Translation of Inhaled Drug Optimization Strategies into Clinical Pharmacokinetics and Pharmacodynamics Using GSK2292767A, a Novel Inhaled Phosphoinositide 3-Kinase δ Inhibitor
| Autor: | Malcolm Begg, Eleni Pefani, Jonathan Clark, Carla F. Newman, Miriam Marotti, Martin I. Hingle, Disala Fernando, David N. Mallett, Anthony Cahn, Sorif Uddin, Filzah Ehtesham, Josie Morrell, Robert Wilson, Giovanni Vitulli, J. Nicole Hamblin, Jane Gilbert, Chris D. Edwards, Edith M. Hessel, Andrew W Harrell |
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| Rok vydání: | 2019 |
| Předmět: |
Adult
Male 0301 basic medicine Drug Indazoles media_common.quotation_subject Pharmacology Bronchoalveolar Lavage Permeability Translational Research Biomedical Mice 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Administration Inhalation Eosinophilia medicine Animals Humans Dosing Adverse effect Lung Phosphoinositide-3 Kinase Inhibitors media_common Sulfonamides medicine.diagnostic_test Inhalation business.industry Sputum Middle Aged 030104 developmental biology Bronchoalveolar lavage medicine.anatomical_structure Solubility Molecular Medicine Female Safety medicine.symptom business 030217 neurology & neurosurgery |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 369:443-453 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.119.257311 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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