Clinical Pharmacokinetics and Pharmacodynamics of the Next Generation Androgen Receptor Inhibitor-Darolutamide. 2023

Eva Podgoršek, and Niven Mehra, and Inge M van Oort, and Diederik M Somford, and Emmy Boerrigter, and Nielka P van Erp
Department of Clinical Pharmacy, Radboud University Medical Center, Route 864, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.

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.

UI MeSH Term Description Entries
D008297 Male Males
D009363 Neoplasm Proteins Proteins whose abnormal expression (gain or loss) are associated with the development, growth, or progression of NEOPLASMS. Some neoplasm proteins are tumor antigens (ANTIGENS, NEOPLASM), i.e. they induce an immune reaction to their tumor. Many neoplasm proteins have been characterized and are used as tumor markers (BIOMARKERS, TUMOR) when they are detectable in cells and body fluids as monitors for the presence or growth of tumors. Abnormal expression of ONCOGENE PROTEINS is involved in neoplastic transformation, whereas the loss of expression of TUMOR SUPPRESSOR PROTEINS is involved with the loss of growth control and progression of the neoplasm. Proteins, Neoplasm
D011944 Receptors, Androgen Proteins, generally found in the CYTOPLASM, that specifically bind ANDROGENS and mediate their cellular actions. The complex of the androgen and receptor migrates to the CELL NUCLEUS where it induces transcription of specific segments of DNA. Androgen Receptors,5 alpha-Dihydrotestosterone Receptor,Androgen Receptor,Dihydrotestosterone Receptors,Receptor, Testosterone,Receptors, Androgens,Receptors, Dihydrotestosterone,Receptors, Stanolone,Stanolone Receptor,Testosterone Receptor,5 alpha Dihydrotestosterone Receptor,Androgens Receptors,Receptor, 5 alpha-Dihydrotestosterone,Receptor, Androgen,Receptor, Stanolone,Stanolone Receptors,alpha-Dihydrotestosterone Receptor, 5
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000070997 ATP Binding Cassette Transporter, Subfamily G, Member 2 ATP-binding cassette transporter, sub-family G protein that functions as a high capacity UREA exporter, transporter of STEROLS, and in the absorption and efflux of many drugs. Its efflux activity for ANTINEOPLASTIC AGENTS contributes to DRUG RESISTANCE. It functions as a homodimer and is expressed by cells in a variety of organs, as well as by NEOPLASTIC STEM CELLS. ABCG2 Protein,ABCG2 Transporter,ATP Binding Cassette Transporter, Sub-Family G, Member 2,CD338 Antigen
D059002 Androgen Receptor Antagonists Compounds that bind to and inhibit the activation of ANDROGEN RECEPTORS. Androgen Receptor Antagonist,Antagonist, Androgen Receptor,Antagonists, Androgen Receptor,Receptor Antagonist, Androgen,Receptor Antagonists, Androgen
D064129 Prostatic Neoplasms, Castration-Resistant Tumors or cancer of the PROSTATE which can grow in the presence of low or residual amount of androgen hormones such as TESTOSTERONE. Androgen-Independent Prostatic Cancer,Androgen-Independent Prostatic Neoplasms,Androgen-Insensitive Prostatic Cancer,Androgen-Insensitive Prostatic Neoplasms,Androgen-Resistant Prostatic Cancer,Androgen-Resistant Prostatic Neoplasms,Castration-Resistant Prostatic Cancer,Castration-Resistant Prostatic Neoplasms,Hormone Refractory Prostatic Cancer,Hormone Refractory Prostatic Neoplasms,Prostatic Cancer, Androgen-Independent,Prostatic Cancer, Androgen-Insensitive,Prostatic Cancer, Androgen-Resistant,Prostatic Cancer, Castration-Resistant,Prostatic Cancer, Hormone Refractory,Prostatic Neoplasms, Androgen-Independent,Prostatic Neoplasms, Androgen-Insensitive,Prostatic Neoplasms, Androgen-Resistant,Prostatic Neoplasms, Hormone Refractory,Androgen Independent Prostatic Cancer,Androgen Independent Prostatic Neoplasms,Androgen Insensitive Prostatic Cancer,Androgen Insensitive Prostatic Neoplasms,Androgen Resistant Prostatic Cancer,Androgen Resistant Prostatic Neoplasms,Androgen-Independent Prostatic Cancers,Androgen-Independent Prostatic Neoplasm,Androgen-Insensitive Prostatic Cancers,Androgen-Insensitive Prostatic Neoplasm,Androgen-Resistant Prostatic Cancers,Androgen-Resistant Prostatic Neoplasm,Cancer, Androgen-Independent Prostatic,Cancer, Androgen-Insensitive Prostatic,Cancer, Androgen-Resistant Prostatic,Cancer, Castration-Resistant Prostatic,Cancers, Androgen-Independent Prostatic,Cancers, Androgen-Insensitive Prostatic,Cancers, Androgen-Resistant Prostatic,Cancers, Castration-Resistant Prostatic,Castration Resistant Prostatic Cancer,Castration Resistant Prostatic Neoplasms,Castration-Resistant Prostatic Cancers,Castration-Resistant Prostatic Neoplasm,Neoplasm, Androgen-Independent Prostatic,Neoplasm, Androgen-Insensitive Prostatic,Neoplasm, Androgen-Resistant Prostatic,Neoplasm, Castration-Resistant Prostatic,Neoplasms, Androgen-Independent Prostatic,Neoplasms, Androgen-Insensitive Prostatic,Neoplasms, Androgen-Resistant Prostatic,Neoplasms, Castration-Resistant Prostatic,Prostatic Cancer, Androgen Independent,Prostatic Cancer, Androgen Insensitive,Prostatic Cancer, Androgen Resistant,Prostatic Cancer, Castration Resistant,Prostatic Cancers, Androgen-Independent,Prostatic Cancers, Androgen-Insensitive,Prostatic Cancers, Androgen-Resistant,Prostatic Cancers, Castration-Resistant,Prostatic Neoplasm, Androgen-Independent,Prostatic Neoplasm, Androgen-Insensitive,Prostatic Neoplasm, Androgen-Resistant,Prostatic Neoplasm, Castration-Resistant,Prostatic Neoplasms, Androgen Independent,Prostatic Neoplasms, Androgen Insensitive,Prostatic Neoplasms, Androgen Resistant,Prostatic Neoplasms, Castration Resistant

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