Characterization of Antineovascularization Activity and Ocular Pharmacokinetics of Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Inhibitor GNE-947
| Autor: | Jenninfer LeCouter, Xingrong Liu, Cristine Quiason, Jacob Z. Chen, Joe Lubach, Jay Cheng, Eric Solon, Timothy P. Heffron, Thomas H. Lee, Jim Nonomiya, Matthew Wright, Xiaorong Liang, Savita Ubhayakar, Cornelis E. C. A. Hop, Sheerin K. Shahidi-Latham |
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| Rok vydání: | 2019 |
| Předmět: |
Male
genetic structures Pharmaceutical Science Angiogenesis Inhibitors Pharmacology 030226 pharmacology & pharmacy Models Biological Umbilical vein Neovascularization 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Pharmacokinetics In vivo medicine Human Umbilical Vein Endothelial Cells Distribution (pharmacology) Animals Humans Tissue Distribution PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors Phosphoinositide 3-kinase biology TOR Serine-Threonine Kinases Retinal eye diseases Choroidal Neovascularization Rats Disease Models Animal chemistry Solubility 030220 oncology & carcinogenesis Injections Intravenous Intravitreal Injections biology.protein sense organs Rabbits medicine.symptom Ophthalmic Solutions Half-Life |
| Zdroj: | Drug metabolism and disposition: the biological fate of chemicals. 48(5) |
| ISSN: | 1521-009X |
| Popis: | The objectives of the present study were to characterize GNE-947 for its phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitory activities, in vitro anti-cell migration activity in Human Umbilical Vein Endothelial Cells (HUVEC), in vivo anti-neovascularization activity in laser induced rat choroidal neovascular (CNV) eyes, pharmacokinetics in rabbit plasma and eyes, and ocular distribution using Matrix-Assisted Laser Desorption Ionization Imaging mass spectrometry (MALDI-IMS) and autoradioluminography. Its PI3K and mTOR Ki were 0.0005 µM and 0.045 µM, respectively, and its HUVEC IC50 was 0.093µM. GNE-947 prevented neovascularization in the rat CNV model at 50 or 100 µg/eye with repeat dosing. Following a single intravenous injection at 2.5 and 500 μg/kg in rabbits, its plasma terminal half-lives (t1/2) were 9.11 and 9.59 hours, respectively. Following a single intravitreal injection of a solution at 2.5 μg/eye in rabbits, its apparent t1/2 values were 14.4, 16.3, and 23.2 hours in the plasma, vitreous humor, and aqueous humor, respectively. Following a single intravitreal injection of a suspension at 33.5, 100, 200 μg/eye in rabbits, the t1/2 were 29, 74, and 219 days in the plasma; and 46, 143, and 191 days in the eyes, respectively. MALDI-IMS and autoradioluminography images show that GNE-947 did not homogenously distribute in the vitreous humor and aggregated at the injection sites following injection of the suspension, which was responsible for the long t1/2 of the suspension due to slow dissolution process. This hypothesis was supported by pharmacokinetic modeling analyses. In conclusion, PI3K/mTOR inhibitor GNE-947 prevented neovascularization in a rat CNV model with t1/2 up to approximately six months following a single intravitreal injection of the suspension in rabbit eyes. SIGNIFICANCE STATEMENT GNE-947 is a potent PI3K/mTOR inhibitor and exhibits anti-CNV activity in rat eyes. The duration of GNE-947 in the rabbit eyes following intravitreal injection in a solution is short with t1/2 less than a day. However, the duration following intravitreal dose of a suspension is very long with t1/2 up to six months due to its low solubility and slow dissolution process. These results indicate that intravitreal injection of a suspension formulation for low solubility drugs can be used to achieve long-term drug exposure potentially useful for the treatment of wet AMD and other retinal diseases. |
| Databáze: | OpenAIRE |
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