Supersaturated Lipid-Based Formulations to Enhance the Oral Bioavailability of Venetoclax

• Main Authors: Niklas J. Koehl (Author), Laura J. Henze (Author), Martin Kuentz (Author), René Holm (Author), Brendan T. Griffin (Author)
• Format: Book
• Published: MDPI AG, 2020-06-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/pharmaceutics12060564; 1999-4923
• Keywords: lipid-based formulation; venetoclax; Super-SNEDDS; supersaturation; amorphous solubility; landrace pigs; Pharmacy and materia medica; RS1-441
• Source: Pharmaceutics, Vol 12, Iss 6, p 564 (2020)

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.