Pharmacokinetic, Safety, and Pharmacodynamic Properties of Teverelix Trifluoroacetate, a Novel Gonadotropin‐Releasing Hormone Antagonist, in Healthy Adult Subjects

Abstract

Teverelix trifluoroacetate is a decapeptide, gonadotropin‐releasing hormone antagonist that binds competitively and reversibly to gonadotropin‐releasing hormone receptors in the pituitary gland, resulting in immediate suppression of luteinizing hormone and follicle‐stimulating hormone, which in turn causes a very rapid decrease in testosterone production in the Leydig cells of the testes in men and in estradiol in the ovaries in women. This phase 1 clinical study was an open‐label, parallel‐design, single‐center, single‐dose study in older, healthy male subjects. Following injection, teverelix is released into the systemic circulation in a biphasic manner. An initial rapid phase is followed by a slow‐release phase thought to be due to the formation of a depot, which limits the diffusion of teverelix into the blood. The release characteristics differ significantly for the subcutaneous (SC) and intramuscular (IM) routes. Teverelix maximum concentration and exposure increased in an approximately dose‐proportional manner across the 60 to 120 mg SC doses. All 3 pharmacodynamic end points (luteinizing hormone, follicle‐stimulating hormone, and total testosterone) showed reductions that were more prolonged following the 90 mg IM administration compared to 90 mg SC administration.

Safety, Pharmacokinetic and Pharmacodynamic Evaluation of Teverelix for the Treatment of Hormone-Sensitive Advanced Prostate Cancer: Phase 2 Loading-Dose-Finding Studies

“…The data from these five Phase 2 clinical studies adds to the evidence from a Phase 1 clinical study that was conducted in older, healthy male subjects, showing that teverelix DP has a good safety profile and is well tolerated [18]. In the Phase 1 study, the maximum concentration and exposure generally increased in proportion to the various doses evaluated (i.e., 60, 90 and 120 mg SC single doses), while reductions in LH, FSH and testosterone were more prolonged with an IM administration (90 mg) compared an SC administration at the same dose [18]. Here, we found that the longest mean duration of castration was observed after SC dosing for 3 consecutive days, and that IM administration had a delayed onset of castration compared to SC administration.…”

“…Due to the different milieu following IM injection-where there is a high degree of vascularization and less adipose tissue-induration is not an issue. Indeed, this different milieu explains the different PK profiles (late phase Tmax and Cmax) observed following SC versus IM administration [18].…”

“…Teverelix drug product (DP) is a decapeptide GnRH antagonist characterized by relatively good water solubility, little in vitro aggregation, and low histamine-releasing potency, with a dose that produces the half-maximal response [18]. Upon reconstitution, a fixed amount of trifluoroacetate (TFA) can be added to the teverelix base, achieving an exact and desired molar ratio to obtain a microcrystalline aqueous teverelix-TFA suspension at a concentration of 75 mg/mL [18]. This enables the parenteral (subcutaneous [SC] or intramuscular (IM)) administration of a large amount of peptide in a relatively small volume.…”

Myrrh Attenuates Gonadal Toxicity and DNA Fragmentation Induced by Ethanol in Male Rats

“…Consequently, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are produced. FSH acts on Sertoli cells to enhance sperm production, while LH binds to Leydig cells to promote testosterone synthesis (MacLean et al, 2022). Previous research has indicated that alcohol consumption may negatively affect the efficiency of the endocrine system, including the HPG axis, thus inhibiting the production of LH and testosterone (Enebeli et al, 2022).…”

A Model‐Informed Drug Development Approach to Design a Phase 3 Trial of Teverelix Drug Product in Advanced Prostate Cancer Patients with Increased Cardiovascular Risk

“…The release characteristics differ significantly between the SC and IM routes. 28 Initial high levels of exposure are seen following IM injection but teverelix DP is eliminated within a relatively short period of time (6-8 weeks). Following SC injection of teverelix DP there is a much slower release over time and teverelix remains measurable in the blood for up to 12 months following a single 120-mg injection.…”