Absorption, distribution, metabolism and excretion of darolutamide (a novel non-steroidal androgen receptor antagonist) in rats

Abstract

1. Darolutamide is a novel selective androgen receptor antagonist consisting of two pharmacologically equipotent diastereoisomers. The absorption, distribution, metabolism and excretion properties of darolutamide in rats are reported.

2. Non- or [¹⁴C]-labelled darolutamide, its diastereoisomers and major metabolite were studied in intact and bile duct-cannulated rats (oral and intravenous administration), and rat hepatocytes.

3. Darolutamide was quickly (1 h to reach maximum plasma concentration) and completely absorbed after oral administration. Absolute bioavailability was high. Keto-darolutamide was the most abundant metabolite in rat hepatocytes and the only major one in plasma. Interconversion between diastereoisomers was observed.

4. After oral administration, radioactivity distributed widely and homogeneously. Penetration into brain was low (brain/blood ratio = 0.079). Elimination was rapid from most tissues. Excretion occurred rapidly, and routes were similar irrespective of administration routes. Complete mass balance was reached by 168 h post-dose. Most radioactivity (61–64%) was excreted in faeces, while relevant amounts (30–33%) were also excreted into urine. The main clearance routes were metabolism via oxidative reactions and glucuronidation. After intravenous administration, a relevant extent of the dose (20%) underwent extrabiliary excretion as darolutamide.

Keywords:

• Absorption
• distribution
• metabolism and excretion (ADME)
• blood–brain barrier
• pharmacokinetics
• autoradiography
• rats
• preclinical
• androgen receptor antagonist

Acknowledgements

Thomas Schwarz, Bayer AG, was the study director for the animal experimental part of bile duct cannulated rat. Anne Luiro, Orion Pharma, was the radiochemist who developed the synthesis method and was responsible for the synthesis of synthesising [¹⁴C]darolutamide for most of the studies in this manuscript. Arja Vuorela, Orion Pharma, is acknowledged for her support in study planning. Medical writing support, including assisting authors with the development of the original draft and incorporation of comments was provided by Rebecca Hopkins, BSc, of Scion (London, UK). Editorial assistance was provided by Annabel Ola, MSc, of Scion (London, UK). Funding for this publication was provided by Bayer HealthCare Pharmaceuticals, Inc. (Whippany, NJ), in line with GPP3 guidelines (http://annals.org/aim/fullarticle/2424869/good-publication-practice-communicating-company-sponsored-medical-research-gpp3). Bayer AG, Pharmaceuticals and Orion Pharma division were involved in the study design, collection, analysis and interpretation of data, as well as data checking of information provided in the manuscript. Charles River Laboratories conducted and reported most of the in vivo rat studies under the direction of Bayer AG and Orion Pharma. However, ultimate responsibility for opinions, conclusions, and data interpretation lies with the authors.

Disclosure statement

Dr. Gieschen, Dr. Sandmann and Dr. Prien report employment by and stock ownership in Bayer. Dr. Niehues, and Dr. Janssen report employment by Bayer. Dr. Taavitsainen, Dr. Kähkönen and Dr. Malmström report employment by Orion. Dr. Korjamo and Dr. Koskinen report employment by and stock ownership in Orion.

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