Researchers Describe PopPK Model Developed for HLX01

The Center for Biosimilars Staff

Because stand-alone pharmacokinetic (PK) studies are usually designed to focus on intrinsic and extrinsic factors that have a high potential to affect drug exposure, they leave other possible interactions unstudied; population PK (popPK) analysis allows for an assessment of multiple factors that are not otherwise evaluated in healthy volunteers and allows for a larger number of individuals to be included.

HLX01, a biosimilar rituximab approved by China’s National Medicinal Products Administration in February of this year, is China’s first biosimilar product to be approved under national guidelines that were set forth in 2015. The biosimilar was approved to treat lymphoma, and it was simultaneously developed as a novel product for the treatment of rheumatoid arthritis (RA), as the reference rituximab was not approved to treat RA in China, so no extrapolation for the indication could be granted.

The biosimilar is currently in phase 3 clinical development for RA, and during the European Society for Medical Oncology Asia Congress 2019, held last week in Singapore, researchers reported on their development of a population (pop) pharmacokinetic (PK) model that used PK data from the biosimilar and its reference in patients with RA and employed validation from patients with diffuse large B-cell lymphoma (DLBCL).

Because stand-alone PK studies are usually designed to focus on intrinsic and extrinsic factors that have a high potential to affect drug exposure, they leave other possible interactions unstudied; popPK analysis allows for an assessment of multiple factors that are not otherwise evaluated in healthy volunteers and allows for a larger number of individuals to be included.

The popPK model of the biosimilar and the EU-licensed reference from the study in 196 patients with RA had a serum sample number of 4289. It was developed with a nonlinear mixed-effect modeling using a first-order estimation with interaction method. PK and pharmacodynamic relationships were characterized using covariates including demographics and medical history, and these were examined using forward addition and backward elimination. The final model was validated using PK samples from the biosimilar and China-licensed reference rituximab from a study in 110 patients with DLBCL.

Using the model, the estimated clearance (CL), central volume (Vc), peripheral compartment volume, and clearance-of-distribution from the central to the peripheral compartment were 27.32%, 16.56%, 21.61%, and 40.79%, respectively. Correlation between CL and Vc was 0.02239.

The observed concentrations and simulations-based 95% CIs for the corresponding model successfully predicted all subjects in the data set, demonstrating PK similarity of the biosimilar and the reference in patients with RA and DLBCL, and no significant difference in area under the curve from zero to infinity was observed between the products.

According to the authors, the results of the model provide further evidence of the PK similarity of the biosimilar and its reference in both patients with RA and DLBCL.

Reference

Shi Y, Quin Y, Zhao S, et al. A population pharmacokinetic model: assessment of pharmacokinetic similarity of HLX01 and rituximab in diffuse large B-cell lymphoma. Presented at: European Society for Medical Oncology Asia Congress 2019; November 22-24, 2019; Singapore.