Abstract The Bcl-2 inhibitor, Venetoclax, is a notable example of a therapeutic emerging from modern drug development pipelines with structural and physiochemical properties sitting beyond Lipinski’s “Rule of 5”. The classification of VTX as a biopharmaceutical classification system (BCS) Class IV compound aligns with its observed low solubility and permeability in the gastrointestinal tract. Its inherent “brick-dust” properties further limit solubility in lipid delivery vehicles, collectively constraining its maximum potential for oral absorption. With a low fasted oral bioavailability (< 5%) and a fivefold positive food effect, a clinical dose of 600 mg is required daily and is prescribed to patients with a meal to ensure therapeutic efficacy. The impact of critical formulation design parameters on the performance of previously reported formulation strategies such as amorphous solid dispersions, nanocrystals and lipid-based systems will be examined. Mechanistic insight into how bio-enabling strategies improve oral absorption of VTX is provided, including enhanced solubility in lipid vehicles, improved solubilisation upon dispersion, mitigation of the gastrointestinal pH gradient, reduced particle size, amorphous state enhanced-solubility and reduced metabolism. Potential alternative formulation strategies such as inorganic vehicles or advanced lipid-based systems are reviewed, with their capability to enhance VTX’s bioavailability whilst reducing the high clinical dose and dependence on food for optimal absorption. Key silica and polymer selection is necessary for loading VTX mesoporous silica nanoparticles and polymeric nanoparticles. Novel formulation avenues, including solidified self-emulsifying systems, supersaturated self-emulsifying systems, solid-lipid nanoparticles, and nanostructured lipid-carriers, are also explored. Systematic in vitro and in vivo investigations of these formulations can provide essential in vitro-in-vivo correlation insights. Integration of lipid formulation-specific parameters into a physiologically based pharmacokinetics model can facilitate improved clinical translation of lipid-based VTX formulations. Article highlights <UnorderedList Mark="Bullet"> <ItemContent> Venetoclax can benefit from reformulation using novel bio-enabling strategies for enhanced oral absorption </ItemContent> <ItemContent> Rational formulation design can beneficially affect the performance of bio-enabling systems </ItemContent> <ItemContent> Use of advanced lipid-based formulations and/or inorganic vehicles, can enhance pharmacokinetics and reduce limitations of the current clinical use of venetoclax </ItemContent> <ItemContent> Combining advanced formulation science and modelling is key for clinical success of venetoclax-based lipid formulations </ItemContent> </UnorderedList> Graphical Abstract

Overcoming the oral delivery challenges of venetoclax: advancing a clinically improved Bcl-2 inhibitor

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2026年3月10日

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Yukta Hegishte,
Paul Joyce,
Clive Prestidge,
Kristen Bremmell

摘要

Abstract

The Bcl-2 inhibitor, Venetoclax, is a notable example of a therapeutic emerging from modern drug development pipelines with structural and physiochemical properties sitting beyond Lipinski’s “Rule of 5”. The classification of VTX as a biopharmaceutical classification system (BCS) Class IV compound aligns with its observed low solubility and permeability in the gastrointestinal tract. Its inherent “brick-dust” properties further limit solubility in lipid delivery vehicles, collectively constraining its maximum potential for oral absorption. With a low fasted oral bioavailability (< 5%) and a fivefold positive food effect, a clinical dose of 600 mg is required daily and is prescribed to patients with a meal to ensure therapeutic efficacy. The impact of critical formulation design parameters on the performance of previously reported formulation strategies such as amorphous solid dispersions, nanocrystals and lipid-based systems will be examined. Mechanistic insight into how bio-enabling strategies improve oral absorption of VTX is provided, including enhanced solubility in lipid vehicles, improved solubilisation upon dispersion, mitigation of the gastrointestinal pH gradient, reduced particle size, amorphous state enhanced-solubility and reduced metabolism. Potential alternative formulation strategies such as inorganic vehicles or advanced lipid-based systems are reviewed, with their capability to enhance VTX’s bioavailability whilst reducing the high clinical dose and dependence on food for optimal absorption. Key silica and polymer selection is necessary for loading VTX mesoporous silica nanoparticles and polymeric nanoparticles. Novel formulation avenues, including solidified self-emulsifying systems, supersaturated self-emulsifying systems, solid-lipid nanoparticles, and nanostructured lipid-carriers, are also explored. Systematic in vitro and in vivo investigations of these formulations can provide essential in vitro-in-vivo correlation insights. Integration of lipid formulation-specific parameters into a physiologically based pharmacokinetics model can facilitate improved clinical translation of lipid-based VTX formulations.

Article highlights

Venetoclax can benefit from reformulation using novel bio-enabling strategies for enhanced oral absorption

Rational formulation design can beneficially affect the performance of bio-enabling systems

Use of advanced lipid-based formulations and/or inorganic vehicles, can enhance pharmacokinetics and reduce limitations of the current clinical use of venetoclax

Combining advanced formulation science and modelling is key for clinical success of venetoclax-based lipid formulations

Graphical Abstract