Higher blood–brain barrier penetration of [14C]apalutamide and [14C]enzalutamide compared to [14C]darolutamide in rats using whole-body autoradiography.

156 Background: Darolutamide ([14C]Daro) is an investigational oral androgen receptor antagonist, structurally distinct from enzalutamide ([14C]Enza) and apalutamide ([14C]Apa). In a retrospective analysis of the ARADES database, central nervous system (CNS)-related adverse events (AEs) were not linked with Daro (Fizazi, et al. 2015). CNS-related AEs have been observed with Enza and Apa, eg, fatigue, mental impairment, and seizure (Hussain et al, 2018; Smith et al, 2018). In preclinical studies, low blood–brain barrier (BBB) penetration of Daro was observed, suggesting low impact on the CNS. To understand the different CNS effects, we report in vivo tissue distribution data in rats with [14C]-labeled Apa compared to previously presented [14C]Enza and [14C]Daro distribution data (Zurth, ASCO GU 2018) using quantitative whole-body autoradiography (QWBA). Methods: Male rats were orally dosed with 10 mg/kg [14C]Apa under similar experimental conditions as previously reported for [14C]Daro or [14C]Enza, prior to QWBA. One animal was sacrificed at each timepoint: (tmax) 3h, 8h, and 24h post-dose. Timepoint selection was based on a single oral Apa dose pharmacokinetic study in rats. Results: Apa displayed good absorption and homogeneous distribution throughout the body early post-dose, comparable to previous observations for Enza and Daro. As observed for [14C]Enza, [14C]Apa remained constant in the body (t1/2 ~4h vs ~3h) up to 8h post-dose, whereas [14C]Daro was eliminated from all tissues (t1/2 ~1h). High concentrations of [14C]Apa persisted in the brain for up to 8h, although concentrations were ~2-fold lower than previously reported for [14C]Enza. [14C]Daro brain concentrations were near the lower limit of quantification, and ~26x and 46x lower than [14C]Apa and [14C]Enza brain concentrations, respectively. Conclusions: The current preclinical study demonstrated moderate BBB penetration for Apa, similar to the previous Enza data, whereas Daro displayed > 25-fold lower BBB penetration, suggesting that Daro may be less likely to induce CNS-related AEs, which is expected to be confirmed by data from the ARAMIS study.

Blood-brain barrier penetration of [14C]darolutamide compared with [14C]enzalutamide in rats using whole body autoradiography.

345 Background: Darolutamide (ODM-201) (Daro) is an investigational oral and high-affinity androgen receptor antagonist. In preclinical studies, penetration of Daro through the blood–brain barrier (BBB) is negligible and in a retrospective safety analysis of the ARADES database for CNS-related adverse events (AEs), only 1 report of urinary incontinence was linked to Daro (Fizazi K, et al. 2015). Various clinical trials on enzalutamide (Enza) have reported CNS AEs (eg, seizure, falls, fatigue, pain). To understand the differences in CNS outcomes, we report an in vivo tissue distribution study with [14C]-labelled Enza and Daro in a head-to-head study in rats by means of quantitative whole-body autoradiography (QWBA). Methods: Male rats were orally dosed with 10 mg/kg [14C]Daro or [14C]Enza in the same formulation, administration volume, and radioactive dose. The animals were sacrificed at each drug’s specific tmax (time to reach the maximum concentration) in blood and brain and processed for QWBA. Results: At early time points [14C]Daro- and [14C]Enza-derived radioactivity was rapidly absorbed from the gastrointestinal tract and homogenously distributed throughout the body. By 8 h post dose, [14C]Daro was significantly eliminated from almost all organs/tissues, whereas [14C]Enza remained constant within the body. In contrast to [14C]Daro, high and persistent radioactivity was observed in brain for [14C]Enza. At tmax, the brain/blood-ratio of [14C]Enza was ~0.765, while [14C]Daro was about 10-fold lower at ~0.074. Conclusions: Results show that post dose, there was a 10-fold lower BBB penetration of [14C]Daro compared with [14C]Enza. At 8 h, [14C]Daro was rapidly eliminated and almost undetectable in all tissues, including brain, in contrast to [14C]Enza that remained constant. These data suggest that Daro might have a lower risk of inducing CNS-related AEs than Enza. Further clinical studies are ongoing.