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

Niklas J. Koehl, Laura J. Henze, Martin Kuentz, René Holm, Brendan T. Griffin*

*Kontaktforfatter for dette arbejde

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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.

Udgave nummer6
Antal sider20
StatusUdgivet - 18. jun. 2020
Udgivet eksterntJa

Bibliografisk note

Funding Information:
Funding: This research was funded by the Horizon 2020 Marie Sklodowska-Curie Innovative Training Networks programme, grant agreement number 674909. Authors N.J. Koehl, L.J. Henze, B.T. Griffin, R. Holm and M. Kuentz are part of the PEARRL European Training network.

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.


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