Pharmacokinetics of rituximab and clinical outcomes in patients with anti-neutrophil cytoplasmic antibody associated vasculitis

Divi Cornec, Brian F. Kabat, John R. Mills, Melissa Cheu, Amber M. Hummel, Darrell R. Schroeder, Matthew D. Cascino, Paul Brunetta, David L. Murray, Melissa R. Snyder, Fernando Custodio Fervenza, Gary S. Hoffman, Cees G.M. Kallenberg, Carol A. Langford, Peter A. Merkel, Paul A. Monach, Philip Seo, Robert F. Spiera, E. William St Clair, John H. StoneDavid R. Barnidge, Ulrich Specks

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Objectives. To study the determinants of the pharmacokinetics (PK) of rituximab (RTX) in patients with ANCA-associated vasculitis (AAV) and its association with clinical outcomes. Methods. This study included data from 89 patients from the RTX in AAV trial who received the full dose of RTX (four weekly infusions of 375 mg/m2). RTX was quantified at weeks 2, 4, 8, 16 and 24, and summarized by computing the trapezoidal area under the curve. We explored potential determinants of the PK-RTX, and analysed its association with clinical outcomes: achievement of remission at 6 months, duration of B-cell depletion and time to relapse in patients who achieved complete remission. Results. RTX serum levels were significantly lower in males and in newly diagnosed patients, and negatively correlated with body surface area, baseline B-cell count and degree of disease activity. In multivariate analyses, the main determinants of PK-RTX were sex and new diagnosis. Patients reaching complete remission at month 6 had similar RTX levels compared with patients who did not reach complete remission. Patients with higher RTX levels generally experienced longer B-cell depletion than patients with lower levels, but RTX levels at the different time points and area under the curve were not associated with time to relapse. Conclusion. Despite the body-surface-area-based dosing protocol, PK-RTX is highly variable among patients with AAV, its main determinants being sex and newly diagnosed disease. We did not observe any relevant association between PK-RTX and clinical outcomes. The monitoring of serum RTX levels does not seem clinically useful in AAV.

Original languageEnglish (US)
Pages (from-to)639-650
Number of pages12
JournalRheumatology (United Kingdom)
Volume57
Issue number4
DOIs
StatePublished - Apr 1 2018

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Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Pharmacokinetics
B-Lymphocytes
Body Surface Area
Rituximab
Area Under Curve
Recurrence
Serum

Keywords

  • ANCA-associated vasculitis
  • Outcomes
  • Pharmacokinetics
  • Rituximab

ASJC Scopus subject areas

  • Rheumatology
  • Pharmacology (medical)

Cite this

Pharmacokinetics of rituximab and clinical outcomes in patients with anti-neutrophil cytoplasmic antibody associated vasculitis. / Cornec, Divi; Kabat, Brian F.; Mills, John R.; Cheu, Melissa; Hummel, Amber M.; Schroeder, Darrell R.; Cascino, Matthew D.; Brunetta, Paul; Murray, David L.; Snyder, Melissa R.; Fervenza, Fernando Custodio; Hoffman, Gary S.; Kallenberg, Cees G.M.; Langford, Carol A.; Merkel, Peter A.; Monach, Paul A.; Seo, Philip; Spiera, Robert F.; William St Clair, E.; Stone, John H.; Barnidge, David R.; Specks, Ulrich.

In: Rheumatology (United Kingdom), Vol. 57, No. 4, 01.04.2018, p. 639-650.

Research output: Contribution to journalArticle

Cornec, D, Kabat, BF, Mills, JR, Cheu, M, Hummel, AM, Schroeder, DR, Cascino, MD, Brunetta, P, Murray, DL, Snyder, MR, Fervenza, FC, Hoffman, GS, Kallenberg, CGM, Langford, CA, Merkel, PA, Monach, PA, Seo, P, Spiera, RF, William St Clair, E, Stone, JH, Barnidge, DR & Specks, U 2018, 'Pharmacokinetics of rituximab and clinical outcomes in patients with anti-neutrophil cytoplasmic antibody associated vasculitis', Rheumatology (United Kingdom), vol. 57, no. 4, pp. 639-650. https://doi.org/10.1093/rheumatology/kex484
Cornec, Divi ; Kabat, Brian F. ; Mills, John R. ; Cheu, Melissa ; Hummel, Amber M. ; Schroeder, Darrell R. ; Cascino, Matthew D. ; Brunetta, Paul ; Murray, David L. ; Snyder, Melissa R. ; Fervenza, Fernando Custodio ; Hoffman, Gary S. ; Kallenberg, Cees G.M. ; Langford, Carol A. ; Merkel, Peter A. ; Monach, Paul A. ; Seo, Philip ; Spiera, Robert F. ; William St Clair, E. ; Stone, John H. ; Barnidge, David R. ; Specks, Ulrich. / Pharmacokinetics of rituximab and clinical outcomes in patients with anti-neutrophil cytoplasmic antibody associated vasculitis. In: Rheumatology (United Kingdom). 2018 ; Vol. 57, No. 4. pp. 639-650.
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abstract = "Objectives. To study the determinants of the pharmacokinetics (PK) of rituximab (RTX) in patients with ANCA-associated vasculitis (AAV) and its association with clinical outcomes. Methods. This study included data from 89 patients from the RTX in AAV trial who received the full dose of RTX (four weekly infusions of 375 mg/m2). RTX was quantified at weeks 2, 4, 8, 16 and 24, and summarized by computing the trapezoidal area under the curve. We explored potential determinants of the PK-RTX, and analysed its association with clinical outcomes: achievement of remission at 6 months, duration of B-cell depletion and time to relapse in patients who achieved complete remission. Results. RTX serum levels were significantly lower in males and in newly diagnosed patients, and negatively correlated with body surface area, baseline B-cell count and degree of disease activity. In multivariate analyses, the main determinants of PK-RTX were sex and new diagnosis. Patients reaching complete remission at month 6 had similar RTX levels compared with patients who did not reach complete remission. Patients with higher RTX levels generally experienced longer B-cell depletion than patients with lower levels, but RTX levels at the different time points and area under the curve were not associated with time to relapse. Conclusion. Despite the body-surface-area-based dosing protocol, PK-RTX is highly variable among patients with AAV, its main determinants being sex and newly diagnosed disease. We did not observe any relevant association between PK-RTX and clinical outcomes. The monitoring of serum RTX levels does not seem clinically useful in AAV.",
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T1 - Pharmacokinetics of rituximab and clinical outcomes in patients with anti-neutrophil cytoplasmic antibody associated vasculitis

AU - Cornec, Divi

AU - Kabat, Brian F.

AU - Mills, John R.

AU - Cheu, Melissa

AU - Hummel, Amber M.

AU - Schroeder, Darrell R.

AU - Cascino, Matthew D.

AU - Brunetta, Paul

AU - Murray, David L.

AU - Snyder, Melissa R.

AU - Fervenza, Fernando Custodio

AU - Hoffman, Gary S.

AU - Kallenberg, Cees G.M.

AU - Langford, Carol A.

AU - Merkel, Peter A.

AU - Monach, Paul A.

AU - Seo, Philip

AU - Spiera, Robert F.

AU - William St Clair, E.

AU - Stone, John H.

AU - Barnidge, David R.

AU - Specks, Ulrich

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N2 - Objectives. To study the determinants of the pharmacokinetics (PK) of rituximab (RTX) in patients with ANCA-associated vasculitis (AAV) and its association with clinical outcomes. Methods. This study included data from 89 patients from the RTX in AAV trial who received the full dose of RTX (four weekly infusions of 375 mg/m2). RTX was quantified at weeks 2, 4, 8, 16 and 24, and summarized by computing the trapezoidal area under the curve. We explored potential determinants of the PK-RTX, and analysed its association with clinical outcomes: achievement of remission at 6 months, duration of B-cell depletion and time to relapse in patients who achieved complete remission. Results. RTX serum levels were significantly lower in males and in newly diagnosed patients, and negatively correlated with body surface area, baseline B-cell count and degree of disease activity. In multivariate analyses, the main determinants of PK-RTX were sex and new diagnosis. Patients reaching complete remission at month 6 had similar RTX levels compared with patients who did not reach complete remission. Patients with higher RTX levels generally experienced longer B-cell depletion than patients with lower levels, but RTX levels at the different time points and area under the curve were not associated with time to relapse. Conclusion. Despite the body-surface-area-based dosing protocol, PK-RTX is highly variable among patients with AAV, its main determinants being sex and newly diagnosed disease. We did not observe any relevant association between PK-RTX and clinical outcomes. The monitoring of serum RTX levels does not seem clinically useful in AAV.

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KW - Outcomes

KW - Pharmacokinetics

KW - Rituximab

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