IL-18 binding protein (BP) neutralizes the activity of IL-18, a cytokine implicated in psoriasis and rheumatoid arthritis (RA). We investigated the pharmacokinetics, pharmacodynamics and safety of recombinant human IL-18 BP (r-hIL-18 BP) in healthy volunteers and subjects with psoriasis or RA in four phase I studies. A) Healthy volunteers (n = 24) were randomised to receive a single subcutaneous (sc) injection of r-hIL-18 BP (20, 70, 210 or 350 mg) or placebo. B) Healthy volunteers (n = 10) were randomised to receive six sc injections of r-hIL-18 BP (35 or 175 mg, 48 h between injections) or placebo. C) Subjects with moderate-to-severe plaque psoriasis (n = 35) were randomised to receive r-hIL-18 BP (20, 160 or 320 mg, sc tiw) or placebo for 6 weeks. D) Subjects with active, moderate-to-severe RA (n = 36) were randomised to receive r-hIL-18 BP (20, 80, 160 mg, sc tiw) or placebo for 6 weeks. Pharmacokinetics, pharmacodynamics and safety were assessed in all four studies. r-hIL-18 BP showed a dose-dependent pharmacokinetic profile, with a peak serum concentration of 6-48 hours. With repeated sc injections tiw, a steady state was achieved in 1-2 weeks among subjects with psoriasis or RA. The majority of adverse events were mild or moderate in severity. Injection site reactions were the most frequently reported event in subjects with psoriasis or RA. r-hIL-18 BP displays dose-dependent pharmacokinetics, has a favourable safety profile and is well-tolerated in healthy volunteers and in subjects with moderate-to-severe plaque psoriasis or active, moderate-to-severe RA.

Atacicept, a soluble recombinant fusion protein of the human immunoglobulin (Ig) G(1) Fc and the extracellular domain of the human transmembrane activator and calcium modulator and cyclophylin ligand interactor receptor, acts as an antagonist of both B lymphocyte stimulator and a proliferating-inducing ligand. Here we determined the nonclinical safety, pharmacokinetics and pharmacodynamics of atacicept in mice and cynomolgus monkeys. Subcutaneous atacicept treatment (twice weekly in cynomolgus monkeys, three times weekly in mice) was generally safe and well tolerated safe and well tolerated with dosing up to 10 mg/kg every other day for up to 39 weeks or up to 80 mg/kg when dosed for 4 weeks. At a dose of 1 mg/kg subcutaneous (sc) bioavailability of atacicept in mice and monkeys was 76 and 92%, with a mean serum t(1/2) of 44 and 179 h, respectively. In accord with its anticipated mechanism of action, repeated administration of atacicept decreased serum IgG concentrations up to 50%, IgM concentrations >99%, and circulating mature B-cell concentrations up to 60%. These effects were dose-related but reversible, as determined in a 25-week follow-up period. Microscopically, B cells numbers were reduced in the follicular marginal zone of the spleen and the mantle surrounding germinal centers of the lymph nodes. These data confirm the preclinical safety and the pharmacological activity of atacicept and support its clinical development.

This study aimed to explore the currently competing and new semimechanistic clearance models for monoclonal antibodies and the impact of clearance model misspecification on exposure metrics under different study designs exemplified for cetuximab. Six clearance models were investigated under four different study designs (sampling density and single/ multiple-dose levels) using a rich data set from two cetuximab clinical trials (226 patients with metastatic colorectal cancer) and using the nonlinear mixed-effects modeling approach. A two-compartment model with parallel Michaelis-Menten and time-decreasing linear clearance adequately described the data, the latter being related to post-treatment response. With respect to bias in exposure metrics, the simplified time-varying linear clearance (CL) model was the best alternative. Time-variance of the linear CL component should be considered for biotherapeutics if response impacts pharmacokinetics. Rich sampling at steady-state was crucial for unbiased estimation of Michaelis-Menten elimination in case of the reference (parallel Michaelis-Menten and time-varying linear CL) model.

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