Background: Darolutamide is recently approved for the treatment of non-metastatic castrate resistance prostate cancer.
Hitherto, no stereoselective pharmacokinetic data has 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 stability and protein binding (b) characterization of in vivo oral and intravenous pharmacokinetics in mice.
Method: 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,R-darolutamide. 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,Sdarolutamide 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 the various darolutamide, S,S-darolutamide and S,R-darolutamide
were 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,R-darolutamide and S,S-darolutamide relative to darolutamide in future clinical pharmacology studies.