The Role of Lymphatic Transport on the Systemic Bioavailability of the Bcl-2 Protein Family Inhibitors Navitoclax (ABT-263) and ABT-199

◢ Drug Metab Dispos. 2014 Feb;42(2):207-12. doi: 10.1124/dmd.113.055053. Epub 2013 Nov 8.

Edna F Choo ¹, Jason Boggs, Chunqiang Zhu, Joseph W Lubach, Nathaniel D Catron, Gary Jenkins, Andrew J Souers, Richard Voorman

¹Departments of Drug Metabolism and Pharmacokinetics (E.F.C., J.B.) and Pharmaceutics (J.W.L.), Genentech Inc, South San Francisco, California; Department of Drug Metabolism and Pharmacokinetics, WuXi AppTec (Suzhou) Co., Ltd, Suzhou, Jiangsu Province ,China (C.Z.); Departments of Physical Chemistry (N.D.C.), Drug Metabolism (G.J., R.V.) and Cancer Research (A.J.S.), AbbVie, North Chicago, Illinois.

Abstract

Navitoclax (ABT-263), a Bcl-2 family inhibitor and ABT-199, a Bcl-2 selective inhibitor, are high molecular weight, high logP molecules that show low solubility in aqueous media. While these properties are associated with low oral bioavailability (F), both navitoclax and ABT-199 showed moderate F in preclinical species. The objective of the described study was to determine if lymphatic transport contributes to the systemic availability of navitoclax and ABT-199 in dogs. The intravenous pharmacokinetics of navitoclax and ABT-199 were determined in intact (noncannulated) dogs. In oral studies, tablets (100 mg) of navitoclax and ABT-199 were administered to both intact and thoracic lymph duct-cannulated (TDC) dogs. The clearance of navitoclax and ABT-199 was low; 0.673 and 0.779 ml/min per kilogram, respectively. The volume of distribution of both compounds was low (0.5-0.7 l/kg). The half-lives of navitoclax and ABT-199 were 22.2 and 12.9 hours, respectively. The F of navitoclax and ABT-199 were 56.5 and 38.8%, respectively, in fed intact dogs. In fed TDC dogs, 13.5 and 4.67% of the total navitoclax and ABT-199 doses were observed in lymph with the % F of navitoclax and ABT-199 of 21.7 and 20.2%, respectively. The lower lymphatic transport of ABT-199 corresponds to the lower overall % F of ABT-199 versus navitoclax despite similar systemic availability via the portal vein (similar % F in TDC animals). This is consistent with the higher long chain triglyceride solubility of navitoclax (9.2 mg/ml) versus ABT-199 (2.2 mg/ml). In fasted TDC animals, lymph transport of navitoclax and ABT-199 decreased by 1.8-fold and 10-fold, respectively.