Various clinical trials on enzalutamide have reported CNS adverse events, including seizures, falls, fatigue, pain. Thus, in order to understand the differences in CNS outcomes between these two agents, the objective of this study was to report an in vivo tissue distribution assessment with [14C]-labelled enzalutamide and darolutamide in a head-to-head study in rats by means of quantitative whole-body autoradiography.
For this study, male rats were orally dosed with 10 mg/kg [14C]-darolutamide or [14C]-enzalutamide in the same formulation, administration volume, and radioactive dose. The animals were then sacrificed at each drug’s specific tmax (time to reach the maximum concentration) in blood and the brain and processed for whole body autoradiography. The authors found that at early time points, [14C]-darolutamide and [14C]-enzalutamide derived radioactivity was rapidly absorbed from gastrointestinal tract and distributed throughout the body. By 8 hours after the medication, [14C]-darolutamide was significantly eliminated from almost all organs/tissues, whereas [14C]-enzalutamide remained constant within the body. In contrast to [14C]-darolutamide, high and persistent radioactivity was observed in the brain for [14C]-enzalutamide. At tmax, the brain/blood-ratio of [14C]-enzalutamide was ~0.765, while [14C]-darolutamide was ~10-fold lower at ~0.074.
The authors concluded that post-treatment, there was a 10-fold lower blood-brain barrier penetration of [14C]-darolutamide compared with [14C]-enzalutamide. At 8 h, [14C]-darolutamide was rapidly eliminated and almost undetectable in all tissues, including brain, in contrast to [14C]-enzalutamide which remained constant. These results suggest that darolutamide may have a lower risk of inducing CNS-related adverse events compared to enzalutamide, which will ultimately be decided/confirmed in ongoing clinical studies.
Presented by: Christian Zurth, Bayer AG, Berlin, Germany
Co-Authors: Steffen Sandmann, Dagmar Trummel, Dietrich Seidel, Hille Gieschen
Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre @zklaassen_md at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA
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