RT Journal Article SR Electronic T1 Translation of inhaled drug optimization strategies into clinical pharmacokinetics and pharmacodynamics using GSK2292767A, a novel inhaled PI3Kδ inhibitor JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP jpet.119.257311 DO 10.1124/jpet.119.257311 A1 Malcolm Begg A1 Chris D Edwards A1 J. Nicole Hamblin A1 Eleni Pifani A1 Robert Wilson A1 Jane Gilbert A1 Giovanni Vitulli A1 David Mallett A1 Josie Morrell A1 Martin I Hingle A1 Sorif Uddin A1 Filzah Ehtesham A1 Miriam Marotti A1 Andrew Harell A1 Carla Newman A1 Disala Fernando A1 Jonathan Clark A1 Anthony Cahn A1 Edith M Hessel YR 2019 UL http://jpet.aspetjournals.org/content/early/2019/04/02/jpet.119.257311.abstract AB This study describes the pharmacokinetic (PK) and pharmacodynamic (PD) profile of GSK2292767A, a novel low solubility inhaled PI3Kδ inhibitor developed as an alternative to nemiralisib, which is a highly soluble inhaled inhibitor of PI3Kδ with a lung profile consistent with once-daily dosing. GSK2292767A has a similar in vitro cellular profile to nemiralisib and reduces eosinophilia in a murine PD model by 63% (n=5, p<0.05). To explore whether a low soluble compound results in effective PI3Kδ inhibition in humans, a first time in human study was conducted with GSK2292767A in healthy volunteers who smoke. GSK2292767A was generally well tolerated with headache being the most common reported adverse event. PD changes in induced sputum were measured in combination with drug concentrations in plasma from single (0.05-2 mg, n=37), and 14-day repeat (2 mg, n=12) doses of GSK2292767A. Trough bronchoalveolar lavage (BAL) for PK was taken after 14 days repeat dosing. GSK2292767A displayed a linear increase in plasma exposure with dose, with marginal accumulation after 14 days. Induced sputum showed a 27% (90% CI 15, 37) reduction in phosphatidylinositol-trisphosphate (PIP3, the product of PI3K activation) 3 h after a single dose. Reduction was not maintained 24 h after single or repeat dosing. BAL analysis confirmed presence of GSK2292767A in lung at 24 h, consistent with the preclinical lung retention profile. Despite good lung retention, target engagement was only present at 3 h. This exposure-response disconnect is an important observation for future inhaled drug design strategies considering low solubility to drive lung retention.