Metabolism and Mass Balance of the Novel Nonsteroidal Androgen Receptor Inhibitor Darolutamide in Humans

Abstract

The biotransformation and excretion of darolutamide were investigated in a phase I study. Six healthy male volunteers received a single dose of 300 mg 14 Cdarolutamide as oral solution in the fasted state. Plasma, urine, and feces samples were analyzed for mass balance evaluation by liquid scintillation counting (LSC).Metabolite profiling and identification were determined using liquid chromatography mass spectrometry with off-line radioactivity detection using LSC. Complete mass balance was achieved, with mean radioactivity recovery of 95.9% within 168 hours (63.4% in urine, 32.4% in feces). The administered 1:1 ratio of (S,R)-and (S,S)darolutamide changed to approximately 1:5, respectively, in plasma. Darolutamide and the oxidation product, keto-darolutamide, were the only components quantifiable by LSC in plasma, accounting for 87.4% of total radioactivity, with a 2.1-fold higher plasma exposure for keto-darolutamide. Aside from darolutamide, the most prominent metabolites in urine were O-glucoronide (M-7a/b) and N-glucuronide (M-15a/b) as well as pyrazole sulfates (M-29, M-24) and glucuronides (M-21, M-22)resulting from oxidative cleavage of the parent. The darolutamide diastereomers were mainly detected in feces. In vitro assays showed that darolutamide metabolism involves a complex interplay between oxidation and reduction, as well as glucuronidation. Interconversion of the diastereomers involves oxidation to ketodarolutamide, primarily mediated by CYP3A4, followed by reduction predominantly catalyzed by cytosolic reductase(s), with aldo-keto reductase 1C3 playing the major role. The latter reaction showed stereoselectivity with preferential formation of (S,S)darolutamide.

Clinical Pharmacokinetics of the Androgen Receptor Inhibitor Darolutamide in Healthy Subjects and Patients with Hepatic or Renal Impairment

“…It is rapidly interconverted between the two diastereomers as measured in plasma, with a 1:1 ratio in the administered dose changing to favor ( S,S )-darolutamide over ( S,R )-darolutamide regardless of the dosing route or formulation (diastereomer ratios for ( S,R )-darolutamide and ( S,S )-darolutamide, respectively, ranged from 1:3 to 1:5). In vitro studies in human hepatocytes [ 6 ] and clearance and t ½ data confirm there is more rapid elimination of ( S,R )-darolutamide than ( S , S )-darolutamide from plasma, resulting in the observed preponderance of ( S,S )-darolutamide following dosing. As ( S,R )-darolutamide and ( S,S )-darolutamide exhibit the same physicochemical, pharmacologic, and toxicologic properties, both diastereomers are considered to contribute equally and interchangeably to the efficacy and safety of darolutamide [ 4 , 17 ].…”

“…The ARIADME study was a phase I, single-center, open-label, non-randomized, two-part trial to determine the absolute bioavailability and pharmacokinetics of darolutamide, its diastereomers, and keto-darolutamide, as well as evaluations of mass balance, metabolism, and excretion routes of darolutamide, which are reported elsewhere [ 6 ]. In Part 1, six healthy male subjects received a single oral dose of darolutamide 300 mg as a tablet, followed by a single IV microtracer dose administered as a 15-min infusion ending at the expected t max for the oral tablet (3 h post-dose) to assess absolute bioavailability.…”

“…These diastereomers interconvert via the major metabolite keto-darolutamide (Fig. 1 in the Electronic Supplementary Material [ESM]), and all three compounds have similar pharmacologic activity in vitro [ 2 – 6 ].…”

Clinical Pharmacokinetics and Pharmacodynamics of the Next Generation Androgen Receptor Inhibitor—Darolutamide

“…In addition, the darolutamide diastereomers, (S,S)-darolutamide and (S,R)-darolutamide, interconvert via keto-darolutamide (Fig. 2 ) [ 10 , 38 ]. Interconversion is a two-step process consisting of oxidative biotransformation to keto-darolutamide and reductive metabolism back to the diastereomers, favoring the formation of (S,S)-darolutamide.…”

“…Interconversion is a two-step process consisting of oxidative biotransformation to keto-darolutamide and reductive metabolism back to the diastereomers, favoring the formation of (S,S)-darolutamide. This process is mainly catalyzed by CYP3A4 and aldo-keto reductase (AKR) 1C isoforms, respectively [ 9 , 10 , 38 ]. Keto-darolutamide is also a substrate for further CYP3A4 oxidation.…”