Modeling and Simulation of Abatacept Exposure and Interleukin-6 Response in Support of Recommended Doses for Rheumatoid Arthritis.

Abatacept is a recombinant soluble fusion protein that inhibits the CD80/CD86:CD28 costimulatory signal required for T cell activation and has demonstrated efficacy in the treatment of rheumatoid arthritis. The objectives of this analysis were to provide support for a body weight—tiered dosing regimen approximating 10 mg/kg by (1) quantifying the effect of body weight on exposure and (2) characterizing the relationship between exposure and serum interleukin (IL)—6 concentration. The abatacept exposure and exposure-response models were developed with 2148 abatacept serum concentrations (from 388 subjects) and 1894 IL-6 serum concentrations (from 799 subjects), respectively, followed by simulation with these models to address the above objectives. Abatacept exposure was characterized by a linear 2-compartmental model, in which clearance was linearly related to body weight. The IL-6 response was characterized by an indirect-response model, in which the IL-6 production rate increased with baseline C-reactive protein levels. Model-based simulations demonstrated that body weight—tiered dosing was desirable to ensure consistent steady-state abatacept trough concentrations across a range of body weights; doses approximating 10 mg/kg (500, 750, 1000 mg for subjects weighing <60, 60-100, and >100 kg, respectively) provided consistent exposure across the body weight groups. In addition, doses >10 mg/kg did not result in further increases in IL-6 suppression. These modeling and simulation results indicate that the body weight—tiered abatacept therapeutic doses approximating 10 mg/kg will ensure consistent abatacept exposure and optimal IL-6 suppression. [ABSTRACT FROM PUBLISHER]

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