RT Journal Article SR Electronic T1 The safety, tolerability and pharmacokinetics of AZD5069, a novel CXCR2 antagonist, in healthy Japanese volunteers JF European Respiratory Journal JO Eur Respir J FD European Respiratory Society SP P4842 VO 40 IS Suppl 56 A1 Ulrike Lorch A1 Hedigo Negi A1 Hirobumi Tabata A1 Heather Wray A1 Marie Cullberg A1 Bengt Larsson YR 2012 UL http://erj.ersjournals.com/content/40/Suppl_56/P4842.abstract AB BACKGROUND:AZD5069 is a reversible antagonist at the human CXC chemokine receptor-2, with potential as an oral treatment of inflammatory diseases such as COPD. It has previously only been administered to Caucasian healthy volunteers and patients.METHODS:This was a Phase I, randomised, double-blind, placebo-controlled, single-centre, 6 cohort study in healthy Japanese males (n=63; 22–39 yrs). Subjects received a single dose of AZD5069 (10–120 mg) on Day 1 (n=42), then twice-daily doses of AZD5069 (10–80 mg) for 7 days and a single dose on the last dosing day (n=36), or placebo (n=21). The safety and tolerability of AZD5069 was assessed primarily, with pharmacokinetics assessed by non-compartmental analysis.RESULTS:AZD5069 ≤80 mg twice-daily was well-tolerated with an acceptable safety profile. Expected clinically significant changes in laboratory safety parameters led to study withdrawals due to low blood neutrophil levels and elevated high sensitivity-C-reactive protein (hs-CRP) levels, meeting stopping criteria. Circulating neutrophil levels decreased with increasing plasma AZD5069 concentrations, but were recovering by 12 hrs post-dose and had returned to near normal at follow-up, 7–10 days post-last dose. AZD5069 was rapidly absorbed and AUC and Cmax increased dose-proportionally with single and multiple doses. Steady-state was reached within 2–3 days following twice-daily dosing, with no, or minor, drug accumulation.CONCLUSIONS:AZD5069 was well-tolerated. Decreases in neutrophil counts and increases in hs-CRP levels were observed as expected. No safety concerns were identified to preclude future evaluation. Systemic exposure to AZD5069 was dose proportional.