Supersaturated lipid-based formulations to enhance the oral bioavailability of venetoclax

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Koehl, Niklas J.
Henze, Laura J.
Kuentz, Martin
Holm, René
Griffin, Brendan T.
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Increasing numbers of beyond Rule-of-Five drugs are emerging from discovery pipelines, generating a need for bio-enabling formulation approaches, such as lipid-based formulations (LBF), to ensure maximal in vivo exposure. However, many drug candidates display insufficient lipid solubility, leading to dose-loading limitations in LBFs. The aim of this study was to explore the potential of supersaturated LBFs (sLBF) for the beyond Rule-of-Five drug venetoclax. Temperature-induced sLBFs of venetoclax were obtained in olive oil, Captex® 1000, Peceol® and Capmul MCM®, respectively. A Peceol®-based sLBF displayed the highest drug loading and was therefore evaluated further. In vitro lipolysis demonstrated that the Peceol®-based sLBF was able to generate higher venetoclax concentrations in the aqueous phase compared to a Peceol®-based suspension and an aqueous suspension. A subsequent bioavailability study in pigs demonstrated for sLBF a 3.8-fold and 2.1-fold higher bioavailability compared to the drug powder and Peceol®-based suspension, respectively. In conclusion, sLBF is a promising bio-enabling formulation approach to enhance in vivo exposure of beyond Rule-of-Five drugs, such as venetoclax. The in vitro lipolysis results correctly predicted a higher exposure of the sLBF in vivo. The findings of this study are of particular relevance to pre-clinical drug development, where maximum exposure is required.
Amorphous solubility , Landrace pigs , Lipid suspensions , Lipid-based formulation , SEDDS , Self-emulsifying drug delivery system Super-SNEDDS , Supersaturated lipid-based formulations , Supersaturation , Venetoclax
Koehl, N. J., Henze, L. J., Kuentz, M., Holm, R. and Griffin, B. T. (2020) 'Supersaturated lipid-based formulations to enhance the oral bioavailability of venetoclax', Pharmaceutics, 12(6), 564 (20pp). doi: 10.3390/pharmaceutics12060564