Effects of single and repeated oral doses of TAK-013, a new non-peptide gonadotropin-releasing hormone (GnRH) antagonist, in healthy post-menopausal women

Abstract

Objective: TAK-013 is a new, orally active, non-peptide GnRH antagonist in animals in vivo. It is highly selective for the human GnRH receptor in vitro. We studied the safety, tolerability, pharmacodynamics, pharmacokinetics, and metabolic effects of TAK-013 in healthy post-menopausal women. Design: The study was double-blind, parallel-group, and dose-rising, with randomised placebo controls. 36 women (3 groups of 12) took a single dose of TAK-013 (50, 100 or 200 mg; 9 subjects per group) or placebo (3 subjects per group). 1 week later, they started taking 25, 50 or 100 mg (or placebo) twice daily for 14 days. Materials/Methods: We took frequent blood samples before and after the single dose, before and after the first and last of the repeated doses, and before several other morning doses, to assay luteinising hormone (LH), follicle stimulating hormone (FSH), and TAK-013. We collected urine for 24 hours before the single dose and on the last day of the repeated doses, to measure urinary 6-hydroxycortisol:cortisol ratio (6-OHC:C). We monitored vital signs, ECG, and adverse events. We calculated Cmin and AUC of LH and FSH, and compared means using analysis of variance. We calculated tmax, Cmax, t1/2, and AUC of TAK-013, and assessed dose proportionality. Results: There were no differences among treatments with respect to vital signs, ECG and adverse events. Single doses of TAK-013 reduced LH and FSH rapidly, substantially, and for at least 48 h; there were no differences in median AUC or Cmin between doses. Repeated doses of TAK-013 also substantially reduced LH and FSH; the effects were dose-dependent and sustained, persisting for at least 36 h after the last dose. After single doses of TAK-013, median tmax was 2–4 h, mean t1/2 was about 24 h, and Cmax and AUC were linearly related to dose. TAK-013 was at steady state by Day 7. Between the single dose and the last of the repeated doses of TAK-013, there was a significant reduction in mean t1/2 of 5.3 h (95% CI -8.3 to -2.4 h). There was also a significant reduction in mean AUC (corrected for dose level) to 76% (90% CI 55–105%) of AUC after the single dose. Cmax and AUC were dose-proportional after repeated doses of TAK-013. There was a dose-dependent increase in urinary 6-OHC:C after repeated doses of TAK-013, consistent with CYP3A4 induction. That would explain the reduction in t1/2 and AUC. But despite the change in pharmacokinetic parameters after repeated doses of TAK-013, the pharmacodynamic effects were sustained. Conclusions: TAK-013 was a well-tolerated, orally active, and effective GnRH antagonist in older women and warrants development as a treatment for hormone-dependent diseases. Supported by: Takeda Europe R & D Centre Ltd. Table TableMedian (range) PD parameters after the last of the repeated dosesParameterPlacebo (n = 9)25 mg bd (n = 9)50 mg bd (n = 9)100 mg bd (n = 9)FSH Cmin (IU/L)55 (30–101)16 (1–39)7 (2–21)3 (1–11)FSH AUC12–24 (IU/L.h)708 (400–1298)203 (22–531)85 (23–271)34 (18–145)LH Cmin (IU/L)16 (14–34)2 (0–6)1 (0–2)0 (0–1)LH AUC12–24 (IU/L.h)260 (194–445)37 (3–86)17 (0–41)0 (0–19) Open table in a new tab