Rituximab PK and PKPD evaluation based on a study in diffuse large B-cell lymphoma: influence of tumor size on PK and assessment of PK similarity.

DRL-rituximab (DRL_RI, Dr. Reddy's Laboratories SA, Basel, Switzerland) is under development as a rituximab biosimilar. Study RI-01-002 (CTRI/2012/11/003129), comparing DRL_RI to the reference medicinal product MabThera® (RMP, Roche, Grenzach-Wyhlen, Germany), demonstrated pharmacokinetic (PK) equivalence and showed comparable pharmacodynamic, efficacy, safety, and immunogenicity profiles. We used data from the same study to perform population PK and pharmacokinetic-pharmacodynamic (PKPD) analyses: first exploring possible factors influencing the PK similarity assessment between products, then performing simulations to investigate the impact of tumor size on rituximab PK. Nonlinear mixed-effects models for PK, tumor size, tumor size-PK, and tumor response were developed independently. The final PK model included drug product as a dose scaling parameter and predicted a 6.75% higher dose reaching the system in RMP-treated patients. However, when tumor size was included in the tumor size-PK model, the drug product effect was no longer observed. The model rather indicated that patients with larger tumor size have higher clearance. Further simulations confirmed that higher baseline tumor size is associated to slightly lower rituximab exposure. Tumor response, described by a Continuous-time Markov model, did not differ between drug products. Both had higher effects during the first 20 weeks of treatment. Also, the model described a sub-population of non-responders to treatment (42%) with faster transitions to a worse state. The different rituximab exposure initially detected between drug products (6.75%) was shown using PK/PKPD analysis to be due to a tumor size imbalance between treatment groups. PK/PKPD analyses may contribute to PK similarity assessments.