Clinical Pharmacokinetics of the Androgen Receptor Inhibitor Darolutamide in Healthy Subjects and Patients with Hepatic or Renal Impairment
Christian Zurth, Pirjo Nykänen, Gary Wilkinson, Päivi Taavitsainen, Annamari Vuorela, Funan Huang, Susanne Reschke, Mikko Koskinen, Christian Zurth, Pirjo Nykänen, Gary Wilkinson, Päivi Taavitsainen, Annamari Vuorela, Funan Huang, Susanne Reschke, Mikko Koskinen
Abstract
Background: Darolutamide is a second-generation androgen receptor inhibitor approved for the treatment of nonmetastatic castration-resistant prostate cancer at a dosage of 600 mg orally twice daily.
Objective: We aimed to fully characterize the pharmacokinetic profile of darolutamide, its diastereomers, and its main active metabolite, keto-darolutamide.
Methods: Single-dose and multiple-dose pharmacokinetics of 14C-labeled and non-labeled darolutamide were evaluated in healthy subjects and patients with hepatic or renal impairment.
Results: Following darolutamide oral tablet administration, peak plasma concentrations were reached 4-6 h after dosing. Darolutamide elimination was characterized by a half-life of 13 h. Steady state was reached after approximately 2 days of twice-daily dosing. Pharmacokinetics of the diastereomers and keto-darolutamide followed similar trends to the parent compound. Darolutamide absorption from the tablet was lower than from the oral solution; tablet absolute bioavailability was ~30% in the fasted state but improved to 60-75% when given with food. The unbound fraction of darolutamide in plasma was 7.8%. The administered 1:1 ratio of the diastereomers (S,R)-darolutamide and (S,S)-darolutamide changed to ~1:6 in plasma following multiple dosing. Similar exposure and diastereomer ratios after single and multiple dosing indicate time-independent (no autoinduction) linear pharmacokinetics. Darolutamide exposure increased in patients with moderate hepatic or severe renal impairment vs healthy subjects; dose adaptation at treatment initiation should be considered in these patients.
Conclusions: Darolutamide 600 mg twice daily demonstrates predictable linear pharmacokinetics and sustainably high plasma concentrations, suggesting the potential for constant inhibition of the androgen receptor signaling pathway.
Clinical trials registration: NCT02418650, NCT02894385, NCT02671097.
Conflict of interest statement
Susanne Reschke reports employment by Bayer. Christian Zurth, Funan Huang, and Gary Wilkinson report employment by and stock ownership in Bayer. Pirjo Nykänen, Päivi Taavitsainen, and Annamari Vuorela report employment by Orion Pharma. Mikko Koskinen reports employment by and stock ownership in Orion Pharma. Medical writing support, including assisting authors with the development of the outline and initial draft and incorporation of comments, was provided by Francesca Kolbe, PhD, and Tamsin Williamson, and editorial support was provided by Annabel Ola, MSc, all of Scion (London, UK) supported by Bayer Healthcare Pharmaceuticals, Inc. (Whippany, NJ, USA). Medical writing support, including assisting authors with the development of the submission draft, was provided by Sara Black, ISMPP CMPP™, of OPEN Health Communications (London, UK), supported by Bayer.
© 2021. The Author(s).
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Source: PubMed