Increasing the efficacy of abiraterone - from pharmacokinetics, through therapeutic drug monitoring to overcoming food effects with innovative pharmaceutical products

Danielak, Dorota; Krejčí, Tereza; Beránek, Josef

doi:10.1016/j.ejps.2022.106254

Cited by 6 publications

(3 citation statements)

References 77 publications

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“…Taken together, PCa organoids are considered as promising model systems for systematically evaluating the efficacies of therapeutic drugs and investigating the molecular mechanisms underlying drug resistance in PCa [159,160].…”

Section: Pca Organoid Models For Exploring Drug Resistance Mechanismsmentioning

confidence: 99%

Organoids: An Emerging Precision Medicine Model for Prostate Cancer Research

Waseem,

Wang

2024

IJMS

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Prostate cancer (PCa) has been known as the most prevalent cancer disease and the second leading cause of cancer mortality in men almost all over the globe. There is an urgent need for establishment of PCa models that can recapitulate the progress of genomic landscapes and molecular alterations during development and progression of this disease. Notably, several organoid models have been developed for assessing the complex interaction between PCa and its surrounding microenvironment. In recent years, PCa organoids have been emerged as powerful in vitro 3D model systems that recapitulate the molecular features (such as genomic/epigenomic changes and tumor microenvironment) of PCa metastatic tumors. In addition, application of organoid technology in mechanistic studies (i.e., for understanding cellular/subcellular and molecular alterations) and translational medicine has been recognized as a promising approach for facilitating the development of potential biomarkers and novel therapeutic strategies. In this review, we summarize the application of PCa organoids in the high-throughput screening and establishment of relevant xenografts for developing novel therapeutics for metastatic, castration resistant, and neuroendocrine PCa. These organoid-based studies are expected to expand our knowledge from basic research to clinical applications for PCa diseases. Furthermore, we also highlight the optimization of PCa cultures and establishment of promising 3D organoid models for in vitro and in vivo investigations, ultimately facilitating mechanistic studies and development of novel clinical diagnosis/prognosis and therapies for PCa.

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Section: Pca Organoid Models For Exploring Drug Resistance Mechanismsmentioning

confidence: 99%

Organoids: An Emerging Precision Medicine Model for Prostate Cancer Research

Waseem,

Wang

2024

IJMS

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“…Abi inhibits androgen production in the human body, significantly reduces testosterone levels, effectively reduces tumor volume, and extends the overall survival of patients with metastatic castration-resistant PCa (mCRPC). − However, it is a lipid-soluble compound, with low solubility (<0.5 μg/mL in water and 4.4 ± 1.5 μg/mL in FaSSIF upon 5 h of incubation) and permeability (<3.46 × 10 –6 cm/s in the A to B direction detected using Caco-2 cell monolayers) . Thus, it is poorly absorbed and most of the drug is excreted from the body, making it difficult to obtain the desired therapeutic effect. − In addition, the low solubility (<0.5 μg/mL in water and 25.3 ± 2.0 μg/mL in FaSSIF upon 5 h of incubation) , and high lipophilicity (LogP 5.12) of abiraterone acetate (AbA) lead to poor bioavailability (<10% in the fasted state) . Increasing the dose to improve efficacy raises the cost and toxic side effects of the medication .…”

Section: Introductionmentioning

confidence: 99%

“…Studies have focused on the development of novel formulations to improve Abi bioavailability. ,, Liu et al used nanocrystal technology to develop tablets and increased the dissolution rate of AbA, which improved the oral bioavailability with C max and AUC 0–t being 3.51-fold and 2.80-fold compared to the Zytiga tablets . Schultz et al formulated a supersaturated silica–lipid hybrid (SLH), typically used to increase the oral bioavailability of lipophilic medicines with poor water solubility, to enhance the solubilization and oral bioavailability of AbA. , Compared to the unformulated AbA and Zytiga tablets, SLH (90% S eq ) increased 31-fold and 1.43-fold in the oral bioavailability while super-SLH P enhanced 16–19-fold and 2–2.5-fold in AbA solubilization, respectively.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Methoxypolyethylene-Glycol-Substituted Abiraterone Derivatives as Potential Antiprostate Cancer Agents

Meng,

Zhu,

Han

et al. 2024

Mol. Pharmaceutics

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Globally, prostate cancer is the most commonly diagnosed tumor and a cause of death in older men. Abiraterone, an orally administered irreversible CYP17 inhibitor, is employed to treat prostate cancer. However, abiraterone has several clinical limitations, such as poor water solubility, low dissolution rate, low bioavailability, and toxic side effects in the liver and kidney. Therefore, there is a need to identify high-efficiency and lowtoxicity water-soluble abiraterone derivatives. In this work, we aimed to design and synthesize a series of abiraterone derivatives by methoxypoly(ethylene glycol) (mPEG) modification. Their antitumor activities and toxicology were analyzed in vitro and in vivo. The most potent compound, 2e, retained the principle of action on the CYP17 enzyme target and significantly improved the abiraterone water solubility, cell permeability, and blood safety. No significant abnormalities were observed in toxicology. mPEGmodification significantly improved abiraterone's antitumor activity and efficiency while reducing the associated toxic effects. The finding will provide a theoretical basis for future clinical application of mPEG-modified abiraterone.

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