Comparative assessment of pharmacokinetics, and pharmacodynamics between RTXM83™, a rituximab biosimilar, and rituximab in diffuse large B-cell lymphoma patients: a population PK model approach

Abstract

Purpose The main objective was to quantify any potential differences in pharmacokinetic (PK) parameters (AUC and C max ) between RTXM83, a proposed rituximab biosimilar, and its reference product, using a population PK model approach. Methods Rituximab PK and PD data were obtained from a randomized, double-blind, phase III clinical study (RTXM83-AC-01-11) in patients with diffuse large B-cell lymphoma (DLBCL) that received 375 mg/m 2 intravenous RTXM83 or its reference product with CHOP regimen, every 3 weeks, for six cycles. Rituximab levels were quantified by Meso Scale Discovery assay. PK analysis was performed using NONMEM 7.3.0. The effect of disease and patient covariates on RXTM83 PK was investigated. Model was evaluated using visual predictive check and non-parametric bootstrap. Results In total, 251 DLBCL patients (127 and 124 in RXTM83-CHOP and rituximab-CHOP arms, respectively) and 5341 serum concentrations (2703 for RXTM83 and 2638 for rituximab, respectively) were available for the population PK analysis. The volume of distribution of the central compartment (V 1 ) and clearance of RXTM83 were estimated at 3.19 L and 12.5 mL/h, respectively. Body surface area allowed to explain the interindividual variability for V 1 . A statistical analysis showed that systemic exposure (AUC and C max ) of RTXM83 was similar to rituximab. The 90% confidence intervals for all pairwise comparisons were within the predefined bioequivalence interval of 0.80-1.25. PD similarity of B-cell depletion and recovery was also observed. Conclusions The time course of RTXM83 was well characterized by the model developed. The systemic exposure of RTXM83 and its associated variability were similar to those for rituximab reference in DLBCL patients, demonstrating PK similarity. The PD similarity of RTXM83 and rituximab reference product was also demonstrated.

Population pharmacokinetic modeling of PF-06439535 (a bevacizumab biosimilar) and reference bevacizumab (Avastin®) in patients with advanced non-squamous non-small cell lung cancer

“…Although population PK analyses have been previously reported for biosimilar products in patients [13] and healthy subjects [14,15], this is, to the best of our knowledge, the first published population PK analysis for a bevacizumab biosimilar product based on a comparative clinical study in patients with cancer. The current modeling effort was conducted by developing a model for PF-06439535 and bevacizumab-EU utilizing the combined sparse PK data set from a comparative clinical efficacy and safety study, with covariate analysis incorporating a direct quantitative assessment of the impact of drug product (i.e., the biosimilar or the reference product) on PK parameters.…”

Rituximab biosimilar RTXM83 versus reference rituximab in combination with CHOP as first-line treatment for diffuse large B-cell lymphoma: a randomized, double-blind study

“…Consequently, a prospective, multicenter, double-blind, randomized clinical study was conducted to confirm comparable clinical performance (efficacy, PK, PD, safety, and immunogenicity) of RTXM83 vs. R-rituximab, both in combination with CHOP chemotherapy as first-line treatment in DLBCL patients. The RTXM83-AC-01-11 study has been completed and the main results are described here, while a detailed description of the PK/PD and immunogenicity results have been reported elsewhere [14].…”

Nonlinear pharmacokinetics of rituximab in non‐Hodgkin lymphomas: A pilot study

“…Rituximab, a chimaeric IgG1 therapeutic monoclonal antibody binding CD20 antigen, is approved in 2 B‐cell malignancies, non‐Hodgkin lymphomas (NHL) and chronic lymphocytic leukaemia (CLL). The pharmacokinetics of rituximab were described in 12 pharmacokinetic modelling studies in NHL, CLL and rheumatoid arthritis . and in patients under plasmapherisis .…”

“…Indeed, higher CD20 expression in CLL, larger metabolic tumour volume (MTV) in lymphomas and higher CD19+ count in rheumatoid arthritis were associated with lower rituximab concentrations. Rituximab pharmacokinetics were reported to be linear in lymphomas and rheumatoid arthritis, despite the influence of antigen mass on either rituximab clearance or volume of distribution . Nonlinear pharmacokinetics were reported in a murine model of lymphoma expressing human CD20, where rituximab clearance increased with tumour volume .…”