Pharmacokinetics of Darolutamide in Mouse - Assessment of the Disposition of the Diastereomers, Key Active Metabolite and Interconversion Phenomenon: Implications to Cancer Patients

Author(s): Neeraj K. Saini, Bhavesh B. Gabani, Umesh Todmal, Suresh P. Sulochana, Vinay Kiran, Mohd. Zainuddin, Narayanan Balaji, Sai B. Polina, Nuggehally R. Srinivas, Ramesh Mullangi*

Journal Name: Drug Metabolism Letters

Volume 14 , Issue 1 , 2021

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Graphical Abstract:


Background: Darolutamide is recently approved for the treatment of non-metastatic castrate resistance prostate cancer. Hitherto, no stereoselective pharmacokinetic data have been published pertaining to darolutamide and its diastereomers in animals or humans. The key aims of the experiment were to examine darolutamide, S,S-darolutamide and S,R-darolutamide with respect to (a) assessment of in vitro metabolic stability and protein binding and (b) characterization of in vivo oral and intravenous pharmacokinetics in mice.

Methods: In vitro (liver microsomes stability and protein binding) and in vivo experiments (oral/intravenous dosing to mice) were carried out using darolutamide, S,S-darolutamide and S,Rdarolutamide. Besides, tissue levels of darolutamide, S,S-darolutamide and S,R-darolutamide were measured following oral and intravenous dosing. Appropriate plasma/tissue samples served to determine the pharmacokinetics of various analytes in mice. Liquid chromatography in tandem with mass spectrometry procedures enabled the delineation of the plasma pharmacokinetics, in vitro and tissue uptake data of the various analytes.

Results: Chiral inversion was absent in the metabolic stability study. However, darolutamide showed profound stereoselectivity (S,S-darolutamide greater than S,R-darolutamide) after either intravenous or oral dosing. S,R-darolutamide but not S,S-darolutamide showed conversion to its antipode post oral and intravenous dosing to mice. Regardless of oral or intravenous dosing, active keto darolutamide formation was evident after administration of darolutamide, S,S-darolutamide or S,R- darolutamide. Tissue data supported the observations in plasma; however, tissue exposure of darolutamide, S,Sdarolutamide and S,R-darolutamide was much lower as compared to plasma.

Conclusion: In lieu of the human pharmacokinetic data, although the administration of diastereomeric darolutamide was justified, it is proposed to delineate the clinical pharmacokinetics of S,Rdarolutamide and S,S-darolutamide relative to darolutamide in future clinical pharmacology studies.

Keywords: Darolutamide, ORM-15341, diastereomers, stereoselective, disposition, mice.

Body, A.; Pranavan, G.; Tan, T.H.; Slobodian, P. Medical management of metastatic prostate cancer. Aust. Prescr., 2018, 41(5), 154-159.
[ ] [PMID: 30410212]
Baciarello, G.; Gizzi, M.; Fizazi, K. Advancing therapies in metastatic castration-resistant prostate cancer. Expert Opin. Pharmacother., 2018, 19(16), 1797-1804.
[ ] [PMID: 30311804]
Maia, M.C.; Pereira, A.A.L.; Lage, L.V.; Fraile, N.M.; Vaisberg, V.V.; Kudo, G.; Barroso-Sousa, R.; Bastos, D.A.; Dzik, C. Efficacy and safety of docetaxel in elderly patients with metastatic castration-resistant prostate cancer. J. Glob. Oncol., 2018, 4, 1-9.
[ ] [PMID: 30241182]
Scott, L.J. Abiraterone acetate: A review in metastatic castration-resistant prostrate cancer. Drugs, 2017, 77(14), 1565-1576.
[ ] [PMID: 28819727]
Scott, L.J. Enzalutamide: A review in castration-resistant prostate cancer. Drugs, 2018, 78(18), 1913-1924.
[ ] [PMID: 30535926]
Han, C.S.; Patel, R.; Kim, I.Y. Pharmacokinetics, pharmacodynamics and clinical efficacy of abiraterone acetate for treating metastatic castration-resistant prostate cancer. Expert Opin. Drug Metab. Toxicol., 2015, 11(6), 967-975.
[ ] [PMID: 25936418]
Hong, J.H. Pharmacokinetic/pharmacodynamic drug evaluation of enzalutamide for treating prostate cancer. Expert Opin. Drug Metab. Toxicol., 2018, 14(3), 361-369.
[ ] [PMID: 29431540]
FDA 2019 FDA approves darolutamide for non-metastatic castration-resistant prostate cancer., Available at: drugs/fda-approves-darolutamide-non-metastatic-castration-resistant-prostate- [Accessed: 25 Aug. 2019]
Moilanen, A.; Riikonen, R.; Oksala, R.; Ravanti, L.; Aho, E.; Wohlfahrt, G.; Törmäkangas, O.; Kallio, P.J. ODM-201- new generation antiandrogen with excellent antiandrogenic and antitumor activity in nonclinical models of CRPC. Eur. J. Cancer, 2013, 49, 2869.
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.
[ ] [PMID: 26137992]
Shore, N.D. Darolutamide (ODM-201) for the treatment of prostate cancer. Expert Opin. Pharmacother., 2017, 18(9), 945-952.
[ ] [PMID: 28490267]
Zurth, C.; Koskinen, M.; Fricke, R.; Prien, O.; Korjamo, T.; Graudenz, K.; Denner, K.; Bairlein, M.; von Bühler, C.J.; Wilkinson, G.; Gieschen, H. drug-drug interaction potential of darolutamide: In vitro and clinical studies. Eur. J. Drug Metab. Pharmacokinet., 2019, 44(6), 747-759.
[ ] [PMID: 31571146]
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. American Association of Pharmaceutical Scientists., Nov 13-17, Denver, CO.2016. Abstract no: 10W1100. (a) 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.
[ ] [PMID: 28801852]
Rej, R.K.; Acharyya, R.K.; Nanda, S. Assymetric synthesis of dihydroarteminisic acid through intramolecular Stetter reaction. Tetrahedron, 2016, 72, 4931-4937.
Dittakavi, S.; Nagasuri, P.K.V.S.P.; Sulochana, S.P.; Saim, S.M.; Mallurwar, S.R.; Zainuddin, M.; Dewang, P.; Rajagopal, S.; Mullangi, R. LC-MS/MS-ESI method for simultaneous quantification of darolutamide and its active metabolite, ORM-15341 in mice plasma and its application to a pharmacokinetic study. J. Pharm. Biomed. Anal., 2017, 145, 454-461.
[ ] [PMID: 28743076]
Balaji, N.; Sulochana, S.P.; Saini, N.K. A, S.K.; Mullangi, R. A, S.K.; Mullangi, R. Validated chiral LC-ESI-MS/MS method for the simultaneous quantification of darolutamide diastereomers and its active metabolite in mice plasma: Application to a pharmacokinetic study. Drug Res. (Stuttg.), 2018, 68(11), 615-624. b
[ ] [PMID: 29558780]
Ariëns, E.J. Implications of the neglect of stereochemistry in pharmacokinetics and clinical pharmacology. Drug Intell. Clin. Pharm., 1987, 21(10), 827-829.
[ ] [PMID: 3322758]
Srinivas, N.R.; Hubbard, J.W.; Quinn, D.; Midha, K.K. Enantioselective pharmacokinetics and pharmacodynamics of dl-threo-methylphenidate in children with attention deficit hyperactivity disorder. Clin. Pharmacol. Ther., 1992, 52(5), 561-568.
[ ] [PMID: 1424430]
Srinivas, N.R.; Hubbard, J.W.; Korchinski, E.D.; Midha, K.K. Enantioselective pharmacokinetics of dl-threo-methylphenidate in humans. Pharm. Res., 1993, 10(1), 14-21.
[ ] [PMID: 8430051]
Srinivas, N.R.; Barbhaiya, R.H.; Midha, K.K. Enantiomeric drug development: Issues, considerations, and regulatory requirements. J. Pharm. Sci., 2001, 90(9), 1205-1215.
[ ] [PMID: 11745774]
Testa, B. Types of stereoselectivity in drug metabolism: A heuristic approach. Drug Metab. Rev., 2015, 47(2), 239-251.
[ ] [PMID: 25410915]
Dash, R.P.; Rais, R.; Srinivas, N.R. Stereoselective and nonstereoselective pharmacokinetics of rabeprazole - an overview. Xenobiotica, 2018, 48(4), 422-432. a
[ ] [PMID: 28294690]
Dash, R.P.; Rais, R.; Srinivas, N.R. Chirality and neuropsychiatric drugs: An update on stereoselective disposition and clinical pharmacokinetics of bupropion. Xenobiotica, 2018, 48(9), 945-957. b
[ ] [PMID: 28876959]
Balaji, N.; Sulochana, S.P.; Saini, N.K.A, S.K.; Mullangi, R. Simultaneous quantitation of darolutamide diastereomers in mouse plasma and its application to a stereoselective pharmacokinetic study in mice. Biomed. Chromatogr., 2018a, 32e4173
[ ] [PMID: 29315691]
Srinivas, N.R.; Hubbard, J.W.; Quinn, D.; Korchinski, E.D.; Midha, K.K. Extensive and enantioselective presystemic metabolism of dl-threo-methylphenidate in humans. Prog. Neuropsychopharmacol. Biol. Psychiatry, 1991, 15(2), 213-220.
[ ] [PMID: 1871323]
Cheng, H.; Rogers, J.D.; Demetriades, J.L.; Holland, S.D.; Seibold, J.R.; Depuy, E. Pharmacokinetics and bioinversion of ibuprofen enantiomers in humans. Pharm. Res., 1994, 11(6), 824-830.
[ ] [PMID: 7937520]
Gabani, B.B.; Todmal, U.; Saini, N.K.; Balakrishna, V.A.; Sulochana, S.P.; Timmapuram, A.; Zainuddin, M.; Balaji, N.; Shuvranshu, P.; Srinivas, N.R.; Mullangi, R. Stereoselective pharmacokinetics and tissue distribution of levodropropizine after administration of pure levodropropizine and the rac-dropropizine to Sprague-Dawley rats. Xenobiotica, 2020, 50(2), 135-144.
[ ] [PMID: 30896275]

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Article Details

Year: 2021
Published on: 20 May, 2020
Page: [54 - 65]
Pages: 12
DOI: 10.2174/1872312814666200521091236
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