Article ; Online: A randomised, placebo-controlled study of omipalisib (PI3K/mTOR) in idiopathic pulmonary fibrosis.
The European respiratory journal
2019 Volume 53, Issue 3
Abstract: Phosphatidylinositol 3-kinases (PI3Ks) and mammalian target of rapamycin (mTOR) play a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Omipalisib (GSK2126458) is a potent inhibitor of PI3K/mTOR.A randomised, placebo-controlled, double- ... ...
| Abstract | Phosphatidylinositol 3-kinases (PI3Ks) and mammalian target of rapamycin (mTOR) play a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Omipalisib (GSK2126458) is a potent inhibitor of PI3K/mTOR.A randomised, placebo-controlled, double-blind, repeat dose escalation, experimental medicine study of omipalisib in subjects with IPF was conducted (NCT01725139) to test safety, tolerability, pharmacokinetics and pharmacodynamics. Omipalisib was dosed at 0.25 mg, 1 mg and 2 mg twice daily for 8 days in four cohorts of four subjects randomised 3:1 to receive omipalisib or placebo (two cohorts received 2 mg twice daily).17 subjects with IPF were enrolled. The most common adverse event was diarrhoea, which was reported by four participants. Dose-related increases in insulin and glucose were observed. Pharmacokinetic analysis demonstrated that exposure in the blood predicts lung exposure. Exposure-dependent inhibition of phosphatidylinositol 3,4,5 trisphosphate and pAKT confirmed target engagement in blood and lungs. |
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| MeSH term(s) | Administration, Oral ; Aged ; Dose-Response Relationship, Drug ; Double-Blind Method ; Female ; Fluorodeoxyglucose F18 ; Humans ; Idiopathic Pulmonary Fibrosis/diagnostic imaging ; Idiopathic Pulmonary Fibrosis/drug therapy ; Lung/diagnostic imaging ; Lung/pathology ; Male ; Middle Aged ; Phosphatidylinositol 3-Kinases/metabolism ; Positron Emission Tomography Computed Tomography ; Pyridazines ; Quinolines/administration & dosage ; Sulfonamides/administration & dosage ; TOR Serine-Threonine Kinases/metabolism ; Treatment Outcome | ||||||||||
| Chemical Substances | Pyridazines ; Quinolines ; Sulfonamides ; Fluorodeoxyglucose F18 (0Z5B2CJX4D) ; omipalisib (1X8F5A3NA0) ; MTOR protein, human (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.11.1) | ||||||||||
| Language | English | ||||||||||
| Publishing date | 2019-03-18 | ||||||||||
| Publishing country | England | ||||||||||
| Document type | Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't | ||||||||||
| ZDB-ID | 639359-7 | ||||||||||
| ISSN | 1399-3003 ; 0903-1936 | ||||||||||
| ISSN (online) | 1399-3003 | ||||||||||
| ISSN | 0903-1936 | ||||||||||
| DOI | 10.1183/13993003.01992-2018 | ||||||||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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