2008 - Marseille - France

PAGE 2008: Applications- Biologicals/vaccines
Micha Levi

Relationship Between Serum Concentration of the Interleukin-6 Receptor Inhibitor, Tocilizumab (TCZ), and Disease Activity Score (DAS28) in Patients with Rheumatoid Arthritis

Micha Levi (1), Nicolas Frey (2) , Susan Grange (2), Thasia Woodworth (3)

(1) Roche, Nutley, NJ, USA; (2) Roche, Basel, Switzerland, (3) Roche, Hertfordshire, UK

Objective: To describe the relationship between tocilizumab concentration and the clinical endpoint (DAS28). A secondary objective was to investigate potential effects of the demographic, the disease- and treatment related covariates on parameters of the PK/PD model.

Methods: Data were pooled from, two randomized, double-blind, placebo-controlled, phase 3 trials in adults with moderate-to-severe active RA, who received TCZ 4 or 8 mg/kg via IV infusion every 4 weeks for 24 weeks or placebo, in combination with DMARDs. A population PK/PD model was developed using these studies to describe the time course of DAS28 with TCZ treatment, a third study, was used for external validation. The impact of demographic and disease-related covariates on parameters of the PK/PD model was assessed.

Results: In total, 1703 RA patients with available PK and DAS28 values were used for model development and 443 were used for external validation. An indirect response model with an inhibitory effect on DAS28 'production' rate by TCZ serum concentrations following a sigmoid Emax relationship, accurately described the magnitude and time course of DAS28 reduction. At baseline, DAS28 was 6.8. The TCZ serum concentration that induced 50% of the Emax was 3.72 mg/ml (slightly higher than the mean trough concentration with 4 mg/kg), with high (170%) inter-patient variability. Emax was 72.5%, corresponding to a maximum 5-point DAS reduction. DMARD background therapy represented only a small fraction of the total effect on DAS28 observed for the two TCZ doses (estimated 0.8-point DAS reduction from baseline). None of the covariates had a clinical impact on the relationship between TCZ exposure and DAS28 time course.

Simulations to reproduce the estimated between-patient variability, showed that TCZ 8 mg/kg versus 4 mg/kg was associated with higher proportions of patients with DAS28 remission (35% vs 21%) and good EULAR response (53% vs 35%).

Conclusions: In this analysis, the relationship between TCZ serum concentration levels and DAS28 were characterized reasonably well by using an indirect response model with sgimoidal Emax inhibitory effect of TCZ on DAS28 ‘production' rate. Demographic and disease-related covariates had no effect on parameters of the PK/PD model, suggesting that subpopulations of patients with RA may not require TCZ dose adjustment. The concentrations corresponding to 8 mg/kg were more effective in reducing RA disease activity (DAS28) than those corresponding to 4 mg/kg.

Reference: PAGE 17 (2008) Abstr 1329 [www.page-meeting.org/?abstract=1329]
Poster: Applications- Biologicals/vaccines