAbs,15, 19 the potential relation between baseline CRP level and golimumab pharmacokinetics was also explored in this study.
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Patients
Study participants were aged 18 years or older and had RA according to the revised 1987 criteria of the American College of Rheumatology20 for at least 3 months before screening. Active RA was defined as persistent disease activity with at least four swollen and four tender joints and at least two of the following at screening, baseline, or both: (1) CRP ≥1.5 mg/dL or erythrocyte sedimentation rate by Westergren method of ≥28 mm, (2) morning stiffness ≥30 minutes, and (3) anti-cyclic
Patient Disposition
Fifty-one patients were randomized to receive the study agent, and 49 received the study agent (Figure 1). Before the first administration of study agent, one patient was found to not meet all of the inclusion and exclusion criteria, and another withdrew consent. Among the 49 treated patients, 33 were assigned to Group I, and 16 were assigned to Group II. Demographic and baseline disease characteristics are summarized in Table I. The population was predominantly Caucasian (83.7%, 41/49) and
Discussion
The pharmacokinetic characteristics of golimumab have been evaluated previously in healthy subjects after a single IV10 or SC11 administration. The present study evaluated the pharmacokinetics of golimumab after repeated SC and IV administrations in patients with active RA. After the first and last SC administrations of golimumab 100 mg, the median Tmax observed in these patients (3.5 and 3.0 days, respectively) was comparable to that observed in healthy subjects (4.0 days).11, 30 The mean Cmax
Conclusions
Golimumab administered as an SC injection or IV infusion appeared to be well tolerated in these patients with RA. Pharmacokinetics of golimumab after SC or IV administration in patients with RA were consistent in this study.
Conflicts of Interest
This study was funded by Janssen Research & Development, LLC. Janssen Research & Development, LLC employees designed the study, collected and analyzed the data, and wrote and reviewed the manuscript. Editorial support was provided by employees of Janssen Biotech, Inc. All authors reviewed and approved the manuscript for submission.
Y. Zhuang, Z. Xu, B. Frederick, J. A. Ford, M. Keen, M. K. Doyle, K. J. Petty, H. M. Davis, and H. Zhou are employees of Janssen Research & Development, LLC and own
Acknowledgments
The authors thank Mahboob Rahman, MD, formerly of Janssen Research & Development, LLC, for his contribution to the study conception and design; Alice Zong, MS, of Janssen Research & Development, LLC, for supporting the data analysis; and Rebecca Clemente, PhD, and Mary Whitman, PhD, of Janssen Biotech, Inc., for editorial support.
References (36)
The epidemiology of rheumatoid arthritis
Rheum Dis Clin North Am
(2001)- et al.
Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial
Lancet
(2004) - et al.
Role of cytokines, acute-phase proteins, and chemokines in the progression of rheumatoid arthritis
Semin Arthritis Rheum
(1996) The value of C-reactive protein measurement in rheumatoid arthritis
Semin Arthritis Rheum
(1994)- et al.
Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor alpha inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial
Lancet
(2009) - et al.
Applications of a planar electrochemiluminescence platform to support regulated studies of macromolecules: benefits and limitations in assay range
J Pharm Biomed Anal
(2010) - et al.
Tumour necrosis factor in synovial exudates
Ann Rheum Dis
(1988) - et al.
Role of cytokines in rheumatoid arthritis
Annu Rev Immunol
(1996) - et al.
Cellular mechanisms and the role of cytokines in bone erosions in rheumatoid arthritis
Arthritis Rheum
(2000) - et al.
Characterization of golimumab, a human monoclonal antibody specific for human tumor necrosis factor alpha
MAbs
(2010)
The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment
Arthritis Rheum
Infliximab and methotrexate in the treatment of rheumatoid arthritisAnti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group
N Engl J Med
Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial
Arthritis Rheum
Pharmacokinetics and safety of golimumab, a fully human anti-TNF-alpha monoclonal antibody, in subjects with rheumatoid arthritis
J Clin Pharmacol
Subcutaneous bioavailability of golimumab at 3 different injection sites in healthy subjects
J Clin Pharmacol
Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis
Arthritis Rheum
Effect of methotrexate (MTX) coadministration on the pharmacokinetics (PK) of adalimumab (HUMIRA, Abbott) following a single intravenous (IV) injection
Arthritis Rheum
Simponi [package insert]
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These authors contributed equally to this work.