Enhancing the pharmacokinetics of abiraterone acetate through lipid-based formulations: addressing solubility and food effect challenges

Abiraterone acetate, a prodrug of abiraterone, is an effective antiandrogen for treating metastatic prostate cancer. However, its poor aqueous solubility restricts oral bioavailability to under 10% in fasted conditions. Additionally, its pharmacokinetics are significantly influenced by food intake, leading to variable exposure that can impact treatment safety and efficacy. To overcome these challenges, we developed a series of lipid-based formulations aimed at reducing food effects and enhancing the fasted bioavailability of abiraterone acetate by incorporating the drug into colloidal delivery systems. Medium- and long-chain self-nanoemulsifying drug delivery systems (MC-SNEDDS and LC-SNEDDS) were formulated with abiraterone acetate loading at 80% of their respective preconcentrate equilibrium solubility. In-vitro gastrointestinal lipolysis experiments demonstrated that the SNEDDS formulations increased drug solubilisation by over 6-fold compared to pure abiraterone acetate and over 2-fold compared to the reference product after 60 min in the intestinal environment. In-vivo pharmacokinetic studies in rats revealed that both MC-SNEDDS and LC-SNEDDS formulations, along with their enteric-coated (EC) forms, exhibited enhanced bioavailability, with EC-LC-SNEDDS providing the highest performance, demonstrating a 7.32-fold increase in abiraterone exposure compared to the reference. Strong correlations were observed between in-vitro solubilisation and in-vivo AUC_{0 - 8 h} (R² = 0.980) and C_max (R² = 0.925). In-vivo pharmacokinetic studies in pigs demonstrated that EC-LC-SNEDDS improved drug systemic exposure in fasted conditions and mitigated positive food effects, showing a fed-to-fasted AUC_{0 - 8 h} ratio of 108% compared to 334% with the reference. The developed lipid-based formulations hold promise in overcoming the pharmacokinetic challenges associated with abiraterone, potentially offering improved outcomes for patients.