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Cancer Chemother Pharmacol ; 81(3): 515-527, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29362903

RESUMO

PURPOSE: The main objective was to quantify any potential differences in pharmacokinetic (PK) parameters (AUC and Cmax) 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/m2 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 (V1) 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 V1. A statistical analysis showed that systemic exposure (AUC and Cmax) 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.


Assuntos
Medicamentos Biossimilares , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Rituximab , Imunidade Adaptativa/efeitos dos fármacos , Administração Intravenosa , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacocinética , Área Sob a Curva , Medicamentos Biossimilares/administração & dosagem , Medicamentos Biossimilares/farmacocinética , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Linfoma Difuso de Grandes Células B/patologia , Masculino , Modelos Estatísticos , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Rituximab/química , Rituximab/farmacocinética , Equivalência Terapêutica , Resultado do Tratamento
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