Elsevier

Clinical Therapeutics

Volume 34, Issue 1, January 2012, Pages 77-90
Clinical Therapeutics

Pharmacotherapy
Original research
Golimumab Pharmacokinetics After Repeated Subcutaneous and Intravenous Administrations in Patients with Rheumatoid Arthritis and the Effect of Concomitant Methotrexate: An Open-Label, Randomized Study

These data were presented, in part, at the annual meeting of the American Society for Clinical Pharmacology and Therapeutics, March 17–20, 2010, Atlanta, Georgia.
https://doi.org/10.1016/j.clinthera.2011.11.015Get rights and content

Abstract

Background

The pharmacokinetics of golimumab, a human monoclonal antibody that inhibits the activity of tumor necrosis factor α, after a single subcutaneous (SC) or intravenous (IV) administration have been previously studied.

Objectives

The purpose of this study was to assess the pharmacokinetics of golimumab after multiple SC or IV administrations in patients with active rheumatoid arthritis (RA). The effect of concomitant methotrexate (MTX) use on golimumab pharmacokinetics was evaluated.

Methods

In this open-label, randomized, Phase I study, 49 adult patients with RA received SC golimumab 100 mg (n = 33) every 4 weeks through week 20 or IV golimumab 2 mg/kg (n = 16) at weeks 0 and 12. Serial blood samples were collected, and serum golimumab concentration was measured with an electrochemiluminescent immunoassay. Golimumab pharmacokinetic parameters were derived with the use of a noncompartmental analysis. Adverse events were monitored at every visit.

Results

The population was predominantly Caucasian (84%) and female (76%), and the median age was 57 years. After SC golimumab administration, the serum golimumab concentration achieved steady state by ∼12 weeks with mean trough serum concentrations ranging from 1.15 to 1.24 μg/mL. After the final 30-minute IV infusion of golimumab 2 mg/kg, the mean (SD) clearance (CL) was 7.5 (2.6) mL/d/kg. The mean terminal half-life after SC and IV administrations was ∼13 days. The mean absolute bioavailability for SC golimumab was estimated to be 53%. The geometric mean of golimumab CL/F in patients with and without concomitant MTX use was 13.9 and 21.2 mL/d/kg, respectively, and the geometric mean ratio of CL/F was 65.5% (90% CI: 45.2%–94.9%, P = 0.06). Golimumab was generally well tolerated. No malignancies or deaths occurred during the study.

Conclusions

Pharmacokinetics of golimumab were consistent after SC or IV administration in this population of patients with RA. Golimumab was well tolerated and no unexpected adverse events were observed in this trial. ClinialTrials.gov identifier: NCT01362153.

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.

Section snippets

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.

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