Rheumatoid Arthritis: Pendley C

Visvanathan S, Marini JC, Smolen JS, Clair EW, Pritchard C, Shergy W, Pendley C, Baker D, Bala M, Gathany T, Han J, Wagner C. · Centocor, Inc., Malvern, Pennsylvania, USA. · J Rheumatol. · Pubmed #17552048 No free full text.

Abstract: OBJECTIVE: To determine if changes in biomarkers of inflammation and bone turnover in response to treatment with infliximab plus methotrexate (MTX) versus MTX alone are associated with improvement in clinical measures of signs, symptoms, and structural damage in early rheumatoid arthritis. METHODS: Sera were collected from patients in the ASPIRE study who received 3 mg/kg (n = 48) or 6 mg/kg infliximab plus MTX (n = 55), or MTX alone (n = 41). Several baseline biomarker levels correlated with changes in median percentage of American College of Rheumatology improvement (ACR-N), 50% improvement in ACR response (ACR50), and van der Heijde-modified Sharp score (vdHSS) at Week 54. RESULTS: Infliximab plus MTX treatment resulted in more rapid decreases in levels of matrix metalloproteinase-3 (MMP-3), intercellular cell adhesion molecule-1, interleukin 8 (IL-8), and tumor necrosis factor-a than treatment with MTX alone. Baseline levels and decreases from baseline to Weeks 6 and 54 in MMP-3 correlated with improvement in ACR-N response at Week 54. An increase in IL-8 levels from baseline to Week 54 correlated with worsening in vdHSS at Week 54 in the MTX-alone group. Regression analysis of markers at baseline showed that MMP-3 was the only variable associated with ACR50 response and less worsening in vdHSS at Week 54. CONCLUSION: Treatment with infliximab plus MTX resulted in a rapid decrease in inflammation markers. MMP-3 levels at different timepoints were consistently associated with clinical improvements at Week 54 in the infliximab plus MTX group, while increases in IL-8 levels correlated with a worsening in vdHSS at Week 54 in the MTX-alone group.

Zhou H, Jang H, Fleischmann RM, Bouman-Thio E, Xu Z, Marini JC, Pendley C, Jiao Q, Shankar G, Marciniak SJ, Cohen SB, Rahman MU, Baker D, Mascelli MA, Davis HM, Everitt DE. · Clinical Pharmacology & Experimental Medicine, Centocor Research & Development, 200 Great Valley Parkway, Malvern, PA 19355, USA. · J Clin Pharmacol. · Pubmed #17322150 No free full text.

Abstract: Golimumab is a fully human antitumor necrosis factor alpha (TNF-alpha) monoclonal antibody that is being developed for intravenous and subcutaneous administration. To assess the pharmacokinetics and safety of the intravenous formulation of golimumab, 36 adult subjects with rheumatoid arthritis were randomly assigned to receive a single infusion of placebo or golimumab (0.1, 0.3, 1, 3, 6, or 10 mg/kg). Serum concentrations of golimumab were determined using a validated enzyme-linked immunosorbent assay method. In addition to the noncompartmental analysis and compartmental modeling, a population pharmacokinetics analysis using NONMEM was also conducted. Both the maximum serum concentration and the area under the serum concentrationtime curve appeared to increase in a dose-proportional manner. The median half-life ranged from 7 to 20 days. A 2-compartment population pharmacokinetic model adequately described the pharmacokinetics of golimumab. The following pharmacokinetic parameters (typical value [% coefficient of variation]) were estimated from the population pharmacokinetic model: clearance (CL: 0.40 [10.1%] L/d), volume of distribution in the central compartment (V(c): 3.07 [6.4%] L), intercompartmental clearance (Q: 0.42 [15.5%] L/d), and volume of distribution in the peripheral compartment (V(p): 3.68 [11.8%] L). Interindividual variability of the pharmacokinetic parameters was quantified for CL (44.3%), V(c) (25.5%), Q (44.6%), and V(p) (44.6%). Residual variability was estimated to be 15.0%. Body weight was found to be an important covariate on V(c). Golimumab was generally well tolerated. The pharmacokinetics of golimumab appeared to be linear over the dose range evaluated in this study.

Horninger D, Eirikis E, Pendley C, Giles-Komar J, Davis HM, Miller BE. · Department of Clinical Pharmacology and Experimental Medicine, Centocor, Inc., 145 King of Prussia Road, Radnor, PA 19087, USA. · J Pharm Biomed Anal. · Pubmed #15967298 No free full text.

Abstract: A quantitative, one-step, competitive electrochemiluminescence (ECL)-based immunoassay for the determination of a fully human, anti-TNFalpha monoclonal antibody in human serum has been developed. A biotinylated, mouse anti-variable region-specific antibody and a ruthenium-labeled anti-TNFalpha antibody were the only specific reagents needed to develop the assay. A single incubation step of 2 h followed by ECL detection was used. The assay was capable of measuring the analyte in neat serum over approximately a 1600-fold range with higher concentrations measured following a single dilution. Assay accuracy, precision, and reproducibility were suitable to support pharmacokinetic studies of the analyte. This competitive assay format offers an alternative approach to the development of immunoassays for the measurement of macromolecules in complex matrices to support preclinical and clinical studies.