ADMET & DMPK

Yazarlar: Srinivas Maddi, Ravi Akkireddy, Srinivas Lenkalapelly, Pratima Srivastava, Joshodeep Boruwa, Chandra Deb, Arnab Roy Chowdhury, Duraiswamy A. Jeyaraj, Ramana Reddy, Premkumar Reddy, Manoj Maniar, Sachin Bansal, Jang B. Gupta

Konular:-

DOI:10.5599/admet.4.4.341

Anahtar Kelimeler:GBO-006,PLK2 inhibitor,Pharmacokinetics,Efficacy,Triple negative breast cancer

Özet: GBO-006 was shown to be a highly specific and selective PLK2 inhibitor that promoted mitotic arrest in various cancer cell lines, subsequently resulting in their apoptotic death. Intraperitoneal alternate day dosing of GBO-006 using 100 % DMSO as formulation showed significant tumor regression in xenograft models, demonstrating proof of concept of PLK2 inhibition in vivo. These studies necessitated the development of a suitable and GRAS (generally considered as safe) preformulation for pharmacokinetic and efficacy studies. GBO-006 possesses challenging physicochemical and biopharmaceutical properties like poor solubility in aqueous media, low permeability and a crystalline nature. Different methods like cosolvency, complexation and micellar solubilization were employed to improve the solubility of GBO-006. A strategy of co-solvency is used to solubilize the GBO-006 up to 10 mg/mL. A formulation with 20 % DMSO, 40 % PEG 400, 30 % of 100 mM citrate buffer (pH 3.0) and 10 % solutol displayed clear solution without any visual precipitation of the drug even after 2 weeks of storage. GBO-006 showed moderate clearance in rat and high systemic clearance in mouse and dog. It showed poor oral bioavailability across all species. Intraperitoneal dosing of GBO-006 demonstrated the linear exposure. GBO-006 showed significant inhibition of tumor progression.

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