OBJECTIVE: TU2670 is a novel competitive pituitary GnRH receptor antagonist to treat endometriosis. We investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of TU2670 after multiple oral administration in healthy female subjects. Population PK/PD analysis using pooled phase I clinical trial data was also performed to suggest efficacious doses to treat endometriosis.
DESIGN: Phase I, single-blind, randomized, placebo-controlled, multiple-dose first-in-human clinical trial
Materials and Methods: Subjects were randomized and received 80 mg QD, 160 mg QD, 160 mg BID and 320 mg QD or placebo for 7 days a week after the onset of menstrual bleeding. Twenty-eight pre-menopausal women aged 18 to 45 (n=5 each group) were recruited and randomized. Treatment/placebo ratio was 5:2. Serial PK-PD blood samples were collected up to 72 hours. A non-compartmental analysis for PK parameters and calculated relative minimum concentration values (Cmin, % Baseline) of serum PD markers (LH, FSH, and estradiol). The population PK model of TU2670 was developed using NONMEM (version 7.4). Visual predictive checks and bootstrap methods were performed to determine the adequacy of the model.
RESULTS: Treatment with TU2670 was well tolerated with administrations of up to 320 mg TU2670/day over 7 days. TU2670 was rapidly absorbed after oral administration (tmax of 1 to 1.5 h). Large volume of distribution indicates wide tissue distribution. Elimination is almost completely non-renal, less than 2% of a dose given are excreted via urine. Terminal elimination half-life is around 6 h. TU2670 effectively suppressed FSH, LH, and estradiol. Based on phase I study data of TU2670, a 2-compartment model with first-order absorption and elimination was used to describe the PK profile. The indirect model with negative feedback PD model well described suppression of estradiol after TU2670 administration.
CONCLUSION: Multiple dosing of TU2670 in healthy premenopausal women was well tolerated and resulted in the dose-dependent decrease of LH, FSH and estradiol. Population PK/PD analysis using pooled phase I clinical trial data suggested efficacious doses for Phase IIa proof of concept study for patients with endometriosis.