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.