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Can the Oral Bioavailability of the Discontinued Prostate Cancer Drug Galeterone Be Improved by Processing Method? KinetiSol® Outperforms Spray Drying in a Head-to-head Comparison

AAPS PharmSciTech volume 24, Article number: 137 (2023) Cite this article

Abstract

Galeterone, a novel prostate cancer candidate treatment, was discontinued after a Phase III clinical trial due to lack of efficacy. Galeterone is weakly basic and exhibits low solubility in biorelevant media (i.e., ~ 2 µg/mL in fasted simulated intestinal fluid). It was formulated as a 50–50 (w/w) galeterone-hypromellose acetate succinate spray-dried dispersion to increase its bioavailability. Despite this increase, the bioavailability of this formulation may have been insufficient and contributed to its clinical failure. We hypothesized that reformulating galeterone as an amorphous solid dispersion by KinetiSol® compounding could increase its bioavailability. In this study, we examined the effects of composition and manufacturing technology (Kinetisol and spray drying) on the performance of galeterone amorphous solid dispersions. KinetiSol compounding was utilized to create galeterone amorphous solid dispersions containing the complexing agent hydroxypropyl-β-cyclodextrin or hypromellose acetate succinate with lower drug loads that both achieved a ~ 6 × increase in dissolution performance versus the 50–50 spray-dried dispersion. When compared to a spray-dried dispersion with an equivalent drug load, the KinetiSol amorphous solid dispersions formulations exhibited ~ 2 × exposure in an in vivo rat study. Acid–base surface energy analysis showed that the equivalent composition of the KinetiSol amorphous solid dispersion formulation better protected the weakly basic galeterone from premature dissolution in acidic media and thereby reduced precipitation, inhibited recrystallization, and extended the extent of supersaturation during transit into neutral intestinal media.

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Data Availability

The data that support the findings of this study are available from the corresponding author, SAT, upon reasonable request.

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Funding

Stephen A. Thompson was supported by AustinPx, Georgetown, TX, through a gift to support graduate education.

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Authors and Affiliations

  1. Molecular Pharmaceutics and Drug Delivery Division, The University of Texas at Austin College of Pharmacy, 2409 W. University Ave. PHR 4.214, Austin, Texas, 78712, USA

    Stephen A. Thompson & Robert O. Williams III

  2. AustinPx, LLC. 111 W Cooperative Way, Suite 300, Georgetown, Texas, 78626, USA

    Urvi Gala, Daniel A. Davis Jr, Sandra Kucera & Dave Miller

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  1. Stephen A. Thompson
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  2. Urvi Gala
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  3. Daniel A. Davis Jr
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  4. Sandra Kucera
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Contributions

Conceptualization, Stephen Thompson, Urvi Gala, Daniel Davis Jr., Dave Miller, Sandra Kucera, and Robert Williams III; formal analysis, Stephen Thompson and Urvi Gala; investigation, Stephen Thompson; methodology, Stephen Thompson, Urvi Gala, Daniel Davis Jr., Dave Miller, Sandra Kucera, and Robert Williams III; supervision, Robert Williams III; writing—original draft, Stephen Thompson; writing—review & editing, Stephen Thompson, Urvi Gala, Daniel Davis Jr., Dave Miller, Sandra Kucera, and Robert Williams III.

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Correspondence to Stephen A. Thompson.

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Thompson, S.A., Gala, U., Davis, D.A. et al. Can the Oral Bioavailability of the Discontinued Prostate Cancer Drug Galeterone Be Improved by Processing Method? KinetiSol® Outperforms Spray Drying in a Head-to-head Comparison. AAPS PharmSciTech 24, 137 (2023). https://doi.org/10.1208/s12249-023-02597-6

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