Pharmacokinetics of Darolutamide, its Diastereomers and Active Metabolite in the Mouse: Response to Saini NK et al. (2020)

Author(s): Pirjo Nykänen, Timo Korjamo, Hille Gieschen, Christian Zurth, Mikko Koskinen*

Journal Name: Drug Metabolism Letters

Volume 14 , Issue 1 , 2021


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Graphical Abstract:


Abstract:

Background: Saini et al. recently investigated the pharmacokinetics of darolutamide and its diastereomers in vitro and in vivo in Balb/c mice, reporting higher levels of (S,S)-darolutamide than (S,R)-darolutamide following intravenous or oral dosing, and interconversion of (S,R)-darolutamide to (S,S)-darolutamide.

Objective: To present our in vitro and in vivo studies of darolutamide pharmacokinetics in mice, which contrast with the findings of Saini et al.

Methods: Nude male Balb/c mice were orally dosed for 7 days with 25, 50, or 100 mg/kg of darolutamide twice daily. Pharmacokinetic parameters in plasma and tissue samples were assessed by liquid chromatography-tandem mass spectrometry. Metabolism and interconversion of darolutamide and its diastereomers were investigated in cryopreserved Balb/c mouse hepatocytes. Protein binding was determined in plasma samples by equilibrium dialysis.

Results: On day 7, Cmax was reached 30 min after the last dose. Rapid formation and greater exposure of keto-darolutamide versus darolutamide were observed. Plasma exposure of (S,R)-darolutamide was 3-5-fold higher than that of (S,S)-darolutamide. The fraction of unbound keto-darolutamide was almost 6-fold lower than for darolutamide.

In mouse hepatocytes, the conversion of (S,S)- to (S,R)-darolutamide was observed, but the conversion of (S,R)- to (S,S)-darolutamide was not detectable. Back-formation of keto-darolutamide to both diastereomers occurred at low levels.

Conclusion: The darolutamide diastereomer ratio changes upon administration in mice and other species due to interconversion through keto-darolutamide. This is not considered clinically relevant since both diastereomers and keto- darolutamide are pharmacologically similar in vitro. Based on the high protein binding of keto-darolutamide, its contribution in vivo in humans is considered low.

Keywords: Darolutamide, pharmacokinetics, mice, diastereomer, interconversion, metabolism.

[1]
Fizazi, K.; Massard, C.; Bono, P.; Jones, R.; Kataja, V.; James, N.; Garcia, J.A.; Protheroe, A.; Tammela, T.L.; Elliott, T.; Mattila, L.; Aspegren, J.; Vuorela, A.; Langmuir, P.; Mustonen, M. ARADES study group. Activity and safety of ODM-201 in patients with progressive metastatic castration-resistant prostate cancer (ARADES): an open-label phase 1 dose-escalation and randomised phase 2 dose expansion trial. Lancet Oncol., 2014, 15(9), 975-985.
[http://dx.doi.org/10.1016/S1470-2045(14)70240-2] [PMID: 24974051]
[2]
Massard, C.; Penttinen, H.M.; Vjaters, E.; Bono, P.; Lietuvietis, V.; Tammela, T.L.; Vuorela, A.; Nykänen, P.; Pohjanjousi, P.; Snapir, A.; Fizazi, K. Pharmacokinetics, antitumor activity, and safety of ODM-201 in patients with chemotherapy-naive metastatic castration-resistant prostate cancer: an open-label phase 1 study. Eur. Urol., 2016, 69(5), 834-840.
[http://dx.doi.org/10.1016/j.eururo.2015.09.046] [PMID: 26463318]
[3]
Matsubara, N.; Mukai, H.; Hosono, A.; Onomura, M.; Sasaki, M.; Yajima, Y.; Hashizume, K.; Yasuda, M.; Uemura, M.; Zurth, C. Phase 1 study of darolutamide (ODM-201): a new-generation androgen receptor antagonist, in Japanese patients with metastatic castration-resistant prostate cancer. Cancer Chemother. Pharmacol., 2017, 80(6), 1063-1072.
[http://dx.doi.org/10.1007/s00280-017-3417-3] [PMID: 28801852]
[4]
Sugawara, T.; Baumgart, S.J.; Nevedomskaya, E.; Reichert, K.; Steuber, H.; Lejeune, P.; Mumberg, D.; Haendler, B. Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models. Int. J. Cancer, 2019, 145(5), 1382-1394.
[http://dx.doi.org/10.1002/ijc.32242] [PMID: 30828788]
[5]
Bayer HealthCare Pharmaceuticals Inc. Nubeqa (darolutamide) US prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212099Orig1s000lbl.pdf
[6]
Moilanen, A.M.; Riikonen, R.; Oksala, R.; Ravanti, L.; Aho, E.; Wohlfahrt, G.; Nykänen, P.S.; Törmäkangas, O.P.; Palvimo, J.J.; Kallio, P.J. Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies. Sci. Rep., 2015, 5, 12007.
[http://dx.doi.org/10.1038/srep12007] [PMID: 26137992]
[7]
Taavitsainen, P.; Gieschen, H.; Korjamo, T.; Kähkönen, M.; Malmström, C.; Prien, O.; Niehues, M.; Sandmann, S.; Janssen, W.; Koskinen, M. Absorption, distribution, metabolism and excretion of darolutamide (a novel non-steroidal androgen receptor antagonist) in rats. Xenobiotica, 2020, 50(8), 967-979.
[http://dx.doi.org/10.1080/00498254.2020.1723038] [PMID: 32003293]
[8]
Fizazi, K.; Smith, M.R.; Tombal, B. Clinical development of darolutamide: a novel androgen receptor antagonist for the treatment of prostate cancer. Clin. Genitourin. Cancer, 2018, 16(5), 332-340.
[http://dx.doi.org/10.1016/j.clgc.2018.07.017] [PMID: 30197098]
[9]
Saini, N.K.; Gabani, B.B.; Todmal, U.; Sulochana, S.P.; Kiran, V.; Zainuddin, M.; Balaji, N.; Polina, S.B.; Srinivas, N.R.; Mullangi, R. Pharmacokinetics of darolutamide in mouse - assessment of the disposition of the diastereomers, key active metabolite and interconversion phenomenon: implications to cancer patients. Drug Metab. Lett., 2020, 2020
[http://dx.doi.org/10.2174/1872312814666200521091236] [PMID: 32436836]
[10]
Taavitsainen, P.; Prien, O.; Vuorela, A.; Nykanen, P.; Sairanen, U.; Gieschen, H.; Zurth, C. Pharmacokinetics, mass balance, and metabolite profiling of ODM-201 in healthy men: An open-label, phase 1 trial. Presented at: American Association of Pharmaceutical Scientists, , 2016; p. p Nov;13–17; Denver, CO.
[11]
European Medicines Agency. Nubeqa (darolutamide) European public assessment report https://www.ema.europa.eu/en/documents/assessment-report/nubeqa-epar-public-assessment-report_en.pdf


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Article Details

VOLUME: 14
ISSUE: 1
Year: 2021
Published on: 12 November, 2020
Page: [9 - 16]
Pages: 8
DOI: 10.2174/1872312814666201112121129

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