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| |  Golimumab Pharmacokinetics Determined in Patients With Rheumatoid Arthritis: Presented at ACCP By Crina Frincu-Mallos, PhD PHILADELPHIA -- September 18, 2008 -- Researchers have identified several important covariates – eg, baseline levels of C-reactive protein (CRP) and the concomitant use of methotrexate -- that could, to some extent, account for the variability in systemic exposure to golimumab. Zhenhua Xu, PhD, FCP, Research and Development, Centocor, Inc., Malvern, Pennsylvania, presented data on a population pharmacokinetics (PK) model for golimumab in patients with rheumatoid arthritis (RA) here at the American College of Clinical Pharmacology (ACCP) 37th Annual Meeting. Golimumab is a human immunoglobulin G1 kappa monoclonal antibody currently developed for the treatment of RA. Dr. Xu discussed the study findings in a poster session on September 14. Dr. Xu and colleagues sought to characterise the PK of golimumab in patients with active RA. A secondary objective of the study was to identify significant covariates on golimumab PK and to quantify them, added Dr. Xu. Using nonlinear, mixed-effects modelling, the investigators analysed 3,411 serum golimumab samples collected from baseline through week 24 from 315 methotrexate-naïve patients with RA and 279 methotrexate-treated patients accrued in trials CO524T05 and CO524T06, 2 randomised, double-blind, phase 3 trials. The 111 men and 483 women had a mean age of 50.4 years (range, 18-85 years) and mean weight of 73.3 kg (range, 37.5-167.8 kg). The mean duration of disease was 5.9 years (range, 0.1-49.6 years), and the mean creatinine clearance (CrCL) was 108.5 mL/min (range, 32.2-278.4 mL/min). A significant number of patients had a history of hypertension (n = 179) and/or hyperlipidaemia (n = 99), noted Dr. Xu. Golimumab was administered subcutaneously to patients in 3 different regimens: (1) golimumab 50 mg/day for 4 weeks plus methotrexate; (2) golimumab 100 mg/day for 4 weeks plus methotrexate; (3) single-agent golimumab 100 mg/day for 4 weeks. For the regimens that contained methotrexate, the drug was given at 10 mg/week from weeks 0 to 8, followed by escalation to 20 mg/week until week 24. To describe the observed concentration-versus-time data, Dr. Xu and colleagues chose a 1-compartment PK model with first-order absorption and elimination. For a patient with a weight of 70 kg, the apparent clearance of golimumab (CL/F) was 1.91 L/day (95% confidence interval [CI], 1.80-2.03 L/day). The apparent volume of distribution (V/F) was 26.7 L (95% CI, 24.5-28.7 L). The absorption constant (Ka) was 0.668 at day -1 (95% CI, 0.564-0.875 day-1). Looking at the variability between individual patients, Dr. Xu and colleagues reported that the interindividual variability was 41.7% on CL/F, 48.9% on V/F, and 86.3% on Ka. Dr. Xu said that body weight, concomitant use of methotrexate, antibody response to golimumab, and baseline CRP level were significant covariates on CL/F, whereas body weight was not a significant covariate on V/F. The analysis indicated that methotrexate-naïve patients with active RA had a slightly higher CL/F compared with those previously treated with methotrexate. The difference in CL/F did not reach statistical significance, Dr. Xu noted. Funding for this study was provided by Centocor, Inc.
[Presentation title: Population Pharmacokinetics of Golimumab, a Human Anti-Tumor Necrosis Factor-Alpha Monoclonal Antibody, in Patients With Rheumatoid Arthritis. Abstract 61]
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