Lipophilic Salts and Lipid-Based Formulations for Bridging the Food Effect Gap of Venetoclax

Niklas J. Koehl, Laura J. Henze, René Holm, Martin Kuentz, John J. Keating, Thomas De Vijlder, Andreas Marx, Brendan T. Griffin*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Lipid based formulations (LBF) have shown to overcome food dependent bioavailability for some poorly water-soluble drugs. However, the utility of LBFs can be limited by low dose loading due to a low drug solubility in LBF vehicles. This study investigated the solubility and drug loading increases in LBFs using lipophilic counterions to form lipophilic salts of venetoclax. Venetoclax docusate was formed from venetoclax free base and verified by 1H NMR. Formation of stable venetoclax-fatty acid associations with either oleic acid or decanoic acid were attempted, however, the molecular associations were less consistent based on 1H NMR. Venetoclax docusate displayed a up to 6.2-fold higher solubility in self-emulsifying drug delivery systems (SEDDS) when compared to the venetoclax free base solubility resulting in a higher dose loading. A subsequent bioavailability study in landrace pigs demonstrated a 2.5-fold higher bioavailability for the lipophilic salt containing long chain SEDDS compared to the commercially available solid dispersion Venclyxto® in the fasted state. The bioavailability of all lipophilic salt SEDDS in the fasted state was similar to Venclyxto® in the fed state. This study confirmed that lipophilic drug salts increase the dose loading in LBFs and showed that lipophilic salt-SEDDS combinations may be able to overcome bioavailability limitations of drugs with low inherent dose loading in lipid vehicles. Furthermore, the present study demonstrated the utility of a LBF approach, in combination with lipophilic salts, to overcome food dependent variable oral bioavailability of drugs.

Original languageEnglish
JournalJournal of Pharmaceutical Sciences
Volume111
Issue number1
Pages (from-to)164-174
ISSN0022-3549
DOIs
Publication statusPublished - Jan 2022

Bibliographical note

Publisher Copyright:
© 2021 American Pharmacists Association

Keywords

  • Lipid based formulations
  • Lipophilic salts
  • Salt formation, Co-crystals
  • Venetoclax

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