In Vitro and In Vivo Human Metabolism of Degarelix, a Gonadotropin-Releasing Hormone Receptor Blocker

Abstract

Degarelix is a decapeptide that shows high affinity/selectivity to human gonadotropin-releasing hormone receptors and has been approved for the treatment of advanced prostate cancer in the United States, European Union, and Japan. To investigate the metabolism of degarelix in humans, in vitro metabolism was addressed in liver tissue and in vivo metabolism was studied in plasma and excreta samples collected in clinical studies. In addition, drug transporter interaction potential of degarelix with selected efflux transporters and uptake transporters was studied using in vitro membrane vesicle-based assays and whole cell-based assays. In vitro degradation was observed in fresh hepatocytes; less than 25% of the initial concentration of degarelix remained after incubation at 37°C for 2 hours. One metabolite was detected, representing a truncated nonapeptide of degarelix. The same metabolite was also detected at low concentrations in plasma. The in vivo investigations also showed that degarelix is excreted unchanged via the urine but is undergoing extensive sequential peptidic degradation during its elimination via the hepato-biliary pathway. No unique human metabolites of degarelix were detected in the circulation or in the excreta. Degarelix did not show any interaction with selected efflux transporters and uptake transporters up to concentrations representing 200 times the clinical concentration. Because degarelix does not seem to interact with the cytochrome P450 enzyme system as substrate, inhibitor, or inducer and does not show any interaction with hepatic and renal uptake and efflux transporters, the risk for pharmacokinetic drug-drug interactions with this compound is highly unlikely.

Advances in the stability challenges of bioactive peptides and improvement strategies

“…Cetrotide®, a decapeptide containing five unnatural amino acid residues approved by the FDA in 2000, was hydrolyzed by peptidase between Ser-4 and Tyr-5 and became a tetrapeptide before renal elimination ( Chia, 2021 ). Firmagon®, a decapeptide, was degraded in the liver and excreted mainly as tetrapeptide and pentapeptide fragments from the urine ( Sonesson and Rasmussen, 2013 ). Firazyr®, a decapeptide, was metabolized into two inactive fragments through the action of plasma and liver peptidase and excreted by the kidney ( Bork et al, 2007 ; Leach et al, 2015 ).…”

Investigation of the GnRH antagonist degarelix isomerization in biological matrices

“…Most probably, the previous studies of Degarelix degradation considered both the drug and its hydantoin metabolite as a single active substance, due to an inappropriate analytical method used. Indeed, the sum of these two compounds is close to the initial concentration of the drug when taking into account the formation of other metabolites, such as FE 200486(1–9)‐OH, which were not studied in this work 29 . The study of the degradation of the corresponding hydantoin containing peptide did not show a reverse formation of degarelix in serum.…”

“…Degarelix has emerged as a promising GnRH antagonist for prostate cancer treatment and its pharmacologic properties and metabolic pathways have been extensively studied during the past decade. The previous studies of degarelix metabolism in humans showed that the peptide is excreted unchanged via renal pathway, but it is sequentially degraded by the hepatobiliary system 29 . Among the metabolites after 72 h mainly C‐terminally truncated nonapeptide FE200486 (1–9)‐OH was detected in plasma in the amount up to 6.3% 29 .…”

“…Thus, the origin of the nonapeptide in plasma samples could be due to the enzymatic degradation by endopeptidases located in the hepatic tissue. 29 Metabolite pattern study allowed the detection of N-terminal tetra-and penta-peptides as main fragments formed during the passage of the hepatobiliary system. 31 In previous studies of degarelix metabolism, chromatographic cates that the transformation of degarelix in vivo could be rather fast if compared with the rate of the release of the peptide from the depot to reach the maximum concentration in the blood (61.0-71.0 ng/mL in 37-42 h after starting dose injection) and leads to a decrease of the concentration of the circulating peptide.…”

Degarelix versus luteinizing hormone-releasing hormone agonists for the treatment of prostate cancer

“…Prescribing information at this time states it does not require dose adjustment in those with mild renal impairment but should be use with caution in those with moderate or severe impairment. [32] The same is true for those with hepatic impairment; those with mild or moderate impairment do not require dose adjustment, whereas caution should be take for those with severe hepatic impairment. There is no adjustment for age or weight and drug interactions are unlikely with degarelix as it is a poor substrate of the CYP450 system.…”