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

Author information

Cornec D1,2, Kabat BF3, Mills JR4, Cheu M5, Hummel AM1, Schroeder DR3, Cascino MD5, Brunetta P5, Murray DL4, Snyder MR4, Fervenza F6, Hoffman GS7, Kallenberg CGM8, Langford CA7, Merkel PA9, Monach PA10, Seo P11, Spiera RF12, St Clair EW13, Stone JH14, Barnidge DR4, Specks U1. Rheumatology (Oxford). 2018 Jan 10. doi: 10.1093/rheumatology/kex484. [Epub ahead of print]

Abstract

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1 Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA.

2 Rheumatology Department, Brest University Hospital, and INSERM U1227, Brest, France.

3 Department of Health Sciences Research.

4 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.

5 Genentech Inc., South San Francisco, CA.

6 Division of Nephrology, Mayo Clinic, Rochester, MN.

7 Division of Rheumatology, Cleveland Clinic Foundation, Cleveland, OH, USA.

8 Rheumatology, University of Groningen, Groningen, the Netherlands.

9 Division of Rheumatology and Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA.

10 Rheumatology, Boston University Medical Center, Boston, MA.

11 Rheumatology, Johns Hopkins University, Baltimore, MD.

12 Rheumatology, Hospital for Special Surgery, New York, NY.

13 Rheumatology, Duke University, Durham, NC.

14 Rheumatology, Massachusetts General Hospital, Boston, MA, USA.

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.