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 diastereomers was investigated in cryopreserved
Balb/c mouse hepatocytes. Protein binding was determined in plasma samples by equilibrium dialysis.
Results and Discussion: At day 7, Cmax was reached 30 min after last dose. Rapid formation and greater exposure of ketodarolutamide 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, conversion of (S,S)- to (S,R)-darolutamide was observed but 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 ketodarolutamide are pharmacologically similar in vitro. Based on the high protein binding of keto-darolutamide, its
contribution in vivo in humans is considered low.