title: New strategies to address the pharmacodynamics and pharmacokinetics of tumor necrosis factor (TNF) inhibitors: A systematic analysis.
abstract: OBJECTIVE
  To assess the putative link between antibody formation to adalimumab, infliximab and etanercept, circulating drug levels and clinical outcomes.
  
  
  METHODS
  A literature search was conducted using Pubmed from inception to 5th March 2013 of original research articles relating to adalimumab, etanercept and infliximab that investigated the immunogenicity of each drug. Data were extracted to document the disease, anti-TNF-α agent, regimen, study design, use of concomitant immunosuppressive therapy, the relationship between drug administration and antibody assessment, the type of immunoassay and cut-off, plasma drug concentration, frequency of antibody and clinical assessments, antibody positivity rate and relationship between antibody positivity and clinical outcome. Studies were stratified by drug, disease area and whether or not concomitant immunosuppressive therapy had been given. All data were tabulated by publication and analyzed descriptively.
  
  
  RESULTS
  A total of 57 original research articles were included in the analysis (infliximab n=34; adalimumab n=18; etanercept n=5). There was considerable heterogeneity in study design, methodology for anti-drug antibody detection and drug bioavailability evaluation. Consequently, it was difficult to compare the immunogenic potential of infliximab, adalimumab and etanercept, particularly because different assays with variable sensitivity and specificity were used. The timing of occurrence and the persistence of anti-drug antibodies appeared to be influenced by administration schedules and concomitant immunosuppressive therapy. Monitoring of circulating drug levels and anti-drug antibodies appears to be an emerging and cost-effective strategy for the management of the individual patient.
  
  
  CONCLUSIONS
  Monitoring drug and anti-drug antibody levels appears to be a putative strategy for optimal and cost-effective intervention. However studies of consistent and homogeneous design, methodology and duration are warranted to assess the true incidence and consequences of immunogenicity.
authors.affiliation: Division of Rheumatology, University of Milan, Istituto Auxologico Italiano, Milan, Italy. Electronic address: pierluigi.meroni@unimi.it.
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Meroni
authors.affiliation: Rheumatology Section, Dipartimento di Internistica Clinica e Sperimentale Second University of Naples, Naples, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Valentini
authors.affiliation: Section of Dermatology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Ayala
authors.affiliation: Bio@SNS Laboratory, Scuola Normale Superiore, Pisa, Italy; European Brain Research Institute, Roma, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Cattaneo
authors.affiliation: Rheumatology Unit, Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Valesini
mesh_terms: D000068879:Adalimumab; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000068800:Etanercept; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology*; D000069285:Infliximab; D018124:Receptors, Tumor Necrosis Factor; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept
keywords: Adalimumab; Anti-drug detection; Drug bioavailability; Etanercept; Infliximab; Systematic review; TNFα inhibitors