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J Pharmacol Exp Ther. 2019 Apr 2. pii: jpet.119.257311. doi: 10.1124/jpet.119.257311. [Epub ahead of print]

Translation of inhaled drug optimization strategies into clinical pharmacokinetics and pharmacodynamics using GSK2292767A, a novel inhaled PI3Kδ inhibitor.

Author information

1
GlaxoSmithKline.
2
GlaxoSmithKline (at the time of the study).
3
Clinical Unit Cambridge, Addenbrookes Hospital, Cambridge.
4
miriam.c.marotti@gsk.com.
5
Babraham Institute, Cambridge.
6
GSK edith.m.hessel@gsk.com.

Abstract

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.

KEYWORDS:

drug design; inhaled drugs; pharmacodynamics; pharmacokinetics; phosphatidylinositol-3,4,5-trisphosphate; phosphoinositides; respiratory pharmacology

PMID:
30940692
DOI:
10.1124/jpet.119.257311
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