In Vitro Studies Investigating the Interactions between Degarelix, a Decapeptide Gonadotropin‐Releasing Hormone Blocker, and Cytochrome P450

Abstract

The decapeptide degarelix is a novel competitive gonadotropin-releasing hormone receptor antagonist that has been approved for the treatment of advanced prostate cancer by the FDA and the EU authorities. In this study, the interaction of degarelix with human cytochrome P450 (CYP450) enzymes was investigated in vitro. Inhibition of CYP450 was performed in human liver microsomes using documented marker substrates for the CYP450 isozymes CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP2E1. The inhibitory effects on selected P450 enzyme activities were investigated with degarelix concentrations representing the range of 2-200 times of expected clinical concentrations. No inhibition of any isozyme-catalysed biotransformations studied was detected. Induction of CYP450 enzyme activity by degarelix was investigated using primary human hepatocytes. Cryopreserved plateable hepatocytes and fresh hepatocytes in culture were treated for two-three consecutive days with degarelix at concentrations of 0.1, 1.0 and 10 μM. The cultured hepatocytes were also treated with three prototypical CYP450 inducers: omeprazole, phenobarbital and rifampin as positive controls for CYP450 enzyme induction. No induction of the activity of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP3A4 isozymes was observed. Degarelix appears to be a poor substrate of the CYP450 enzyme system, and the in vitro results indicate that the interaction between CYP450 and degarelix is low. These results indicate that degarelix is unlikely to cause any clinically significant drug-drug interactions in vivo.