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The Influence of Underlying Disease on Rituximab Pharmacokinetics May be Explained by Target-Mediated Drug Disposition.
Bensalem, Amina; Cartron, Guillaume; Specks, Ulrich; Mulleman, Denis; Gyan, Emmanuel; Cornec, Divi; Desvignes, Celine; Casasnovas, Olivier; Lamy, Thierry; Leprêtre, Stéphane; Paintaud, Gilles; Ternant, David.
Affiliation
  • Bensalem A; Université de Tours, EA 7501 GICC, Tours, France.
  • Cartron G; CNRS UMR 5235, Université de Montpellier, Montpellier, France.
  • Specks U; Department of Hematology, CHRU Montpellier, Montpellier, France.
  • Mulleman D; Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA.
  • Gyan E; Université de Tours, EA 7501 GICC, Tours, France.
  • Cornec D; Department of Rheumatology, CHRU de Tours, Tours, France.
  • Desvignes C; Department of Hematology and Cell Therapy, Clinical Investigations Center INSERM U1415, CHU Tours, Tours, France.
  • Casasnovas O; Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA.
  • Lamy T; Rheumatology Department, Brest University Hospital, and INSERM U1227, Brest, France.
  • Leprêtre S; Université de Tours, EA 4245 T2I, Tours, France.
  • Paintaud G; Service de Pharmacologie Médicale, CHU Bretonneau, 2 Boulevard Tonnellé, 37044, Tours, France.
  • Ternant D; Department of Clinical Hematology, CHU Dijon, Dijon, France.
Clin Pharmacokinet ; 61(3): 423-437, 2022 03.
Article in En | MEDLINE | ID: mdl-34773607
BACKGROUND AND OBJECTIVES: Rituximab is an anti-CD20 monoclonal antibody approved in several diseases, including chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), rheumatoid arthritis (RA), and anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). The influence of underlying disease on rituximab pharmacokinetics has never been investigated for several cancer and non-cancer diseases simultaneously. This study aimed at assessing this influence using an integrated semi-mechanistic model accounting for target-mediated elimination of rituximab. METHODS: Rituximab concentration-time data from five studies previously published in patients with CLL, DLBCL, FL, RA, and AAV were described using a two-compartment model with irreversible binding of rituximab to its target antigen. Both underlying disease and target antigen measurements were assessed as covariates. RESULTS: Central volume of distribution was [95% confidence interval] 1.7-fold [1.6-1.9] higher in DLBCL than in RA, FL, and CLL, and it was 1.8-fold [1.6-2.1] higher in RA, FL, and CLL than in AAV. First-order elimination rate constants were 1.8-fold [1.7-2.0] and 1.3-fold [1.2-1.5] higher in RA, DLBCL, and FL than in CLL and AAV, respectively. Baseline latent antigen level (L0) was 54-fold [30-94], 20-fold [11-36], and 29-fold [14-64] higher in CLL, DLBCL, and FL, respectively, than in RA and AAV. In lymphoma, L0 increased with baseline total metabolic tumor volume (p = 6.10-7). In CLL, the second-order target-mediated elimination rate constant (kdeg) increased with baseline CD20 count on circulating B cells (CD20cir, p = 0.0081). CONCLUSIONS: Our results show for the first time that rituximab pharmacokinetics is strongly influenced by underlying disease and disease activity. Notably, neoplasms are associated with higher antigen amounts that result in decreased exposure to rituximab compared to inflammatory diseases. Our model might be used to estimate unbound target amounts in upcoming studies.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Arthritis, Rheumatoid / Leukemia, Lymphocytic, Chronic, B-Cell / Lymphoma, Follicular / Lymphoma, Large B-Cell, Diffuse Limits: Humans Language: En Journal: Clin Pharmacokinet Year: 2022 Document type: Article Affiliation country: France Country of publication: Switzerland

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Arthritis, Rheumatoid / Leukemia, Lymphocytic, Chronic, B-Cell / Lymphoma, Follicular / Lymphoma, Large B-Cell, Diffuse Limits: Humans Language: En Journal: Clin Pharmacokinet Year: 2022 Document type: Article Affiliation country: France Country of publication: Switzerland