1080P - A new population model validated pharmacokinetic similarity of HLX01 and rituximab in B-cell lymphoma

Abstract

BackgroundHLX01, the first-ever China (CN)-manufactured rituximab (RTX) biosimilar, was approved by National Medicinal Products Administration (NMPA) for the treatment of diffuse large B-cell lymphoma (DLBCL) on 22 February 2019, and was concurrently developed as a novel drug to treat rheumatoid arthritis (RA) in CN since the indication has not been approved. The objective of this study was to develop a reliable population pharmacokinetic (PopPK) model of rituximab in patients with RA, the most appropriate patient population for PK evaluation, and validate HLX01 and CN-RTX PK data in patients with DLBCL. MethodsA PK model for HLX01 and the EU-RTX from a randomised, double-blind phase 1/2 study (NCT03355872) in 196 RA patients (serum sample n=4289) was developed using non-linear mixed-effect modeling (NONMEM®) with the first-order conditional estimation with interaction (FOCEI) method. PK and PK-pharmacodynamic relationship were characterised with various covariates (ie. demographics, pathphysiologic/disease conditions etc) which were examined by using forward addition (p<0.01) / backward elimination (p<0.001). The final model was evaluated using Bayesian bootstrap and visual predictive check (VPC). A total of 1000 simulations were tested using the observed covariates. The final model was validated using PK samples of HLX01 and CN-RTX from a randomised, double-blind phase 3 registrational study (NCT02787239) in 110 patients with CD20+ DLBCL. ResultsA two-compartment model with first-order elimination provided the best model fit. The estimated clearance (CL), central volume (Vc), peripheral compartment volume (Vp) and clearance of distribution from the central to the peripheral compartment (Q) were 27.32%, 16.56%, 21.61%, and 40.79%, respectively. The correlation between CL and Vcwas 0.02239. The PopPK model of HLX01 and EU-RTX using RA patients adequately predicts the central tendency and variability of the HLX01 and CN-RTX in patients with DLBCL. ConclusionsThis PopPK model derived from RA patients can predict HLX01 and CN-RTX in patients DLBCL. HLX01 and EU-/CN-RTX had similar PK parameters and influential PK covariates. These results provided further evidence for PK similarity between HLX01 and RTXs in patients with RA or DLBCL. Clinical trial identificationTwo trials were listed in this abstract: 1. A Randomised, Double-blind, Phase 1/2 Study to Evaluate the PK, PD, Safety, and Efficacy Between HLX01 and Rituximab in Patients With Moderate to Severe Rheumatoid Arthritis and Inadequate Response to Treatment With DMARDs ClinicalTrials.gov Identifier: NCT03355872 2. Clinical Phase 3 Study to Compare the Efficacy and Safety of Rituximab Biosimilar HLX01 and Rituximab in Combination With CHOP, in Previously Untreated Subjects With CD20+ DLBCL ClinicalTrials.gov Identifier: NCT02787239. Legal entity responsible for the studyShanghai Henlius Biotech, Inc. FundingShanghai Henlius Biotech,Inc. DisclosureY. Shi: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. Y. Dan: Full / Part-time employment: Shanghai Henlius Biotech,Inc. Y. Hong: Shareholder / Stockholder / Stock options, Full / Part-time employment: Shanghai Henlius Biotech, Inc. J. Guo: Full / Part-time employment: Shanghai Henlius Biotech, Inc. S. Zhao: Advisory / Consultancy: Certara Strategic Consulting China. X. Zeng: Research grant / Funding (institution): Peking Union Medical College Hospital. P. Hu: Research grant / Funding (institution): Peking Union Medical College Hospital. W. Jiang: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: I am an employee of Shanghai Henlius Biotech, Inc. S. Liu: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Shanghai Henlius Biotech,Inc. X. Zhang: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Shanghai Henlius Biotech,Inc. A. Luk: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Shanghai Henlius Biotech,Inc. K. Chai: Full / Part-time employment: Shanghai Henlius Biotech,Inc. E. Liu: Leadership role, Full / Part-time employment: I am an employee of Shanghai Henlius Biotech,Inc.