Clinical Pharmacokinetics of the Androgen Receptor Inhibitor Darolutamide in Healthy Subjects and Patients with Hepatic or Renal Impairment

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).

Figures

Fig. 1

Mean (standard deviation) plasma keto-darolutamide/darolutamide, (S,R)-darolutamide/darolutamide, and (S,S)-darolutamide/darolutamide concentration ratio vs time profiles following a single intravenous (IV) dose of 14C-darolutamide 100 μg (n = 6 healthy male subjects). h hours

Fig. 2

Geometric mean (standard deviation) concentration of darolutamide, (S,R)-darolutamide, (S,S)-darolutamide, and keto-darolutamide following a single dose of darolutamide 600 mg as two 300-mg oral tablets in healthy male subjects: linear and semilogarithmic plots (n = 15). h hours

Fig. 3

Mean plasma concentration–time profile of darolutamide 600 mg following single and multiple twice-daily oral administration in healthy male subjects: linear and semilogarithmic plots (n = 15). h hours

Fig. 4

Comparison of healthy male subjects, patients without cancer with hepatic or renal impairment, and patients with cancer for exposure (a) and maximum (peak) plasma concentration [Cmax] (b) after single-dose darolutamide 600 mg, and exposure after repeated twice-daily darolutamide 600 mg [, –11]. Area under the concentration–time curve from time 0 to 12 h after darolutamide administration (AUC0–12) at steady state (including the 5th and 95th percentiles) is presented for patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Studies 17721, 17726, and ARAFOR evaluated single doses of darolutamide, whereas studies 17723, 17719, and ARAMIS evaluated multiple doses. Study 17726 was a phase I, drug–drug interaction study evaluating the effects of cytochrome P450 3A4 inducers on the pharmacokinetics of darolutamide [11]. aTablet A and Tablet B were the same immediate-release formulation of darolutamide, but a coarser grade of drug substance was used in Tablet B [9]. AUC0–tlast area under the concentration–time curve from time 0 to the last concentration above the lower limit of quantification, mCRPC metastatic castration-resistant prostate cancer, nmCRPC nonmetastatic castration-resistant prostate cancer