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

Clin Pharmacokinet. 2020 Apr;59(4):519-530. doi: 10.1007/s40262-019-00826-5.

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.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / drug therapy*
  • Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / immunology
  • Antibodies, Antineutrophil Cytoplasmic / drug effects*
  • Antineoplastic Agents, Immunological / administration & dosage
  • Antineoplastic Agents, Immunological / immunology
  • Antineoplastic Agents, Immunological / pharmacokinetics*
  • Biomarkers / metabolism
  • Double-Blind Method
  • Female
  • Humans
  • Infusions, Intravenous
  • Male
  • Middle Aged
  • Models, Biological
  • Myeloblastin / antagonists & inhibitors
  • Myeloblastin / immunology
  • Myeloblastin / metabolism
  • Nonlinear Dynamics
  • Peroxidase / antagonists & inhibitors
  • Peroxidase / immunology
  • Peroxidase / metabolism
  • Remission Induction
  • Rituximab / administration & dosage
  • Rituximab / immunology
  • Rituximab / pharmacokinetics*

Substances

  • Antibodies, Antineutrophil Cytoplasmic
  • Antineoplastic Agents, Immunological
  • Biomarkers
  • Rituximab
  • Peroxidase
  • Myeloblastin