RT Journal Article
SR Electronic
T1 Safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single (SD) and repeat (RD) inhaled doses of a novel phosphoinositide 3-kinase δ inhibitor (PI3Kδ), GSK2269557, administered to healthy smokers
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 3411
VO 44
IS Suppl 58
A1 Robert Wilson
A1 Anthony Cahn
A1 Mickael Montembault
A1 Joanne Green
A1 Naila Musani
A1 Malcolm Begg
A1 Amanda Deans
A1 Jane Gilbert
A1 Sheelan Ahmed
A1 Anna Kielkowska
A1 Jonathan Clark
A1 Malcolm Boyce
A1 Edith M. Hessel
A1 Pietro Ventresca
YR 2014
UL http://erj.ersjournals.com/content/44/Suppl_58/3411.abstract
AB Introduction: GSK2269557 was investigated as a dry powder formulation in a double blind, placebo controlled study in healthy cigarette smokers. Safety, tolerability, PK and PD data were collected following SD (100, 500, 2000 and 3000 µg) and RD (2000 µg for 14 days). Plasma and lung PK (from bronchoalveolar lavage) and PD (PIP3 proportion [using PIP2] from induced sputum) were measured. Lung PK was the drug concentration in the cellular fraction (CF) and epithelial lining fluid (ELF). PD was measured to demonstrate target engagement.Results: Adverse Events (AE's) were few, of mild to moderate intensity and not different from placebo. SD plasma Cmax (Tmax approx 5 min) dropped rapidly (< 6 hours) followed by a slower elimination (T1/2 was approx 20h). Cmax and AUC(0-t) were 0.04 to 2.6 ng/mL and 0.14 to 33 ng.h/mL for 100 to 3000 µg respectively. RD showed accumulation in plasma with increased peak (3-fold) and trough (4.5-fold) levels. Lung ELF and CF concentrations at 24h post day 14 dose were 55 ng/mL (ELF:plasma ratio 32:1) and 366 ng/mL (CF:plasma ratio 214:1) respectively. PIP3 proportion levels in sputum were reduced by 6.7%, 8.4% and 18.7% at 3hrs post dose, day 1 for 100, 500 and 2000µg respectively, and by 35.7% at 3 hours post dose, day 12 for 2000µg.Conclusions: GSK2269557 was well tolerated with a low incidence of AE's which was not different from placebo. Plasma PK was well defined with lung data confirming higher levels of drug compared to plasma. Target engagement was confirmed by sputum PIP3 data.