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.
[http://dx.doi.org/10.1016/S1470-2045(14)70240-2] [PMID: 24974051]
[http://dx.doi.org/10.1016/j.eururo.2015.09.046] [PMID: 26463318]
[http://dx.doi.org/10.1007/s00280-017-3417-3] [PMID: 28801852]
[http://dx.doi.org/10.1002/ijc.32242] [PMID: 30828788]
[http://dx.doi.org/10.1038/srep12007] [PMID: 26137992]
[http://dx.doi.org/10.1080/00498254.2020.1723038] [PMID: 32003293]
[http://dx.doi.org/10.2174/1872312814666200521091236] [PMID: 32436836]