Development, Characterization, and Optimization of a Novel Abiraterone Acetate Formulation to Improve Biopharmaceutical Attributes Aided by Pharmacokinetic Modelling

Abstract

Abiraterone acetate has very low bioavailability and drastic food effect to warrant a dosing regimen under fasting state only. Therefore, we aimed to develop and optimize a liquisolid compact formulation of abiraterone acetate to improve biopharmaceutical attributes aided by pharmacokinetic modelling and achieve dose reduction with no food effect on the formulation. Preliminary studies highlighted the importance of the selection of olive oil as a compatible vehicle. The pharmacokinetic model, integrated with gastrointestinal physiology, was used to predict fasted and fed state pharmacokinetic parameters. Optimization of the liquisolid formulation containing abiraterone acetate was carried at more than five times lower dose, i.e. 190 mg, compared to 1000 mg. A central composite design (CCD) was used to identify optimal levels of formulation factors, namely the amount of vehicle (olive oil), the amount of coating agent (silicon dioxide), and the amount of surfactant (polysorbate 80). Graphical optimization using the selected models in conjunction with maximization of the desirability was used to identify the optimized liquisolid formulation. The predicted pharmacokinetic parameters (fasted Cmax 901.83 ng/mL, fasted AUCinf 2723.82 ng·h/mL, fed Cmax 1024.34 ng/mL, and fed AUCinf 3041.83 ng·h/mL) of the optimized formulation were acceptable. Overall, the liquisolid compact formulation of abiraterone acetate was successfully developed and optimized. In vitro solubility and dissolution results aided by pharmacokinetic modelling also showed improved predicted bioavailability with greater than five times reduction in dose and elimination of food effect.