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.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
The data that support the findings of this study are available from the corresponding author, SAT, upon reasonable request.
Gala UH, Miller DA, Williams RO. Harnessing the therapeutic potential of anticancer drugs through amorphous solid dispersions. Biochim Biophys Acta - Rev Cancer [Internet]. 2020;1873(1):188319. Available from: https://doi.org/10.1016/j.bbcan.2019.188319
Rodriguez-Aller M, Guillarme D, Veuthey JL, Gurny R. Strategies for formulating and delivering poorly water-soluble drugs. J Drug Deliv Sci Technol [Internet]. 2015;30:342–51. Available from: https://doi.org/10.1016/j.jddst.2015.05.009
Van Den Mooter G. The use of amorphous solid dispersions: a formulation strategy to overcome poor solubility and dissolution rate. Drug Discov Today Technol [Internet]. 2012;9(2):e79–85. Available from: https://doi.org/10.1016/j.ddtec.2011.10.002
Chen L, Okuda T, Lu XY, Chan HK. Amorphous powders for inhalation drug delivery. Adv Drug Deliv Rev [Internet]. 2016;100:102–15. Available from: https://doi.org/10.1016/j.addr.2016.01.002
Thompson SA, Williams RO. Specific mechanical energy – an essential parameter in the processing of amorphous solid dispersions. Adv Drug Deliv Rev [Internet]. 2021;173:374–93. Available from: https://doi.org/10.1016/j.addr.2021.03.006
Ellenberger DJ, Miller DA, Williams RO. Expanding the application and formulation space of amorphous solid dispersions with KinetiSol®: a review. AAPS PharmSciTech. 2018;19(5):1933–56.
Purushottamachar P, Godbole AM, Gediya LK, Martin MS, Vasaitis TS, Kwegyir-Afful AK, et al. Systematic structure modifications of multitarget prostate cancer drug candidate galeterone to produce novel androgen receptor down-regulating agents as an approach to treatment of advanced prostate cancer. J Med Chem. 2013;56(12):4880–98.
McKay RR, Mamlouk K, Montgomery B, Taplin M-E. Treatment with galeterone in an elderly man with castration-resistant prostate cancer: a case report. clin genitourin cancer [Internet]. 2015 Aug;13(4):e325–8. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1558767314002894
Taplin M-E, Chu F, Morrison JP, Pili R, Rettig MB, Stephenson J, et al. Abstract CT-07: ARMOR1: safety of galeterone (TOK-001) in a phase 1 clinical trial in chemotherapy naïve patients with castration resistant prostate cancer (CRPC). Cancer Res. 2012;72(8_Supplement):CT-07-CT-07.
Taplin M-E, Montgomery RB. ARMOR2: Galeterone in progressive CRPC patients who have failed oral therapy. J Clin Oncol. 2014;32(4_suppl):71–71.
Montgomery B, Eisenberger MA, Rettig MB, Chu F, Pili R, Stephenson JJ, et al. Androgen receptor modulation optimized for response (ARMOR) phase i and II studies: galeterone for the treatment of castration-resistant prostate cancer. Clin Cancer Res. 2016;22(6):1356–63.
Casebier D, Sentissi A, Moreton C, Turnbull M. Novel compositions and methods for treating prostate cancer. World Intellectual Property Organization; WO 2013/012959 A1, 2013.
Kramer WG, Vince B, McGarry C. Comparison of the pharmacokinetics (PK) of galeterone novel oral formulations. J Clin Oncol. 2013;31(15_suppl):e16075–e16075.
Taplin ME, Antonarakis ES, Ferrante KJ, Horgan K, Blumenstein B, Saad F, et al. Androgen receptor modulation optimized for response—splice variant: a phase 3, randomized trial of galeterone versus enzalutamide in androgen receptor splice variant-7–expressing metastatic castration-resistant prostate cancer. Eur Urol [Internet]. 2019;76(6):843–51. Available from: https://doi.org/10.1016/j.eururo.2019.08.034
Yu T, Huang T, Yu L, Nantasenamat C, Anuwongcharoen N, Piacham T, et al. Exploring the chemical space of CYP17A1 inhibitors using cheminformatics and machine learning. Molecules [Internet]. 2023 Feb 9;28(4):1679. Available from: https://www.mdpi.com/1420-3049/28/4/1679
Indulkar AS, Lou X, Zhang GGZ, Taylor LS. Insights into the dissolution mechanism of ritonavir-copovidone amorphous solid dispersions: importance of congruent release for enhanced performance. Mol Pharm. 2019;16(3):1327–39.
Que C, Deac A, Zemlyanov DY, Qi Q, Indulkar AS, Gao Y, Zhang GG, Taylor LS. Impact of drug–polymer intermolecular interactions on dissolution performance of copovidone-based amorphous solid dispersions. Mol Pharm. 2021;18(9):3496–508.
Yang R, Mann AKP, Van Duong T, Ormes JD, Okoh GA, Hermans A, et al. Drug release and nanodroplet formation from amorphous solid dispersions: insight into the roles of drug physicochemical properties and polymer selection. Mol Pharm. 2021;18(5):2066–81.
Yang R, Zhang GGZ, Zemlyanov DY, Purohit HS, Taylor LS. Release mechanisms of amorphous solid dispersions: role of drug-polymer phase separation and morphology. J Pharm Sci [Internet]. 2022;112(1):304–17. Available from: https://doi.org/10.1016/j.xphs.2022.10.021
Que C, Lou X, Zemlyanov DY, Mo H, Indulkar AS, Gao Y, et al. Insights into the dissolution behavior of ledipasvir-copovidone amorphous solid dispersions: role of drug loading and intermolecular interactions. Mol Pharm. 2019;16(12):5054–67.
Gala U, Miller D, Williams RO III. Improved dissolution and pharmacokinetics of abiraterone through KinetiSol® enabled amorphous solid dispersions. Pharmaceutics. 2020;12(4):357.
Gala UH, Miller DA, Su Y, Spangenberg A, Williams RO (Bill. The effect of drug loading on the properties of abiraterone–hydroxypropyl beta cyclodextrin solid dispersions processed by solvent free KinetiSol® technology. Eur J Pharm Biopharm [Internet]. 2021;165(May):52–65. Available from: https://doi.org/10.1016/j.ejpb.2021.05.001
Agrawal AM, Dudhedia MS, Patel AD, Raikes MS. Characterization and performance assessment of solid dispersions prepared by hot melt extrusion and spray drying process. Int J Pharm [Internet]. 2013;457(1):71–81. Available from: https://doi.org/10.1016/j.ijpharm.2013.08.081
Jermain SV, Lowinger MB, Ellenberger DJ, Miller DA, Su Y, Williams RO. In vitro and in vivo behaviors of kinetisol and spray-dried amorphous solid dispersions of a weakly basic drug and ionic polymer †. Mol Pharm. 2020;17(8):2789–808.
Mahmah O, Tabbakh R, Kelly A, Paradkar A. A comparative study of the effect of spray drying and hot-melt extrusion on the properties of amorphous solid dispersions containing felodipine. J Pharm Pharmacol. 2014;66(2):275–84.
Li Y, Mann AK, Zhang D, Yang Z. Processing impact on in vitro and in vivo performance of solid dispersions—a comparison between hot-melt extrusion and spray drying. Pharmaceutics. 2021;13(8):1307.
Thompson SA, Davis DA, Moon C, Williams RO. Increasing drug loading of weakly acidic telmisartan in amorphous solid dispersions through pH modification during hot-melt extrusion. Mol Pharm. 2022;19(1):318–31.
Thielmann F, Burnett DJ, Heng JYY. Determination of the surface energy distributions of different processed lactose. Drug Dev Ind Pharm. 2007;33(11):1240–53.
Dorris GM, Gray DG. Adsorption of n-alkanes at zero surface coverage on cellulose paper and wood fibers. J Colloid Interface Sci. 1980;77(2):353–62.
Della Volpe C, Siboni S. Acid-base surface free energies of solids and the definition of scales in the Good-van Oss-Chaudhury theory. J Adhes Sci Technol. 2000;14(2):235–72.
Donnet JB, Park SJ, Balard H. Evaluation of specific interactions of solid surfaces by inverse gas chromatography - a new approach based on polarizability of the probes. Chromatographia. 1991;31(9–10):434–40.
Njar VCO, Brodie AMH. Discovery and development of galeterone (TOK-001 or VN/124-1) for the treatment of all stages of prostate cancer. J Med Chem. 2015;58(5):2077–87.
Ohtake S, Shalaev E. Effect of water on the chemical stability of amorphous pharmaceuticals: I. small molecules. J Pharm Sci [Internet]. 2013;102(4):1139–54. Available from: https://doi.org/10.1002/jps.23440
Sarabu S, Butreddy A, Bandari S, Batra A, Lawal K, Chen NN, et al. Preliminary investigation of peroxide levels of Plasdone™ copovidones on the purity of atorvastatin calcium amorphous solid dispersions: Impact of plasticizers on hot melt extrusion processability. J Drug Deliv Sci Technol [Internet]. 2022;70(February):103190. Available from: https://doi.org/10.1016/j.jddst.2022.103190
Chen Y, Wang S, Wang S, Liu C, Su C, Hageman M, et al. Initial drug dissolution from amorphous solid dispersions controlled by polymer dissolution and drug-polymer interaction. Pharm Res [Internet]. 2016;33(10):2445–58. Available from: https://doi.org/10.1007/s11095-016-1969-2
Chen Y, Liu C, Chen Z, Su C, Hageman M, Hussain M, et al. Drug-polymer-water interaction and its implication for the dissolution performance of amorphous solid dispersions. Mol Pharm. 2015;12(2):576–89.
Chen Y, Wang S, Wang S, Liu C, Su C, Hageman M, et al. Sodium lauryl sulfate competitively interacts with HPMC-AS and consequently reduces oral bioavailability of posaconazole/HPMC-AS amorphous solid dispersion. Mol Pharm. 2016;13(8):2787–95.
Zhang W, Hate SS, Russell DJ, Hou HH, Nagapudi K. Impact of surfactant and surfactant-polymer interaction on desupersaturation of clotrimazole. J Pharm Sci [Internet]. 2019;108(10):3262–71. Available from: https://doi.org/10.1016/j.xphs.2019.05.035
Lu J, Obara S, Liu F, Fu W, Zhang W, Kikuchi S. Melt extrusion for a high melting point compound with improved solubility and sustained release. AAPS PharmSciTech. 2018;19(1):358–70.
Monschke M, Kayser K, Wagner KG. Influence of particle size and drug load on amorphous Solid dispersions containing pH-dependent soluble polymers and the weak base ketoconazole. AAPS PharmSciTech. 2021;22(1):1–11.
BÜCHI Labortechnik AG. Mini spray dryer B-290: technical data sheet [Internet]. New Castle, DE: BUCHI Corporation; p. 1–9. Available from: http://static1.buchi.com/sites/default/files/downloads/B-290_Data_Sheet_en_D.pdf?83b925aae302a8e76f002d1ce679fa06904d1039
Macheras P, Chryssafidis P. Revising pharmacokinetics of oral drug absorption: I models based on biopharmaceutical/physiological and finite absorption time concepts. Pharmaceutical Research. 2020;37:1–3.
Park HM, Chernish SM, Rosenek BD, Brunelle RL, Hargrove B, Wellman HN. Gastric emptying of enteric-coated tablets. Dig Dis Sci. 1984;29(3):207–12.
Oberle RL, Amidon GL. The influence of variable gastric emptying and intestinal transit rates on the plasma level curve of cimetidine; an explanation for the double peak phenomenon. J Pharmacokinet Biopharm. 1987;15(5):529–44.
Lubach JW, Chen JZ, Hau J, Imperio J, Coraggio M, Liu L, et al. Investigation of the rat model for preclinical evaluation of pH-dependent oral absorption in humans. Mol Pharm. 2013;10(11):3997–4004.
Gentilcore D, Vanis L, Teng JC, Wishart JM, Buckley JD, Rayner CK, et al. The oligosaccharide α-cyclodextrin has modest effects to slow gastric emptying and modify the glycaemic response to sucrose in healthy older adults. Br J Nutr. 2011;106(4):583–7.
Scott Sutton S, Magagnoli J, Hardin JW. Impact of pill burden on adherence, risk of hospitalization, and viral suppression in patients with HIV infection and AIDS receiving antiretroviral therapy. Pharmacotherapy. 2016;36(4):385–401.
Saboo S, Moseson DE, Kestur US, Taylor LS. Patterns of drug release as a function of drug loading from amorphous solid dispersions: a comparison of five different polymers. Eur J Pharm Sci [Internet]. 2020;155(July):105514. Available from: https://doi.org/10.1016/j.ejps.2020.105514
Ho R, Heng JYY. A review of inverse gas chromatography and its development as a tool to characterize anisotropic surface properties of pharmaceutical solids. KONA Powder Part J. 2012;30(30):164–80.
Modi SR, Dantuluri AKR, Perumalla SR, Sun CC, Bansal AK. Effect of crystal habit on intrinsic dissolution behavior of celecoxib due to differential wettability. Cryst Growth Des. 2014;14(10):5283–92.
Ho R, Naderi M, Heng JYY, Williams DR, Thielmann F, Bouza P, et al. Effect of milling on particle shape and surface energy heterogeneity of needle-shaped crystals. Pharm Res. 2012;29(10):2806–16.
Karde V, Ghoroi C. Influence of surface modification on wettability and surface energy characteristics of pharmaceutical excipient powders. Int J Pharm. 2014;475(1):351–63.
Varghese S, Ghoroi C. Improving the wetting and dissolution of ibuprofen using solventless co-milling. Int J Pharm [Internet]. 2017;533(1):145–55. Available from: https://doi.org/10.1016/j.ijpharm.2017.09.062
Modi SR, Dantuluri AKR, Puri V, Pawar YB, Nandekar P, Sangamwar AT, et al. Impact of crystal habit on biopharmaceutical performance of celecoxib. Cryst Growth Des. 2013;13(7):2824–32.
Brokešová J, Slámová M, Zámostný P, Kuentz M, Koktan J, Krejčík L, Vraníková B, Svačinová P, Šklubalová Z. Mechanistic study of dissolution enhancement by interactive mixtures of chitosan with meloxicam as model. Eur J Pharm Sci. 2022;169:106087.
Burnett DJ, Khoo J, Naderi M, Heng JYY, Wang GD, Thielmann F. Effect of processing route on the surface properties of amorphous indomethacin measured by inverse gas chromatography. AAPS PharmSciTech. 2012;13(4):1511–7.
Stephen A. Thompson was supported by AustinPx, Georgetown, TX, through a gift to support graduate education.
Conflict of Interest
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Below is the link to the electronic supplementary material.
About this article
Cite this article
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