Population pharmacokinetics (PK) and association of PK and clinical outcomes of rituximab in patients with non-Hodgkin's lymphoma.

Abstract

e13108 Background: Rituximab is effective and widely used in NHL. To increase our understanding of its PK characteristics and relation to clinical outcomes, we analyzed data from the rituximab pivotal trial (IDEC102-05) in patients with relapsed low-grade or follicular B-cell NHL who were treated with 4 weekly rituximab doses. Methods: Population PK (POP-PK) of rituximab was performed based on 1,848 serum samples from 161 patients using nonlinear mixed-effects modeling (NONMEM VI) software. The association of rituximab PK with response and time to progression (TTP) in the follicular lymphoma (FL) subgroup was evaluated by logistic and Cox regression, respectively. Results: Rituximab clearance was best described by a two-compartment model with time varying clearance comprised of two terms—a target-independent pathway as with other endogenous IgG antibodies, which is unchanged throughout treatment, and a target-mediated pathway that decreases from its initial value following infusion at a constant decay rate related to the extent of B cell/tumor-burden at baseline. In the FL subgroup (N=111), a positive association of rituximab serum concentrations pre-second infusion with overall response rate and TTP was observed among patients with low concentrations (< 35 ug/ml): odds ratio =1.72 (95% CI: 1.14-2.60, p=0.009) for response and HR=0.75 (95% CI: 0.64-0.91, p=0.0032) for TTP (per 5 ug/ml). In contrast, no association with TTP or OR was seen for the FL patients with higher serum concentrations (≥ 35 ug/ml). Similar results were observed for timpoints at 1 and 3 mo post-treatment, and the association is not qualitatively affected by baseline characteristics or disease factors. Conclusions: POP-PK studies suggest that the lower rituximab serum levels are associated with the larger tumor burden and/or antigen load. Among FL patients, higher rituximab concentrations are associated with better clinical outcomes only on those with serum concentrations in a low range. Further studies would be necessary to identify the threshold of rituximab level sufficient to override the effects of tumor burden for FL patients. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Roche