PT  - JOURNAL ARTICLE
AU  - Paul Russell
AU  - Chris Stevenson
AU  - Catherine Charron
AU  - Charlie Brindley
AU  - Dave Singh
TI  - LATE-BREAKING ABSTRACT: Safety, pharmacokinetic and pharmacodynamic profile of RV1162, a narrow spectrum kinase inhibitor, in healthy subjects and COPD patients
AID  - 10.1183/13993003.congress-2015.PA4361
DP  - 2015 Sep 01
TA  - European Respiratory Journal
PG  - PA4361
VI  - 46
IP  - suppl 59
4099  - http://erj.ersjournals.com/content/46/suppl_59/PA4361.short
4100  - http://erj.ersjournals.com/content/46/suppl_59/PA4361.full
SO  - Eur Respir J2015 Sep 01; 46
AB  - Rationale: To evaluate the safety, pharmacokinetic (PK) and pharmacodynamic (PD) profile of RV1162 in healthy subjects and GOLD stage 2/3 Chronic Obstructive Pulmonary Disease (COPD) patients.Methods: Thirty eight healthy subjects aged 18-50 years and 40 COPD patients aged 40–75 years were recruited. Healthy subjects received inhaled RV1162 single doses 5-1000µg and 500µg or placebo daily for 7 days. COPD subjects received 100mg, 500mg or placebo daily for 14 days in a 15:15:10 ratio. Safety was reviewed daily; PK was measured on Day (D) 1, 7 and 14. PD measured on D12 included sputum cell counts, sputum and serum biomarkers measured by Luminex, biochemical assay, MSD or ELISA.Results: Seventy two subjects completed the study. No clinically significant safety signals attributable to RV1162 were reported.PK data in COPD showed low plasma exposure on D14, with mean maximum concentration (Cmax) of 379 picograms (pg) per milliliter (mL) and area under the curve (AUC) of 5490 pg.h/mL, approximately 6.5 fold greater than on D1. The effective half-life was 115 h and 84% steady state was reached by D14.RV1162 showed target engagement in COPD at 500µg with a statistically significant reduction in phosphorylated p38 (p-p38) in sputum cells (p=0.01) and a 10% reduction in sputum neutrophils on D12 compared to baseline (p=0.06). Total sputum cell counts (p=0.02) and macrophages (p=0.04) decreased. At 100µg trends in p-p38 reduction were seen, along with statistically significant changes in MMP12 (p=0.001), IL-13 (p=0.02), MCP1 (p=0.03) and MDA (p=0.04) in sputum supernatant.Conclusions: RV1162 was well tolerated and demonstrated target engagement in COPD.