Population Pharmacokinetic Analysis of Tocilizumab in Patients With Rheumatoid Arthritis

Frey, Nicolas; Grange, Susan; Woodworth, Thasia

doi:10.1177/0091270009350623

Cited by 101 publications

(113 citation statements)

References 34 publications

Supporting

Mentioning

100

Contrasting

Order By: Relevance

“…3.2.2 [28]. More specifically, two-compartment models were used to describe the pharmacokinetics of infliximab [29], rituximab [30], adalimumab [31,32], golimumab [33], and tocilizumab in RA [34,35]. The pharmacokinetics of most mAbs administered by the subcutaneous (SC) route was described using one-compartment models [16], as done for adalimumab in RA [36].…”

Section: Pharmacokinetics Of Mabs Used In Ramentioning

confidence: 99%

Clinical Pharmacokinetics and Pharmacodynamics of Monoclonal Antibodies Approved to Treat Rheumatoid Arthritis

et al. 2015

View full text Add to dashboard Cite

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.

show abstract

Section: Pharmacokinetics Of Mabs Used In Ramentioning

confidence: 99%

Clinical Pharmacokinetics and Pharmacodynamics of Monoclonal Antibodies Approved to Treat Rheumatoid Arthritis

et al. 2015

View full text Add to dashboard Cite

show abstract

“…However, patients treated with TCZ should be monitored for malignancies to provide data that can be used for to assess risk over the longer term. The data for the pharmacokinetics (PK) of TCZ-IV and TCZ-SC are based on population PK analyses of 1793 and 1759 patients with RA, respectively [72][73][74]. In addition, population PK analyses of 75 patients with sJIA and 188 patients with pJIA have been conducted to determine the PK of TCZ-IV in these patients (F. Hoffmann-La Roche Ltd., data on file).…”

mentioning

confidence: 99%

“…In addition, population PK analyses of 75 patients with sJIA and 188 patients with pJIA have been conducted to determine the PK of TCZ-IV in these patients (F. Hoffmann-La Roche Ltd., data on file). We have summarized the PK profiles in Table 1 [37,72,73]. PK exposure parameters for TCZ were found to be similar between healthy individuals and patients with RA, indicating that even the presence of active disease does not impact the PK profile of TCZ [74].…”

mentioning

confidence: 99%

A Review of Recent Advances Using Tocilizumab in the Treatment of Rheumatic Diseases

et al. 2018

View full text Add to dashboard Cite

Tocilizumab (TCZ) is the first humanized antiinterleukin-6 (IL-6) receptor monoclonal antibody approved for the treatment of patients with rheumatoid arthritis (RA), Castleman's disease, polyarticular and systemic juvenile idiopathic arthritis, and, most recently, giant cell arteritis as well as for the treatment of chimeric antigen receptor T cell therapy-induced cytokine release syndrome. The global clinical development program for TCZ provides a wealth of clinical data on intravenous TCZ, and more recent studies in patients with RA have provided evidence characterizing the role of intravenous TCZ as monotherapy in early disease and led to the introduction of a subcutaneous formulation of TCZ. In addition, recently published open-label extension and observational studies continue to support the longterm efficacy and safety of TCZ in both clinical trial and real-world settings. Given the involvement of IL-6-mediated signaling in inflammatory disorders, TCZ is also being investigated in other immunological diseases. In particular, a phase 2 trial on the safety and efficacy of subcutaneous TCZ in adults with systemic sclerosis shows clinically relevant improvements in skin sclerosis and lung function in these patients. Another anti-IL-6 receptor agent, sarilumab, targeting the IL6 receptor alpha subunit, was recently approved for the treatment of patients with RA, although longterm data for this biologic are not yet published. In this article we review the placement of TCZ in current treatment guidelines; recent clinical trial data, including quality of life in patients with RA; recent updates to the TCZ safety profile; recent investigations of TCZ in other immunological diseases; and the clinical development of other novel IL-6-targeted agents. Keywords: Interleukin-6; Rheumatoid arthritis; Tocilizumab TOCILIZUMAB: THE FIRST INTERLEUKIN-6 RECEPTOR-NEUTRALIZING BIOLOGICInterleukin-6 (IL-6) is a multifunctional cytokine that plays an important role in both acute and chronic inflammatory responses. Consequently, the dysregulated or persistent production of IL-6 can lead to the development of inflammatory disorders [1]. Elevated levels of IL-6 in serum, synovial fluid, and various tissues have been correlated with disease activity in patients with rheumatoid arthritis (RA) [2], juvenile idiopathic arthritis (JIA) [3,4], Castleman's disease [5,6], systemic sclerosis (SSc) [7], giant cell arteritis (GCA) [8,9], adult-onset Still's disease (AOSD) [10], familial Mediterranean fever (FMF) [11,12], Schnitzler's syndrome [13,14], polychondritis [15], and amyloidosis [1]. These associations suggest a pathogenetic role for IL-6 in multiple inflammatory conditions and form the basis of the rationale for the development of anti-IL-6 therapies.Tocilizumab (TCZ) is the first humanized monoclonal antibody targeting the IL-6 receptor subunit alpha (IL-6Ra) [16], and its mechanism of action has been described in detail in previous reviews [17,18]. Briefly, TCZ targets both membrane-bound and soluble IL-6Ra, which prevents t...

show abstract

“…The dosedependent or concentration-dependent clearance observed in this study was also observed in interferon-1a [31], other several therapeutic monoclonal antibodies [29] such as tocilizumab [46], PF-04840082 (Dickkopt-1 antibody) [47], panitumumab, cetuximab [32], and concizumab [48], a bivalent humanized nanobody [49], and in the study of the dynamics of TMDD [40]. At very high doses of both protein drugs, the clearance reached the lowest plateau phase, which might be due to the saturation of the targets that are responsible for protein degradation.…”

Section: Discussionsupporting

confidence: 75%

“…At very high doses of both protein drugs, the clearance reached the lowest plateau phase, which might be due to the saturation of the targets that are responsible for protein degradation. At this plateau phase after high dosing, the linear clearance pathway becomes predominant [29,31,32,34,40,46,48].…”

Section: Discussionmentioning

confidence: 99%

Challenges in the Pharmacokinetics of Therapeutic Proteins

Limothai¹

View full text Add to dashboard Cite

Population Pharmacokinetic Analysis of Tocilizumab in Patients With Rheumatoid Arthritis

Cited by 101 publications

References 34 publications

Clinical Pharmacokinetics and Pharmacodynamics of Monoclonal Antibodies Approved to Treat Rheumatoid Arthritis

Clinical Pharmacokinetics and Pharmacodynamics of Monoclonal Antibodies Approved to Treat Rheumatoid Arthritis

A Review of Recent Advances Using Tocilizumab in the Treatment of Rheumatic Diseases

Challenges in the Pharmacokinetics of Therapeutic Proteins

Contact Info

Product

Resources

About