Population Pharmacokinetic Evaluation of a Fully Human IgG2 Monoclonal Antibody in Patients with Inflammatory Diseases

Mohammad      Tabrizi; Bing      Wang; Hong      Lu; Saling      Huang; Gregory      Bell; Gisela      Schwab; Lorin      Roskos

Abstract

ABX-IL8 is a fully human IgG2 monoclonal antibody generated using transgenic mouse technology (Xenomouse®) that binds to human Interleukin-8 with high affinity and specificity. The objective of this study was to evaluate the pharmacokinetic (PK) properties of ABX-IL8 in patients with active inflammatory diseases. Patients with psoriasis and rheumatoid arthritis received single or multiple short intravenous infusions of ABX-IL8 or placebo. Serum concentrations of ABX-IL8, baseline serum IgG and IgG2 concentrations and Anti-Drug Antibody (ADA) response to ABX-IL8 were determined using relevant immunoassays. Pharmacokinetic analyses of the serum ABX-IL8 concentration – time data were performed. Following single-dose administration of ABX-IL8, dose proportional increases in drug exposure were observed. Consistent with the disposition properties of the endogenous IgG antibodies, ABX-IL8 appeared to be primarily distributed into the plasma compartment and the extra-vascular fluid and the steady-sate volume of distribution (61 ± 14 to 71 ± 14 mL/kg) was comparable to that for the endogenous antibodies. Following the multipledose administration, PK properties of the antibody were linear with dose and time. Steady-state clearance (2.6 ± 1.1 to 2.7 ± 1.4 mL/day/kg) was similar to that observed following the single dose administration and no ADA response was detected throughout the study. PK variability and serum exposure to ABX-IL8 following administration of the fixed doses were comparable to those observed following administration of the weight-adjusted doses; the impact of body weight on clearance was minimal and this correlation did not translate into requirements for body weight-adjusted dosing. Additionally, age and disease type (psoriasis or RA) had no impact on ABX-IL8 pharmacokinetics.

Keywords: Anti-IL8 monoclonal antibody, interleukin-8, pharmacokinetics, patients with inflammatory diseases, ABX-IL8, IgG2 monoclonal antibody, Anti-Drug Antibody (ADA), tumors, synovial fluid, lymph nodes, panitumumab, denosumab, xenomouse technology, chemokine, leukocyte chemotaxis, neutrophil degranulation, angiogenesis, plaque psoriasis, enzyme-linked immunosorbant assay, linear regression, Immunogenicity, IgG2 antibody, placebo, rheumatoid arthritis, Fc receptor, 2-microglobulin, immunosuppressive therapy