The effect of chemotherapy on the exposure–response relation of abiraterone in metastatic castration‐resistant prostate cancer

Boerrigter, Emmy; Benoist, Guillemette E.; Overbeek, Joanneke; Donders, Rogier; Mehra, Niven; Oort, Inge M. van; Heine, Rob ter; Erp, Nielka P. van

doi:10.1111/bcp.15057

Cited by 6 publications

(2 citation statements)

References 29 publications

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“…With regard to nmCRPC patients, no dose–response data are available; however, it is suggested that there is no exposure–response relationship in this early state of PC at the registered dose. This is in line with the observation that CRPC gets increasingly less sensitive in more advanced stages of disease as has been shown for other ARSIs [ 42 ].…”

Section: Exposure Response Relationshipsupporting

confidence: 90%

Clinical Pharmacokinetics and Pharmacodynamics of the Next Generation Androgen Receptor Inhibitor—Darolutamide

Podgoršek,

Mehra,

van Oort

et al. 2023

Clin Pharmacokinet

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Darolutamide is a next-generation androgen receptor signaling inhibitor (ARSI) currently approved for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC) and metastatic hormone sensitive prostate cancer (mHSPC). Studies suggest that darolutamide also has the potential to be used to treat other stages of prostate cancer (PC), suggesting that its indications will broaden in the near future. Since ARSIs show similar efficacy for the treatment of PC, pharmacokinetic properties of these drugs and patient characteristics could help physicians decide which drug to select. This review provides an overview of the pharmacokinetic and pharmacodynamic properties of darolutamide. One of the most important pharmacological advantages of darolutamide is its low brain distribution and therefore limited seizure potential and central nervous system adverse effects. In addition, darolutamide has little drug–drug interaction potential and is unlikely to alter the exposure of other cytochrome P450 or P-glycoprotein substrates. Nevertheless, it may significantly increase the exposure of breast cancer resistant protein (BCRP) substrates. The limited solubility and bioavailability of darolutamide increases when taken together with food, regardless of the fat content. Darolutamide is excessively metabolized by oxidation and glucuronidation and excreted in the urine and feces. For this reason, dose reduction is required in patients with moderate and severe renal or severe hepatic impairment. Although no exposure–response relationship was observed with darolutamide, less advanced stages of PC showed better PSA response on treatment. Overall, darolutamide has some advantageous pharmacological properties that may lead to its preferred use, when broader registered, in selected patients across different disease stages.

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Section: Exposure Response Relationshipsupporting

confidence: 90%

Clinical Pharmacokinetics and Pharmacodynamics of the Next Generation Androgen Receptor Inhibitor—Darolutamide

Podgoršek,

Mehra,

van Oort

et al. 2023

Clin Pharmacokinet

Self Cite

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“…Then, after, Blanchet and coworkers reported on an AA metabolite survey and mentioned that a high metabolic ratio could help to identify patients with increased activity of the main AA metabolizing enzyme and who were at risk for a poorer survival rate [9]. The existence of an exposure threshold of AA concentration linked to survival was also underlined by the data reported by Boerrigter and coworkers [10]. Therefore, it is reasonable to assume that AA PKs may reflect treatment outcome, and this relationship should be strengthened by studies based on a large number of patients.…”

Section: Discussionmentioning

confidence: 98%

Long-Term Pharmacokinetic Follow-Up of Abiraterone Acetate in Patients with Metastatic Castration-Resistant Prostate Cancer

Chamorey,

Pujalte-Martin,

Ferrero

et al. 2024

IJMS

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This ABIGENE pharmacokinetic (PK) study sought mainly to characterize the unchanged drug PK during long-term abiraterone acetate (AA) administration in advanced prostate cancer patients (81 patients). It was observed that individual AA concentrations remained constant over treatment time, with no noticeable changes during repeated long-term drug administration for up to 120 days. There was no correlation between AA concentrations and survival outcomes. However, a significant association between higher AA concentrations and better clinical benefit was observed (p = 0.041). The safety data did not correlate with the AA PK data. A significant positive correlation (r = 0.40, p < 0.001) was observed between mean AA concentration and patient age: the older the patient, the higher the AA concentration. Patient age was found to impact steady-state AA concentration: the older the patient, the higher the mean AA concentration. Altogether, these data may help to guide future research and clinical trials in order to maximize the benefits of AA metastatic castration-resistant prostate cancer patients.

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Cortisol as Biomarker for CYP17-Inhibition is Associated with Therapy Outcome of Abiraterone Acetate

Bruin,

Mohmaed Ali,

van Nuland

et al. 2023

Pharm Res

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The effect of chemotherapy on the exposure–response relation of abiraterone in metastatic castration‐resistant prostate cancer

Cited by 6 publications

References 29 publications

Clinical Pharmacokinetics and Pharmacodynamics of the Next Generation Androgen Receptor Inhibitor—Darolutamide

Clinical Pharmacokinetics and Pharmacodynamics of the Next Generation Androgen Receptor Inhibitor—Darolutamide

Long-Term Pharmacokinetic Follow-Up of Abiraterone Acetate in Patients with Metastatic Castration-Resistant Prostate Cancer

Cortisol as Biomarker for CYP17-Inhibition is Associated with Therapy Outcome of Abiraterone Acetate

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