Population Pharmacokinetics of Rituximab (Anti‐CD20 Monoclonal Antibody) in Rheumatoid Arthritis Patients During a Phase II Clinical Trial

Ng, Chee M.; Bruno, René; Combs, Dan; Davies, Brian E.

doi:10.1177/0091270005277075

Cited by 184 publications

(164 citation statements)

References 17 publications

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“…39 Increase in V may therefore be explained by retention of the monoclonal antibody by cellular TNF. A similar phenomenon was reported for another monoclonal antibody, rituximab (an anti-CD20 monoclonal antibody): its volume at steady-state (Vss) was 6.6 L, 5.6 L and 13.5 L, in RA, 40 follicular non-Hodgkin lymphomas 41 and diffuse large-cell lymphomas, 42 respectively. In all, the similar elimination half-life of infliximab observed in IBD and in AS (Table 3) may result from opposite effects of TNF, the higher CL estimated in IBD being compensated by a higher V as compared with AS.…”

Section: Discussionsupporting

confidence: 75%

The underlying inflammatory chronic disease influences infliximab pharmacokinetics

Passot

Mulleman

Bejan-Angoulvant

et al. 2016

mAbs

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Infliximab is an anti-tumor necrosis factor monoclonal antibody approved in chronic inflammatory diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn's disease (CD) and ulcerative colitis (UC). Infliximab pharmacokinetics is variable between patients, but influence of the underlying disease was never assessed. This study aimed at assessing this influence using a cohort of patients monitored in a single center and with the same assay. Infliximab trough concentrations were determined on samples collected between weeks 0 and 22 after treatment initiation in 218 patients treated for RA, PsA, AS, CD or UC. Infliximab pharmacokinetics was analyzed by a onecompartment population model with first-order elimination rate constant. In AS patients, volume of distribution (V) and elimination clearance (CL) were 5.4 L and 0.24 L/day, respectively. In CD and UC patients, V was 49% and 52% higher than in AS, respectively, and CL was 47% and 60% higher than in AS, respectively. In RA patients, CL was 49% higher than in AS patients. Simulations showed that without methotrexate, a 3 mg/kg dosing regimen would lead only 16% of RA patients to reach the target concentration (2.5 mg/L) at week 22, whereas target concentrations would be reached in approximately half of RA patients cotreated with methotrexate, as well as half of CD (3.5 mg/L) and UC (3.7 mg/L) patients. The suboptimality of approved dosing regimens supports the development of dosing optimization based on concentration measurements.

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Section: Discussionsupporting

confidence: 75%

The underlying inflammatory chronic disease influences infliximab pharmacokinetics

Passot

Mulleman

Bejan-Angoulvant

et al. 2016

mAbs

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“…It has also been investigated in addition to the linear elimination for rituximab, but the model did not perform significantly better than the simple linear model. However, goodness-of-fit plots suggest a misspecification for high concentrations (Ng et al, 2005).…”

Section: Discussionmentioning

confidence: 95%

Population pharmacokinetic data analysis of three phase I studies of matuzumab, a humanised anti-EGFR monoclonal antibody in clinical cancer development

et al. 2008

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A population pharmacokinetic model based on data from three phase I studies was to be developed including a covariate analysis to describe the concentration -time profiles of matuzumab, a novel humanised monoclonal antibody. Matuzumab was administered as multiple 1 h i.v. infusions with 11 different dosing regimens ranging from 400 to 2000 mg, q1w -q3w. For analysis, 90 patients with 1256 serum concentration -time data were simultaneously fitted using the software NONMEMt. Data were best described using a two-compartment model with the parameters central (V 1 ) and peripheral distribution volume (V 2 ), intercompartmental (Q) and linear (CLL) clearance and an additional nonlinear elimination pathway (K m , V max ). Structural parameters were in agreement with immunoglobulin characteristics. In total, interindividual variability on V max , CLL, V 1 and V 2 and interoccasion variability on CLL was 22 -62% CV. A covariate analysis identified weight having an influence on V 1 ( þ 0.44% per kg) and CLL ( þ 0.87% per kg). All parameters were estimated with good precision (RSEo39%). A robust population pharmacokinetic model for matuzumab was developed, including a nonlinear pharmacokinetic process. In addition, relevant and plausible covariates were identified and incorporated into the model. When correlated to efficacy, this model could serve as a tool to guide dose selection for this 'targeted' cancer therapy.

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“…Pharmacokinetic modeling in RA suggested that a body surface area-calculated dose would not improve the predictability of drug exposure (32), and clinical trials in RA have found that 2 infusions of 1 gm given 2 weeks apart is both effective (5,6) and safe with repeated use (33). The more extensive organ involvement that usually occurs in vasculitis as compared with RA raises the question of whether 2 infusions of 1 gm given 2 weeks apart would allow sufficient tissue penetration for B cell depletion from lesional tissue, perhaps allowing sustained remissions.…”

Section: Discussionmentioning

confidence: 99%

A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody–associated vasculitis

Jones¹,

Ferraro²,

Chaudhry³

et al. 2009

Arthritis & Rheumatism

323

214

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Objective. B cell depletion with rituximab has allowed remissions in relapsing or refractory antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in small studies. The aim of this study was to determine the efficacy and safety of rituximab for ANCA-associated vasculitis in a larger multicenter cohort. This permitted comparison of rituximab dosing regimens, the value of continuing immunosuppression, and investigation of ANCA and B cell levels as retreatment biomarkers.Methods. Retrospective, standardized data collection from 65 sequential patients receiving rituximab for refractory ANCA-associated vasculitis at 4 centers in the UK was used.Results. All patients achieved B cell depletion. Complete remission occurred in 49 of the 65 patients (75%), partial remission in 15 (23%), and no response in 1 (2%). The prednisolone dosage was reduced from 12.5 mg/day (median) to 9.0 mg/day at 6 months (P ‫؍‬ 0.0006). Immunosuppressive therapy was withdrawn in 37 of 60 patients (62%). Twenty-eight of 49 patients who achieved full remission (57%) experienced relapse (median 11.5 months). B cell return preceded relapse in 14 of 27 patients (52%). Although ANCA levels fell after rituximab therapy, relapse was not associated with ANCA positivity or a rise in ANCA levels. Neither the initial rituximab regimen (4 infusions of 375 mg/m 2 each given 1 week apart or 2 infusions of 1 gm each given 2 weeks apart) nor withdrawal of immunosuppressive therapy (37 of 60 patients [62%]) influenced the timing of relapse. Thirty-eight patients received >2 courses of rituximab, and complete remission was induced or maintained in 32 of them (84%). IgM levels fell, although IgG levels remained stable. Forty-six serious adverse events occurred, including 2 episodes of lateonset neutropenia, which were attributed to rituximab.Conclusion. Rituximab was effective remission induction therapy for refractory ANCA-associated vasculitis in this study. There was no difference in efficacy between the 2 main treatment regimens. Continuing immunosuppression did not reduce relapses. Relapses occurred, but re-treatment was effective and safe. There was no clear influence of rituximab on the frequency of serious adverse events. ANCA and B cell levels lacked sufficient sensitivity to guide the timing of re-treatment.

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Population Pharmacokinetics of Rituximab (Anti‐CD20 Monoclonal Antibody) in Rheumatoid Arthritis Patients During a Phase II Clinical Trial

Cited by 184 publications

References 17 publications

The underlying inflammatory chronic disease influences infliximab pharmacokinetics

The underlying inflammatory chronic disease influences infliximab pharmacokinetics

Population pharmacokinetic data analysis of three phase I studies of matuzumab, a humanised anti-EGFR monoclonal antibody in clinical cancer development

A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody–associated vasculitis

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