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