Clinical Pharmacokinetics and Pharmacodynamics of Monoclonal Antibodies Approved to Treat Rheumatoid Arthritis
- 28 June 2015
- journal article
- review article
- Published by Springer Science and Business Media LLC in Clinical Pharmacokinetics
- Vol. 54 (11), 1107-1123
- https://doi.org/10.1007/s40262-015-0296-9
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.Keywords
This publication has 121 references indexed in Scilit:
- Basic Concepts in Population Modeling, Simulation, and Model‐Based Drug Development: Part 3—Introduction to Pharmacodynamic Modeling MethodsCPT: Pharmacometrics & Systems Pharmacology, 2014
- Placental Transfer of Anti–Tumor Necrosis Factor Agents in Pregnant Patients With Inflammatory Bowel DiseaseClinical Gastroenterology and Hepatology, 2013
- Concordance of preclinical and clinical pharmacology and toxicology of monoclonal antibodies and fusion proteins: soluble targetsBritish Journal of Pharmacology, 2012
- Lifespan based indirect response modelsJournal of Pharmacokinetics and Pharmacodynamics, 2012
- Influence of methotrexate on infliximab pharmacokinetics and pharmacodynamics in ankylosing spondylitisBritish Journal of Clinical Pharmacology, 2011
- Interpreting population pharmacokinetic‐pharmacodynamic analyses – a clinical viewpointBritish Journal of Clinical Pharmacology, 2011
- Population pharmacokinetic analysis of infliximab in patients with ulcerative colitisEuropean Journal of Clinical Pharmacology, 2009
- A mechanism‐based binding model for the population pharmacokinetics and pharmacodynamics of omalizumabBritish Journal of Clinical Pharmacology, 2007
- Anti-TNF Antibody Therapy in Rheumatoid Arthritis and the Risk of Serious Infections and MalignanciesJAMA, 2006
- Development and validation of the european league against rheumatism response criteria for rheumatoid arthritis: Comparison with the preliminary american college of rheumatology and the world health organization/international league against rheumatism criteriaArthritis & Rheumatism, 1996