Category: Formulation and Quality
Purpose: Abiraterone Acetate is a poorly water soluble drug, used in treatment of prostate cancer. It’s commercial formulation Zytiga® contains Abiraterone acetate in crystalline form and has an estimated oral bioavailability of < 10%. It has been shown, that higher Abiraterone exposure is associated with increase in probability of overall survival. However, on increasing the standard dose of Zytiga® from 1000mg to 2000mg, the increase in Abiraterone exposure (mean AUC) is meagre 8%. Thus, the complete therapeutic potential of Abiraterone has not been realized due to its formulation limitation. By developing a more bioavailable formulation, higher exposure of Abiraterone can be achieved, leading to improved therapeutic outcome. Thus, the purpose of this research is to develop an Abiraterone formulation with higher bioavailability and thereby demonstrate improved therapeutic outcome in a preclinical model.
Methods: Abiraterone: Polymer (1:9 %w/w) was processed into a solid dispersion (30056-KSD) using KinetiSol® Compounder. The neat Abiraterone acetate (API) and 30056-KSD were analyzed using X-ray Diffractometry for their physical state, modulated differential scanning calorimetry (mDSC) for their thermal behavior, High-performance liquid chromatography (HPLC) for their purity and dissolution analysis for their in-vitro performance. The in-vivo pharmacokinetics of neat API and 30056-KSD were studied at three different dose levels in male SCID mice. Based on the data from the pharmacokinetic study, two dose levels were selected for pharmacodynamic study. A preclinical prostate cancer xenograft model was developed using 22RV1 cell line. The therapeutic outcomes of two dose levels of neat API and 30056-KSD were assessed by a tumor growth inhibition study in the xenograft model.
Results: The neat API showed sharp diffraction peaks and 30056-KSD showed halo pattern in X-ray diffractometry, thereby indicating their crystalline and amorphous nature, respectively. In mDSC thermogram, the neat API showed a melting endotherm at ~147°C, whereas 30056-KSD showed no endothermic event. Both, the neat API and 30056-KSD showed purity of >99.0%. The area under drug dissolution curve was 12 folds higher for 30056-KSD as compared to neat API. In the pharmacokinetic study, 30056-KSD showed bioavailability enhancement of ~3-7 folds, as compared to neat API. The drug dose- exposure curve showed higher linearity (R2: 0.98 v/s 0.83) for 30056-KSD as compared to neat API. Dose levels of 20mg/kg and 89.2mg/kg of Abiraterone were selected for the tumor growth inhibition study. Both dose levels for 30056-KSD arm showed higher tumor growth inhibition as compared to corresponding neat API arm and control arm. The difference between tumor volume of neat API arm and control arm was not statistically significant (p: 0.165, 0.757) at both dose levels. Whereas, the tumor volume was significantly (p: 0.014, < 0.001) lower for 30056-KSD arm as compared to control arm at both dose levels.
Conclusion: By implementing KinetiSol® technology, the bioavailability of Abiraterone was enhanced. The bioavailable formulation (KSD) was able to deliver higher amount of drug, leading to greater tumor growth inhibition as compared to same dose of neat API. Hence, by enhancing the bioavailability, the therapeutic potential of Abiraterone was maximized.