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Aims AMG 181 pharmacokinetics/pharmacodynamics ( PK/ PD), safety, tolerability and effects after single subcutaneous (s.c.) or intravenous (i.v.) administration were evaluated in a randomized, double-blind, placebo-controlled study. Methods Healthy male subjects ( n= 68) received a single dose of AMG 181 or placebo at 0.7, 2.1, 7, 21, 70 mg s.c. (or i.v.), 210 mg s.c. (or i.v.), 420 mg i.v. or placebo. Four ulcerative colitis ( UC) subjects ( n= 4, male : female 2:2) received 210 mg AMG 181 or placebo s.c. (3:1). AMG 181 concentration, anti- AMG 181-antibody ( ADA), α4β7 receptor occupancy ( RO), target cell counts, serum C-reactive protein, fecal biomarkers and Mayo score were measured. Subjects were followed 3-9 months after dose. Results Following s.c. dosing, AMG 181 was absorbed with a median tmax ranging between 2-10 days and a bioavailability between 82% and 99%. Cmax and AUC increased dose-proportionally and approximately dose-proportionally, respectively, within the 70-210 mg s.c. and 70-420 mg i.v. ranges. The linear β-phase t1/2 was 31 (range 20-48) days. Target-mediated disposition occurred at serum AMG 181 concentrations of less than 1 μg ml−1. The PD effect on α4β7 RO showed an E C50 of 0.01 μg ml−1. Lymphocytes, eosinophils, CD4+ T cells and subset counts were unchanged. AMG 181-treated UC subjects were in remission with mucosal healing at weeks 6, 12 and/or 28. The placebo-treated UC subject experienced colitis flare at week 6. No ADA or AMG 181 treatment-related serious adverse events were observed. Conclusions AMG 181 has PK/ PD, safety, and effect profiles suitable for further testing in subjects with inflammatory bowel diseases. [ABSTRACT FROM AUTHOR]

Brodalumab, a human monoclonal IgG2-antibody, acts as a potent antagonist at the interleukin-17 receptor A, which is important in the pathogenesis of psoriasis. To characterize the pharmacokinetics of brodalumab and assess the effects of covariates, brodalumab concentrations from Phase 1a and Phase 2 clinical studies in healthy adults and subjects with psoriasis were used to construct a population PK model. The final two-compartment model with parallel linear and non-linear elimination pathways fit the data well. The population typical values for PK parameters CL, V, and Vmax were 0.223 L/ day, 4.62 L, and 5.40 mg/day with between-subject-variability of 69.2, 69.6, and 25.9%CV, respectively. Body weight (BW) was an important covariate on CL (and Q), V (and V2) and Vmax, with estimated effect exponents of 0.598, 0.849, and 1.12, respectively. Based on simulations from the final model, for doses between 140 and 210 mg, AUC was predicted to be greater than two fold higher in subjects weighing less than 75 kg compared to reference subjects. Age and diagnosis had smaller influence on exposure and was not clinically significant. These data suggest that BW is an important covariate explaining some of the variability in population PK observed in human clinical trials with brodalumab. [ABSTRACT FROM AUTHOR]