Cyclodextrin Reduces Intravenous Toxicity of a Model Compound

J Pharm Sci. 2019 Jun;108(6):1934-1943. doi: 10.1016/j.xphs.2019.01.004. Epub 2019 Jan 11.

Abstract

Solubilization of new chemical entities for toxicity assessment must use excipients that do not negatively impact drug pharmacokinetics and toxicology. In this study, we investigated the tolerability of a model freebase compound, GDC-0152, solubilized by pH adjustment with succinic acid and complexation with hydroxypropyl-β-cyclodextrin (HP-β-CD) to enable intravenous use. Solubility, critical micelle concentration, and association constant with HP-β-CD were determined. Blood compatibility and potential for hemolysis were assessed in vitro. Local tolerability was assessed after intravenous and subcutaneous injections in rats. A pharmacokinetic study was conducted in rats after intravenous bolus administration. GDC-0152 exhibited pH-dependent solubility that was influenced by self-association. The presence of succinic acid increased solubility in a concentration-dependent manner. HP-β-CD alone also increased solubility, but the extent of solubility enhancement was significantly lower than succinic acid alone. Inclusion of HP-β-CD in the solution of GDC-0152 improved blood compatibility, reduced hemolytic potential by ∼20-fold in vitro, and increased the maximum tolerated dose to 80 mg/kg.

Keywords: complexation; cyclodextrin; hemolysis; micelle; solubilization; toxicity.

MeSH terms

  • 2-Hydroxypropyl-beta-cyclodextrin / administration & dosage
  • 2-Hydroxypropyl-beta-cyclodextrin / pharmacokinetics*
  • Animals
  • Cyclohexanes / administration & dosage
  • Cyclohexanes / pharmacokinetics
  • Cyclohexanes / toxicity*
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical / methods*
  • Drug Interactions
  • Excipients / administration & dosage
  • Excipients / pharmacokinetics*
  • Hemolysis / drug effects
  • Injections, Intravenous
  • Injections, Subcutaneous
  • Male
  • Maximum Tolerated Dose
  • Models, Animal
  • Pyrroles / administration & dosage
  • Pyrroles / pharmacokinetics
  • Pyrroles / toxicity*
  • Rats
  • Solubility
  • Toxicity Tests, Acute / methods*

Substances

  • Cyclohexanes
  • Excipients
  • Pyrroles
  • 2-Hydroxypropyl-beta-cyclodextrin
  • GDC-0152