Preclinical formulation for the pharmacokinetics and efficacy of GBO-006, a selective polo like kinase 2 PLK2 inhibitor for the treatment of triple negative breast cancerReport as inadecuate




Preclinical formulation for the pharmacokinetics and efficacy of GBO-006, a selective polo like kinase 2 PLK2 inhibitor for the treatment of triple negative breast cancer - Download this document for free, or read online. Document in PDF available to download.

ADMET and DMPK, Vol.4 No.4 December 2016. -

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.

GBO-006; PLK2 inhibitor; Pharmacokinetics; Efficacy; Triple negative breast cancer



Author: Srinivas Maddi - orcid.org-0000-0002-7280-4900 ; GVK Biosciences PVT LTD., Nacharam, Hyderabad 500076, India Ravi Akkireddy - ; G

Source: http://hrcak.srce.hr/



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