title: Clinical Pharmacokinetics and Pharmacodynamics of Monoclonal Antibodies Approved to Treat Rheumatoid Arthritis.
abstract: Monoclonal antibodies (mAbs) are increasingly used to treat rheumatoid arthritis (RA). At present, anti-tumor necrosis factor-α drugs (infliximab, adalimumab, certolizumab pegol, and golimumab), rituximab, and tocilizumab are approved for RA treatment. This review focuses on the pharmacokinetics and pharmacodynamics of mAbs approved in RA. Being large proteins, mAbs exhibit complex pharmacokinetic and pharmacodynamic properties. In particular, owing to the interactions of mAbs with their antigenic targets, the pharmacokinetics of mAbs depends on target turnover and exhibits non-specific (linear) and target-mediated (often nonlinear) clearances. Their volume of distribution is low (3-4 L) and their elimination half-life usually ranges from 2 to 3 weeks. The inter-individual pharmacokinetic variability of mAbs is usually large and is partly explained by differences in antigenic burden or by anti-drug antibodies, which accelerate mAb elimination. The inter-individual variability of clinical response is large and influenced by the pharmacokinetics. The analysis of mAbs concentration-effect relationship relies more and more often on pharmacokinetic-pharmacodynamic modeling; these models being suitable for dosing optimization. Even if adverse effects of mAbs used in RA are well known, the relationship between mAb concentration and adverse effects is poorly documented, especially for anti-tumor necrosis factor-α mAbs. Overall, RA patients treated with mAbs should benefit from individualized dosing strategies. Because of the complexity of their pharmacokinetics and mechanisms of action, the current dosing strategy of mAbs is not based on sound knowledge. New studies are needed to assess individual dosing regimen, adjusted notably to disease activity.
authors.affiliation: Laboratory of Pharmacology-Toxicology, Université François-Rabelais de Tours, CNRS, GICC UMR 7292, CHRU de Tours, 2 Boulevard Tonnellé, 37044, Tours Cedex, France. david.ternant@univ-tours.fr.
authors.forename: David
authors.initials: D
authors.lastname: Ternant
authors.affiliation: Department of Pharmacovigilance, Université François-Rabelais de Tours, CNRS, GICC UMR 7292, CHRU de Tours, Tours, France.
authors.forename: Theodora
authors.initials: T
authors.lastname: Bejan-Angoulvant
authors.affiliation: Laboratory of Pharmacology-Toxicology, Université François-Rabelais de Tours, CNRS, GICC UMR 7292, CHRU de Tours, 2 Boulevard Tonnellé, 37044, Tours Cedex, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Passot
authors.affiliation: Department of Rheumatology, Université François-Rabelais de Tours, CNRS, GICC UMR 7292, CHRU de Tours, Tours, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Mulleman
authors.affiliation: Laboratory of Pharmacology-Toxicology, Université François-Rabelais de Tours, CNRS, GICC UMR 7292, CHRU de Tours, 2 Boulevard Tonnellé, 37044, Tours Cedex, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Paintaud
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D017277:Drug Approval; D006207:Half-Life; D006801:Humans; D012213:Rheumatic Fever / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents