(M1530-10-58) In Vivo Bioavailability Enhancement of Abiraterone Acetate Dispersome^® Formulations

Purpose: Abiraterone Acetate is marketed under the brand name Zytiga and is used in the treatment of prostate cancer. Its daily dose it 1000 mg, either given as 4 tablets of 250 mg or 2 large tablets of 500 mg. Abiraterone Acetate is poorly soluble and increasing its solubility and bioavailability may potentially allow a reduction in dose and subsequent number of tablets per administration, significantly reducing the pill burden for patients. Dispersome formulations are amorphous mixtures of the protein beta-lactoglobulin and a given drug and possess the potential to increase bioavailability even of poorly soluble or insoluble drugs. The Dispersome approach is still rather new and literature has so far focused on investigating the mechanism behind the amorphous stabilization [1] or solubility enhancement in vitro [2]. Furthermore, the Dispersome approach has shown to provide a further in vitro solubility enhancement when compared to traditional amorphous solid dispersions for the model drugs rifaximin and nimodipine [3,4]. In this study, spray dried Abiraterone Acetate Dispersome was developed into a tablet formulation and assessed in vitro towards solubility and permeability enhancement compared to Zytiga. In addition, an in vivo PK assessment in dogs was carried out against Zytiga.

Methods: The spray dried Abiraterone Acetate Dispersome intermediate was produced at a drug loading of 40%. The spray dried intermediate was then mixed with additional tableting excipients and developed into the Abiraterone Acetate Dispersome tablet. Solid state characterization was carried out using X-ray powder diffractometry (XRPD), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). In vitro dissolution and permeation testing was done using the MicroFLUX™ device where the donor and acceptor chamber were separated by a PAMPA membrane. The oral pharmacokinetic study was carried out in male beagle dogs by dosing the dogs with either one tablet containing the Abiraterone Acetate Dispersome (125 mg Abiraterone Acetate) or two tablets of the reference Zytiga (2 x 250mg, total 500 mg Abiraterone Acetate).

Results: The spray dried Abiraterone Acetate Dispersome intermediate was successfully prepared as an amorphous formulation and remained physically and chemically stable for at least 3 months under accelerated storage conditions (40 °C closed conditions). The Abiraterone Acetate Dispersome tablets showed low friability, acceptable tensile strength, as well as fast disintegration. The dissolution showed a fast supersaturation from the amorphous Dispersome formulation when compared to Zytiga, which was reflected in a higher in vitro permeability of the PAMPA membrane translating into a 10x increase in the acceptor AUC relative to the dose from the Dispersome tablets compared to Zytiga. The findings from the in vitro analysis were also reflected in the in vivo assessment. Even though, the drug dose from the Abiraterone Acetate Dispersome tablets was only a quarter (125mg) compared to Zytiga (500mg), a much higher plasma concentration profile was obtained (Figure 2), translating into a 10x increase in bioavailability from the Dispersome tablets compared to Zytiga.

Conclusion: This study showed that the poorly soluble drug Abiraterone Acetate can successfully be prepared as a stable amorphous spray dried intermediate, which can be further developed into a fast disintegrating tablet formulation with high in vitro solubility and permeability. The solubility enhancement from the Dispersome formulation was reflected in a higher drug exposure when compared to the originator Zytiga. Despite a lower dose given in form of the Dispersome, the bioavailability was 10-fold increased compared to Zytiga. Hence, the Abiraterone Acetate Dispersome formulation may possess the potential for the development of a dose reduced product also in humans.

References: 1. Kabedev A, Zhuo X, Leng D, Foderà V, Larsson P, Bergström CAS, Löbmann K. Stabilizing Mechanisms of β-Lactoglobulin in Amorphous Solid Dispersions of Indomethacin. Mol Pharm 2022, 19 (11), 3922-3933.
2. Zhuo X, Sener Z, Kabedev A, Zhao M, Arnous A, Leng D, Foderà V, Löbmann K. Mechanisms of Drug Solubility Enhancement Induced by β-Lactoglobulin-Based Amorphous Solid Dispersions. Mol Pharm 2023, 20 (10), 5206-5213.
3. Leng D, Bulduk B, Anlahr J, Müllers W, Löbmann K. Enhanced dissolution rate of nimodipine through β-lactoglobulin based formulations. Int J Pharm, 2023, 635, 122693.
4. Zhuo, X, Kjellin MMB, Schaal Z, Zhang T, Löbmann K, Leng D. A Comparative Study between A Protein Based Amorphous Formulation and Other Dissolution Rate Enhancing Approaches: A Case Study with Rifaximin. Pharmaceutics 15.1 (2022): 126.

Figure 1: Plasma concentration profiles of the Abiraterone Acetate Dispersome® tablet compared to the reference Zytiga.