Development of venetoclax with 2-hydroxypropyl-beta-cyclodextrin inclusion complex for improved bioavailability

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery Systems
• Cancer Therapeutics

Background:

• Venetoclax, a BCL-2 inhibitor, faces challenges with poor aqueous solubility, limiting its therapeutic potential.
• Repurposing venetoclax requires strategies to enhance its bioavailability and efficacy.
• Cyclodextrins offer a promising approach for improving the physicochemical and pharmacokinetic properties of drugs.

Purpose of the Study:

• To develop and characterize cyclodextrin-based inclusion complexes of venetoclax.
• To evaluate the enhanced solubility, anticancer activity, and oral bioavailability of the venetoclax-cyclodextrin complex.
• To investigate the potential of venetoclax as a repurposed drug for lung cancer treatment.

Main Methods:

• Venetoclax-cyclodextrin inclusion complexes were prepared using the kneading method.
• In-silico molecular docking was performed to predict drug-excipient interactions.
• In-vitro cytotoxicity assays were conducted on A-549 lung cancer cells.
• In-vivo pharmacokinetic studies were performed in Wistar rats.

Main Results:

• Aqueous solubility of venetoclax increased by 3.16-fold with an entrapment efficiency of 95.44%.
• The venetoclax-HP-β-CD complex showed significantly reduced IC50 values against A-549 cells compared to pure venetoclax.
• Oral bioavailability was enhanced by 4.03 times for the complex compared to the pure drug.

Conclusions:

• Venetoclax-cyclodextrin inclusion complexes effectively improve the aqueous solubility and oral bioavailability of venetoclax.
• The enhanced formulation demonstrates improved in-vitro anticancer activity, supporting its potential as a repurposed lung cancer therapeutic.
• Cyclodextrin complexation is a viable strategy to overcome venetoclax solubility limitations and boost its therapeutic efficacy.