Amina Bensalem1, Denis Mulleman1,2, Gilles Paintaud1,3, Nicolas Azzopardi1,4, Valérie Gouilleux-Gruart1,5, Divi Cornec6,7,8, Ulrich Specks6, David Ternant9,10,11. 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.
RCT Entities:
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.
Authors: Myrna Candelaria; Derlis Gonzalez; Francisco Javier Fernández Gómez; Alexandra Paravisini; Ana Del Campo García; Luis Pérez; Bernardo Miguel-Lillo; Susana Millán Journal: Cancer Chemother Pharmacol Date: 2018-01-24 Impact factor: 3.333