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.