Abstract
This study describes the pharmacokinetic (PK) and pharmaco-dynamic (PD) profile of N-(5-(4-(5-(((2R,6S)-2,6-dimethylmorpholino)methyl)oxazol-2-yl)-1H-indazol-6-yl)-2-methoxypyridin-3-yl)methanesulfonamide (GSK2292767A), a novel low-solubility inhaled phosphoinositide 3-kinase delta (PI3Kδ) inhibitor developed as an alternative to 2-(6-(1H-indol-4-yl)-1H-indazol-4-yl)-5-((4-isopropylpiperazin-1-yl)methyl)oxazole (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 of repeat dosing. GSK2292767A displayed a linear increase in plasma exposure with dose, with marginal accumulation after 14 days. Induced sputum showed a 27% (90% confidence interval 15%, 37%) reduction in phosphatidylinositol-trisphosphate (the product of phosphoinositide 3-kinase activation) 3 hours after a single dose. Reduction was not maintained 24 hours after single or repeat dosing. BAL analysis confirmed the presence of GSK2292767A in lung at 24 hours, consistent with the preclinical lung retention profile. Despite good lung retention, target engagement was only present at 3 hours. This exposure-response disconnect is an important observation for future inhaled drug design strategies considering low solubility to drive lung retention.
Highlights
Inhaled drug treatments for respiratory disorders have the advantage of being delivered directly to the target organ, resulting in quick onset of action and low systemic exposure, limiting potential unwanted effects in other organs (Lipworth, 1996; Lötvall, 1997; Glossop et al, 2010; Perry et al, 2017; Strong et al, 2018)
Lung retention strategies often rely on slow-release reservoirs, ABBREVIATIONS: AE, adverse event; AUC, area under the plasma concentration-time curve; BAL, bronchoalveolar lavage; CI, confidence interval; ELF, epithelial lining fluid; GSK2292767A, N-(5-(4-(5-(((2R,6S)-2,6-dimethylmorpholino)methyl)oxazol-2-yl)-1H-indazol-6-yl)-2-methoxypyridin-3-yl) methanesulfonamide; HDM, house dust mite; LC-MS/MS, liquid chromatography–tandem mass spectrometry; 2-(6-(1H-indol-4-yl)-1H-indazol-4yl)-5-((4-isopropylpiperazin-1-yl)methyl)oxazole; PD, pharmacodynamic; PIP2, phosphatidylinositol-biphosphate; PIP3, phosphatidylinositoltrisphosphate; PI3Kd, phosphoinositide 3-kinase delta; PK, pharmacokinetic; tmax, time to maximum observed plasma concentration
We have recently described the pharmacokinetic (PK) and pharmacodynamic (PD) profile of 2-(6-(1H-indol-4-yl)-1H-indazol-4-yl)-5-((4-isopropylpiperazin-1-yl)methyl)oxazole, an inhaled inhibitor of phosphoinositide 3-kinase delta (PI3Kd), which was designed as a basic, soluble molecule with moderate lipophilicity
Summary
Inhaled drug treatments for respiratory disorders have the advantage of being delivered directly to the target organ, resulting in quick onset of action and low systemic exposure, limiting potential unwanted effects in other organs (Lipworth, 1996; Lötvall, 1997; Glossop et al, 2010; Perry et al, 2017; Strong et al, 2018). Facilitating drug delivery to its biologic target. This can be achieved either by lung tissue binding or intracellular uptake with highly soluble molecules, or alternatively by slow in situ dissolution with poorly soluble molecules. We have recently described the pharmacokinetic (PK) and pharmacodynamic (PD) profile of 2-(6-(1H-indol-4-yl)-1H-indazol-4-yl)-5-((4-isopropylpiperazin-1-yl)methyl)oxazole (nemiralisib), an inhaled inhibitor of phosphoinositide 3-kinase delta (PI3Kd), which was designed as a basic, soluble molecule with moderate lipophilicity. This physicochemical profile resulted in a oncedaily dose regimen (Begg et al, 2019). Nemiralisib is currently being developed for respiratory diseases as an immune modulator with anti-inflammatory properties (Stark et al, 2015; Cahn et al, 2017; Khindri et al, 2018)
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