for the ATTACH Investigators* Background-Preclinical and preliminary clinical data have suggested that tumor necrosis factor-␣ (TNF␣) may play a role in the evolution and progression of heart failure and that inhibition of TNF␣ may favorably modify the course of the disease. We evaluated the efficacy and safety of infliximab, a chimeric monoclonal antibody to TNF␣, in patients with moderate-to-severe heart failure. Methods and Results-One hundred fifty patients with stable New York Heart Association class III or IV heart failure and left ventricular ejection fraction Յ35% were randomly assigned to receive placebo (nϭ49), infliximab 5 mg/kg (nϭ50), or infliximab 10 mg/kg (nϭ51) at 0, 2, and 6 weeks after randomization and were followed-up prospectively for 28 weeks. Neither dose of infliximab improved clinical status at 14 weeks, the primary endpoint of the study, despite suppression of inflammatory markers (C-reactive protein and interleukin-6) and a modest increase in ejection fraction in the patients receiving 5 mg/kg (Pϭ0.013). Furthermore, after 28 weeks, 13, 10, and 20 patients were hospitalized for any reason in the placebo, 5 mg/kg infliximab, and 10 mg/kg infliximab groups, respectively. The combined risk of death from any cause or hospitalization for heart failure through 28 weeks was increased in the patients randomized to 10 mg/kg infliximab (hazard ratio 2.84, 95% confidence interval 1.01 to 7.97; nominal Pϭ0.043). Conclusions-Short-term TNF␣ antagonism with infliximab did not improve and high doses (10 mg/kg) adversely affected the clinical condition of patients with moderate-to-severe chronic heart failure. (Circulation. 2003;107:3133-3140.)

SummaryBackgroundVedolizumab, an anti‐α4β7 integrin monoclonal antibody (mAb), is indicated for treating patients with moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD). As higher therapeutic mAb concentrations have been associated with greater efficacy in inflammatory bowel disease, understanding determinants of vedolizumab clearance may help to optimise dosing.AimsTo characterise vedolizumab pharmacokinetics in patients with UC and CD, to identify clinically relevant determinants of vedolizumab clearance, and to describe the pharmacokinetic–pharmacodynamic relationship using population modelling.MethodsData from a phase 1 healthy volunteer study, a phase 2 UC study, and 3 phase 3 UC/CD studies were included. Population pharmacokinetic analysis for repeated measures was conducted using nonlinear mixed effects modelling. Results from the base model, developed using extensive phase 1 and 2 data, were used to develop the full covariate model, which was fit to sparse phase 3 data.ResultsVedolizumab pharmacokinetics was described by a 2‐compartment model with parallel linear and nonlinear elimination. Using reference covariate values, linear elimination half‐life of vedolizumab was 25.5 days; linear clearance (CLL) was 0.159 L/day for UC and 0.155 L/day for CD; central compartment volume of distribution (V c) was 3.19 L; and peripheral compartment volume of distribution was 1.66 L. Interindividual variabilities (%CV) were 35% for CLL and 19% for V c; residual variance was 24%. Only extreme albumin and body weight values were identified as potential clinically important predictors of CLL.ConclusionsPopulation pharmacokinetic parameters were similar in patients with moderately to severely active UC and CD. This analysis supports use of vedolizumab fixed dosing in these patients. Clinicaltrials.gov Identifiers: NCT01177228; NCT00783718 (GEMINI 1); NCT00783692 (GEMINI 2); NCT01224171 (GEMINI 3).

Objective. To evaluate the safety and efficacy of infliximab in the treatment of juvenile rheumatoid arthritis (JRA).Methods. This was an international, multicenter, randomized, placebo-controlled, double-blind study. One hundred twenty-two children with persistent polyarticular JRA despite prior methotrexate (MTX) therapy were randomized to receive infliximab or placebo ClinicalTrials.gov identifier: NCT00036374.

Purpose Infliximab, a monoclonal antibody, is approved for the treatment of inflammatory diseases at doses that depend on the patient disease population. It was the aim of this study to evaluate its population pharmacokinetics in patients with moderately to severely active ulcerative colitis and characterize patient covariates that affect its disposition in this population. Methods Information collected from 482 patients in two randomized, double-blind, placebo-controlled international studies were analyzed using NONMEM. Results A two-compartment, population pharmacokinetic model described the serum infliximab concentration-time data. Population pharmacokinetic estimates (typical value ± standard error), based on the final covariate model, were clearance (CL: 0.407±0.0103 L/day), apparent volumes of distribution in the central (V 1 : 3.29 ± 0.0679 L) and peripheral (V 2 : 4.13±0.16 L) compartments, and intercompartment clearance (Q: 7.14±0.489 L/day). Infliximab exhibited interindividual variability for CL and V 1 of 37.7% and 22.1%, respectively. Infliximab t 1/2 was approximately 14 days. Covariate analysis showed that V 1 increased as body weight increased, and CL was higher in patients who developed antibodies to infliximab. An additional novel covariate, serum albumin concentration, was found to be inversely and strongly related to infliximab clearance in this population. Conclusions The disposition of infliximab in patients with moderately to severely active ulcerative colitis, unlike in rheumatoid arthritis, was not affected by coadministration of immunomodulators and corticosteroids but was related to formation of antibodies to infliximab and, notably, to serum albumin levels.

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