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Clin Pharmacokinet. 2019 Oct 5. doi: 10.1007/s40262-019-00826-5. [Epub ahead of print]

Non-Linear Rituximab Pharmacokinetics and Complex Relationship between Rituximab Concentrations and Anti-Neutrophil Cytoplasmic Antibodies (ANCA) in ANCA-Associated Vasculitis: The RAVE Trial Revisited.

Author information

1
Université de Tours, EA 7501 GICC, Tours, France.
2
Department of Rheumatology, CHRU de Tours, Tours, France.
3
Department of Medical Pharmacology, CHRU de Tours, Tours, France.
4
CNRS, ERL 7001, Tours, France.
5
Laboratory of Immunology, CHRU de Tours, Tours, France.
6
Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA.
7
Rheumatology Department, Brest University Hospital, Brest, France.
8
INSERM U1227, Brest, France.
9
Université de Tours, EA 7501 GICC, Tours, France. david.ternant@univ-tours.fr.
10
Department of Medical Pharmacology, CHRU de Tours, Tours, France. david.ternant@univ-tours.fr.
11
Laboratoire de Pharmacologie-toxicologie, CHRU de Tours, 2 Boulevard Tonnellé, 37044, Tours Cedex, France. david.ternant@univ-tours.fr.

Abstract

BACKGROUND AND OBJECTIVES:

Rituximab is approved in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and leads to a decrease of ANCA levels. The objectives of this study were to investigate the non-linear pharmacokinetics of rituximab and the relationship between its concentrations and ANCA levels in AAV patients.

METHODS:

Ninety-two AAV patients from the RAVE (Rituximab in ANCA-Associated Vasculitis) trial were assessed. Both ANCA anti-myeloperoxidase (MPO-ANCA) and anti-proteinase 3 (PR3-ANCA) levels were used as biomarkers. The pharmacokinetics of rituximab were described using a semi-mechanistic two-compartment model that included a latent target antigen turnover and allowed the estimation of specific target-mediated elimination in addition to its non-specific elimination of rituximab. The effect of rituximab on the ANCA level was described using a semi-mechanistic compartment model with a negative feedback (Friberg) model with no transit compartment. A population modeling approach was used.

RESULTS:

Our pharmacokinetic and pharmacokinetic-pharmacodynamic (PK-PD) models satisfactorily described both concentration-time and concentration-effect relationship data. The mean (inter-individual standard deviation) estimated non-specific clearance was 0.15 L/day (0.30%) and the target-mediated elimination rate constant was 2.4 × 10-5 nmol/day. The elimination half-lives for MPO-ANCA and PR3-ANCA were 24 and 18 days, respectively.

CONCLUSIONS:

A non-linear target-mediated elimination of rituximab was detected in AAV patients. Our PK-PD model allowed quantification of the association between rituximab concentrations and ANCA levels. This decrease was deep but delayed, and more sustained in patients with MPO-ANCA than in those with PR3-ANCA. Our results suggest that repeating courses of rituximab might improve the clinical response to rituximab.

PMID:
31586310
DOI:
10.1007/s40262-019-00826-5

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