TAK-448

Disposition of 2-(N-acetyl-d-tyrosyl-trans-4-hydroxy-l-prolyl-l-asparaginyl-l-threonyl-l-phenylalanyl) hydrazinocarbonyl-L-leucyl-N;ω;-methyl-l-arginyl-l-tryptophanamide monoacetate (TAK-448, RVT-602), a synthetic kisspeptin analog, was investigated after parenteral dosing of radiolabeled TAK-448 ([d-Tyr-;14;C]TAK-448) to rats and dogs, and it was confirmed if the radiolabeling position at d-Tyr was eligible for assessment of in vivo disposition. Dosed radioactivity was rapidly and well absorbed after subcutaneous administration and an appreciable amount of unchanged TAK-448 (TAK-448F) and a hydrolyzed metabolite, M-I, were detected in the plasma of rats and dogs. After intravenous administration of [d-Tyr-;14;C]TAK-448 to rats, the radioactivity widely distributed to tissues with relatively higher concentrations in kidney and urinary bladder. The radioactivity was decreased rapidly from the tissues. After subcutaneous administration of [d-Tyr-;14;C]TAK-448 to rats and dogs, the dosed radioactivity was almost completely recovered by 48 and 72 h in rats and dogs, respectively, and most of the radioactivity was excreted in urine after extensive metabolism in the two species. These results suggest that TAK-448 has an acceptable pharmacokinetic profile for clinical evaluation and development, and demonstrate that the synthesized [D-Tyr-;14;C]TAK-448 used in this study represents a favorable labeling position to evaluate disposition properties of this compound.

Gonadotropin releasing hormone (GnRH) analogs have long been used in androgen deprivation therapy (ADT) in the treatment of prostate cancer. Chronic administration of either GnRH agonists or antagonists leads to suppression of testosterone production in the testes via either downregulation or direct blockade of the GnRH receptor in the pituitary, respectively. Chronic administration of kisspeptin analogs has more recently been shown to lead to testosterone suppression via desensitization of GnRH neurons in the hypothalamus and an optimized kisspeptin analog, TAK-448, was proven effective in a small phase 1 trial. The current study explored the hypothesis that co-administration of TAK-448 and the GnRH antagonist, degarelix, would have an additive effect on hormonal suppression, as a result of simultaneous intervention in separate steps in the same pathway. TAK-448 or degarelix were first administered individually to castrated rats in order to identify low doses capable of partial or no suppression of luteinizing hormone (LH). In the second step, combinations of the low doses of TAK-448 and degarelix were assessed in a 14 day study and compared to the drugs administered separately. The results showed that simultaneous intervention at the kisspeptin and GnRH receptors caused a more pronounced LH suppression than either drug alone, demonstrating an additive or potentiating effect.

Metastin/kisspeptin, a hypothalamic peptide, plays a pivotal role in controlling GnRH neurons. Here we studied the effect of chronic sc administration of two kisspeptin analogs, KISS1-305 and TAK-448, on hypothalamic-pituitary-gonadal function in male rats in comparison with a GnRH analogue leuprolide or bilateral orchiectomy (ORX). The prototype polypeptide, KISS1-305 (1-4 nmol/h), caused substantial elevations of plasma LH and testosterone, followed by abrupt reductions of both hormone levels. Notably, testosterone levels were reduced to castrate levels within 3 d and remained depleted throughout the 4-wk dosing period, an effect that was faster and more pronounced than leuprolide (1 nmol/h) dosing. KISS1-305 also reduced genital organ weight more profoundly than leuprolide. In mechanistic studies, chronic KISS1-305 administration only transiently induced c-Fos expression in GnRH neurons, suggesting that GnRH-neural response was attenuated over time. Hypothalamic GnRH content was reduced to 10-20% of control at 3 wk without any changes in Gnrh mRNA expression. Dosing with the investigational peptide TAK-448 was also studied to extend our understanding of hypothalamic-pituitary functions.