Pharmacokinetic and Pharmacodynamic Relationship of AMG 811, An Anti-IFN-γ IgG1 Monoclonal Antibody, in Patients with Systemic Lupus Erythematosus

Purpose To investigate the relationships between AMG 811 exposure, concentration changes in serum IFN-γ, and IFN-γ-induced protein 10 (CXCL10), and to identify important contributions of baseline covariates to these relationships. Methods A mechanism based pharmacokinetic (PK)-pharmacodynamic (PD) model was developed. A target mediated disposition model was used to describe AMG 811 and target IFN-γ interaction. CXCL10 was predicted to be driven by estimated free IFN-γ levels. Results For an average systemic lupus erythematosus (SLE) subject, the linear clearance (CL) of AMG 811 was 0.176 L/day, and the central (V c ) and peripheral (V p ) volumes of distribution were 1.48 and 2.12 L, respectively. Body weight was found to correlate with CL, V c , V p , and inter compartment clearance (Q); and age was found to correlate with V c . The relationship between estimated free serum IFN-γ concentration levels and serum CXCL10 in logarithmic scales was best described by a linear model with slope and intercept estimated to be 0.197 and -0.3, respectively. Conclusions The largest observed reduction of serum CXCL10 concentration was achieved at the highest AMG 811 dose tested (180 mg SC). This model enables simulations of AMG 811 PK-PD profiles under various dosing regimens to support future clinical studies.