Cyclodextrin Reduces Intravenous Toxicity of a Model Compound

Area of Science:

• Pharmacology and Toxicology
• Drug Delivery and Formulation

Background:

• Excipient selection is critical for accurate toxicity assessment of new chemical entities.
• Solubilization methods must not interfere with drug pharmacokinetics or toxicology.
• GDC-0152, a model freebase compound, required formulation for intravenous administration.

Purpose of the Study:

• To evaluate the tolerability of GDC-0152 solubilized by pH adjustment with succinic acid and hydroxypropyl-β-cyclodextrin (HP-β-CD).
• To assess the impact of these excipients on blood compatibility, hemolysis, and in vivo tolerability.
• To determine the pharmacokinetic profile of the solubilized compound.

Main Methods:

• Determined solubility, critical micelle concentration, and association constant with HP-β-CD.
• Assessed in vitro blood compatibility and hemolytic potential.
• Evaluated local tolerability in rats after intravenous and subcutaneous injections.
• Conducted a pharmacokinetic study in rats following intravenous bolus administration.

Main Results:

• GDC-0152 displayed pH-dependent solubility influenced by self-association.
• Succinic acid and HP-β-CD both increased solubility, with succinic acid showing greater enhancement alone.
• HP-β-CD inclusion significantly improved blood compatibility and reduced in vitro hemolytic potential by approximately 20-fold.
• The maximum tolerated dose of GDC-0152 increased to 80 mg/kg when formulated with HP-β-CD.

Conclusions:

• Succinic acid and HP-β-CD are effective solubilizing agents for GDC-0152, enabling intravenous administration.
• HP-β-CD significantly enhances the safety profile by improving blood compatibility and reducing hemolysis.
• The combined formulation strategy supports the use of GDC-0152 in preclinical toxicity studies.