Population Pharmacokinetics of Rituximab in RA (Rheumatoid Arthritis) Patients: Combining two phase II studies

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Objectives: Rituximab (RTX; a CD20+-targeted therapeutic antibody) is currently licensed to treat non-Hodgkin’s lymphoma using a body surface area (BSA)-adjusted dosing regimen. A fixed dose regimen of RTX, in combination with a short course of glucocorticoids (GC), is being explored as a novel approach to treating RA. The goal of this analysis was to explore the population pharmacokinetics (POP PK) of RTX using data from two Phase II studies in patients with RA.

Methods: Data were obtained from two studies: a Phase IIa study with frequent sampling (RTX 1000 mg x 2 infusion, 2 weeks apart) and a larger Phase IIb (RTX 500 vs 1000 mg infusion x 2, 2 weeks apart) with limited sampling. The effect of including various covariates, such as dose, concomitant medication, race, gender, prior anti-TNFa therapy, region, age, BSA and duration of RA disease, in the PK model was evaluated. A POP PK model was simultaneously fitted to the combined data from the two Phase II studies. The model consisted of two distribution compartments and a zero-order infusion. Potential influence of the covariates on the clearance (CL) and the central compartment volume of distribution (Vc) was evaluated. A bootstrap re-sampling procedure was used to validate the model stability and to estimate the 95% confidence intervals.

Results: A total of 3196 RTX concentrations from 423 patients was used in the analysis (1002 samples and 107 patients from the Phase IIa and 2194 samples and 316 patients from Phase IIb study). CL and Vc estimated using the combined data set were similar to the estimates from the Phase IIa data alone (291 mL/day and 3000 mL, for CL and Vc, respectively) (1). Gender and BSA significantly affected the CL and Vc, male had larger CL and Vc compared to female. Concomitant administration of high-dose GC (oral and IV) reduced the CL of RTX by 12% for a typical patient compared with no GC or only IV GC. There was no significant difference in CL between the two RTX doses.

Conclusions: PK parameters from the POP PK analysis of the combined data set did not differ from those published for the Phase IIa study alone. The effects of BSA and gender on the CL and Vc were confirmed. Concomitant administration of high-dose GC decreased RTX clearance by 12%. The PK parameters were not significantly different for the doses studied. The combined data from the two studies support the use of a fixed-dose regimen of RTX in RA.

Reference:
1. Ng CM, Bruno RA, Combs D, Davies B. A population pharmacokinetic model for rituximab in rheumatoid arthritis patients during a Phase II clinical study. ACCP Annual Meeting, 2004.