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Characterization of Antineovascularization Activity and Ocular Pharmacokinetics of Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Inhibitor GNE-947.
Liu, Xingrong; Liang, Xiaorong; LeCouter, Jenninfer; Ubhayakar, Savita; Chen, Jacob; Cheng, Jay; Lee, Tom; Lubach, Joe; Nonomiya, Jim; Shahidi-Latham, Sheerin; Quiason, Cristine; Solon, Eric; Wright, Matthew; Hop, Cornelis E C A; Heffron, Timothy P.
Afiliação
  • Liu X; Genentech, Inc., South San Francisco, California (X.Liu., X.Lia., J.L., S.U., J.Chen, J.Cheng, T.L., J.L., J.N., S.S.-L., C.Q., E.S., M.W., C.E.C.A.H., T.P.H.) and QPS, Delaware Technology Park, Newark, Delaware (E.S.).
  • Liang X; Genentech, Inc., South San Francisco, California (X.Liu., X.Lia., J.L., S.U., J.Chen, J.Cheng, T.L., J.L., J.N., S.S.-L., C.Q., E.S., M.W., C.E.C.A.H., T.P.H.) and QPS, Delaware Technology Park, Newark, Delaware (E.S.).
  • LeCouter J; Genentech, Inc., South San Francisco, California (X.Liu., X.Lia., J.L., S.U., J.Chen, J.Cheng, T.L., J.L., J.N., S.S.-L., C.Q., E.S., M.W., C.E.C.A.H., T.P.H.) and QPS, Delaware Technology Park, Newark, Delaware (E.S.).
  • Ubhayakar S; Genentech, Inc., South San Francisco, California (X.Liu., X.Lia., J.L., S.U., J.Chen, J.Cheng, T.L., J.L., J.N., S.S.-L., C.Q., E.S., M.W., C.E.C.A.H., T.P.H.) and QPS, Delaware Technology Park, Newark, Delaware (E.S.).
  • Chen J; Genentech, Inc., South San Francisco, California (X.Liu., X.Lia., J.L., S.U., J.Chen, J.Cheng, T.L., J.L., J.N., S.S.-L., C.Q., E.S., M.W., C.E.C.A.H., T.P.H.) and QPS, Delaware Technology Park, Newark, Delaware (E.S.).
  • Cheng J; Genentech, Inc., South San Francisco, California (X.Liu., X.Lia., J.L., S.U., J.Chen, J.Cheng, T.L., J.L., J.N., S.S.-L., C.Q., E.S., M.W., C.E.C.A.H., T.P.H.) and QPS, Delaware Technology Park, Newark, Delaware (E.S.).
  • Lee T; Genentech, Inc., South San Francisco, California (X.Liu., X.Lia., J.L., S.U., J.Chen, J.Cheng, T.L., J.L., J.N., S.S.-L., C.Q., E.S., M.W., C.E.C.A.H., T.P.H.) and QPS, Delaware Technology Park, Newark, Delaware (E.S.).
  • Lubach J; Genentech, Inc., South San Francisco, California (X.Liu., X.Lia., J.L., S.U., J.Chen, J.Cheng, T.L., J.L., J.N., S.S.-L., C.Q., E.S., M.W., C.E.C.A.H., T.P.H.) and QPS, Delaware Technology Park, Newark, Delaware (E.S.).
  • Nonomiya J; Genentech, Inc., South San Francisco, California (X.Liu., X.Lia., J.L., S.U., J.Chen, J.Cheng, T.L., J.L., J.N., S.S.-L., C.Q., E.S., M.W., C.E.C.A.H., T.P.H.) and QPS, Delaware Technology Park, Newark, Delaware (E.S.).
  • Shahidi-Latham S; Genentech, Inc., South San Francisco, California (X.Liu., X.Lia., J.L., S.U., J.Chen, J.Cheng, T.L., J.L., J.N., S.S.-L., C.Q., E.S., M.W., C.E.C.A.H., T.P.H.) and QPS, Delaware Technology Park, Newark, Delaware (E.S.).
  • Quiason C; Genentech, Inc., South San Francisco, California (X.Liu., X.Lia., J.L., S.U., J.Chen, J.Cheng, T.L., J.L., J.N., S.S.-L., C.Q., E.S., M.W., C.E.C.A.H., T.P.H.) and QPS, Delaware Technology Park, Newark, Delaware (E.S.).
  • Solon E; Genentech, Inc., South San Francisco, California (X.Liu., X.Lia., J.L., S.U., J.Chen, J.Cheng, T.L., J.L., J.N., S.S.-L., C.Q., E.S., M.W., C.E.C.A.H., T.P.H.) and QPS, Delaware Technology Park, Newark, Delaware (E.S.).
  • Wright M; Genentech, Inc., South San Francisco, California (X.Liu., X.Lia., J.L., S.U., J.Chen, J.Cheng, T.L., J.L., J.N., S.S.-L., C.Q., E.S., M.W., C.E.C.A.H., T.P.H.) and QPS, Delaware Technology Park, Newark, Delaware (E.S.).
  • Hop CECA; Genentech, Inc., South San Francisco, California (X.Liu., X.Lia., J.L., S.U., J.Chen, J.Cheng, T.L., J.L., J.N., S.S.-L., C.Q., E.S., M.W., C.E.C.A.H., T.P.H.) and QPS, Delaware Technology Park, Newark, Delaware (E.S.).
  • Heffron TP; Genentech, Inc., South San Francisco, California (X.Liu., X.Lia., J.L., S.U., J.Chen, J.Cheng, T.L., J.L., J.N., S.S.-L., C.Q., E.S., M.W., C.E.C.A.H., T.P.H.) and QPS, Delaware Technology Park, Newark, Delaware (E.S.) heffron.timothy@gene.com.
Drug Metab Dispos ; 48(5): 408-419, 2020 05.
Article em En | MEDLINE | ID: mdl-32132091
ABSTRACT
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 (HUVECs), in vivo antineovascularization 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 K i were 0.0005 and 0.045 µM, respectively, and its HUVEC IC50 was 0.093 µM. GNE-947 prevented neovascularization in the rat CNV model at 50 or 100 µg per eye with repeat dosing. After a single intravenous injection at 2.5 and 500 µg/kg in rabbits, its plasma terminal half-lives (t 1/2) were 9.11 and 9.59 hours, respectively. After a single intravitreal injection of a solution at 2.5 µg per eye in rabbits, its apparent t 1/2 values were 14.4, 16.3, and 23.2 hours in the plasma, vitreous humor, and aqueous humor, respectively. After a single intravitreal injection of a suspension at 33.5, 100, 200 µg per eye in rabbits, the t 1/2 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 after injection of the suspension, which was responsible for the long t 1/2 of the suspension because of the slow dissolution process. This hypothesis was supported by pharmacokinetic modeling analyses. In conclusion, the PI3K/mTOR inhibitor GNE-947 prevented neovascularization in a rat CNV model, with t 1/2 up to approximately 6 months after a single intravitreal injection of the suspension in rabbit eyes. SIGNIFICANCE STATEMENT GNE-947 is a potent phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor and exhibits anti-choroidal neovascular activity in rat eyes. The duration of GNE-947 in the rabbit eyes after intravitreal injection in a solution is short, with a half-life (t 1/2) of less than a day. However, the duration after intravitreal dose of a suspension is long, with t 1/2 up to 6 months due to low solubility and slow dissolution. These results indicate that intravitreal injection of a suspension for low-solubility drugs can be used to achieve long-term drug exposure.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neovascularização de Coroide / Inibidores da Angiogênese / Serina-Treonina Quinases TOR / Inibidores de Fosfoinositídeo-3 Quinase Tipo de estudo: Etiology_studies / Prognostic_studies Limite: Animals / Humans / Male Idioma: En Revista: Drug Metab Dispos Assunto da revista: FARMACOLOGIA Ano de publicação: 2020 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neovascularização de Coroide / Inibidores da Angiogênese / Serina-Treonina Quinases TOR / Inibidores de Fosfoinositídeo-3 Quinase Tipo de estudo: Etiology_studies / Prognostic_studies Limite: Animals / Humans / Male Idioma: En Revista: Drug Metab Dispos Assunto da revista: FARMACOLOGIA Ano de publicação: 2020 Tipo de documento: Article