Improved prostate cancer therapeutics through KinetiSol® enabled amorphous solid dispersions of Abiraterone

A majority of anticancer drugs have inherently poor water solubility, which limits their oral bioavailability and therapeutic potential. In Chapter one, the ability of amorphous solid dispersions (ASDs), to improve the dissolution, pharmacokinetics, efficacy and safety of anticancer drugs is demonstrated. Abiraterone is a poorly water soluble drug used in treatment of prostate cancer. Its commercial formulation Zytiga®, contains slightly more soluble prodrug, abiraterone acetate. Zytiga has poor oral bioavailability, high pharmacokinetic variability and high food effect, which limits its therapeutic potential. Abiraterone has a high melting point and limited solubility in organic solvents, which makes its ASD development difficult with conventional technologies. In Chapter two, KinetiSol® technology, which is a solvent free thermokinetic process, is utilized and an abiraterone ASD is developed for the first time. In addition to contemporary long-chain polymers, a short-chain oligomer is explored for development of binary and ternary KinetiSol processed ASDs (KSD) of abiraterone. Hydroxypropyl beta cyclodextrin (HPBCD) is identified as a suitable carrier for abiraterone KSD. In Chapter three, the impact of drug loading on abiraterone-HPBCD KSD properties is investigated. 10 to 50 % w/w drug loaded abiraterone KSDs are developed. The solid-state interaction studies revealed that abiraterone forms a complex with HPBCD in the KSD. Overall, as drug loading increased, the stability, in-vitro and in-vivo performance decreased. Thus, 10% drug loading is found to be optimum. In Chapter four, an optimal KSD of the prodrug abiraterone acetate is developed and compared with abiraterone KSD. A physicochemical stability study revealed, that the abiraterone acetate KSD is chemically unstable, while abiraterone KSD is both physically and chemically stable. Both KSDs have similar in-vitro and in-vivo performance. Thus, it is concluded that the active drug abiraterone’s KSD is more ideal and overcomes the issues associated with the prodrug use. In Chapter five, a preclinical prostate cancer xenograft model is developed to investigate the pharmacokinetic and pharmacodynamic performance of abiraterone KSD. This study demonstrated a statistically significant tumor growth inhibition of 33.1% by the abiraterone KSD. Thus, these studies suggest the potential for the abiraterone KSD formulation to improve therapeutic outcomes for prostate cancer patients.