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.

Population pharmacokinetics of Reditux™, a biosimilar Rituximab, in diffuse large B-cell lymphoma

“…Since then, it has been the mainstay in treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia and rheumatoid arthritis [10]. Although in India the drug was well received [11], its relatively higher cost was a major constraint for widespread use in India where majority of patients are not covered by insurance leading to catastrophic out of pocket expenses.…”

Influence of Antigen Mass on the Pharmacokinetics of Therapeutic Antibodies in Humans

“…[125][126][127][128] This may be due to an excess of anti-TNF mAbs compared to TNF-α concentrations. [4] Out of the 85 pharmacokinetic publications that reported an influence of antigen mass, 35 used linear pharmacokinetic models (table 1); an increased mAb clearance with higher antigen mass levels may be due to a higher antigen turnover (i.e. higher ksyn and/or lower kdeg values).…”

“…Notably, FcRn expression was suggested to be increased with inflammation, which would lead to an decrease in mAb intrinsic clearance. [4] Elimination half-life (T½R) estimates of bevacizumab was 21 days in teleangiectasia [147] , 17-20 days in various solid tumours [148,149] , 15-17 days in child sarcoma [144,150] , and 19 days in colorectal cancer (CRC) and, surprisingly, 44 days in multi-metastatic CRC. [130] For trastuzumab, T½R was 28 days in metastatic breast cancer (BC), but highly controversial in early BC, 12 days [94] or 40 days.…”

“…[1][2][3][4][5] The pharmacokinetics of mAbs is usually described using 2-compartment models with first-order transfer rates. [6] Central and steady-state volumes of distribution of mAbs are usually 3-5 L and 5-15 L [1,2,4] , respectively, values which suggest that mAbs are confined to lymphatic and blood vessels, and exhibit low (but not inexistent) tissue penetration. The elimination of IgG involves two different pathways.…”

The underlying inflammatory chronic disease influences infliximab pharmacokinetics

“…Infliximab elimination half-life was reported to be »14 d on average, 16 but with lower values in RA patients without methotrexate (9 days), than in RA patients cotreated with methotrexate (13 days), 4 AS 5,6 and in IBD 9,11,13 patients (»14 d for both conditions) ( Table 1). The increase in infliximab clearance (CL) with pre-infusion CRP 4,11 suggests an influence of target-antigen burden on infliximab pharmacokinetics, the elimination increasing with the target-antigen quantity.…”