Investigation of disposition for TAK-448, a synthetic peptide of kisspeptin analog, in rats and dogs using the radiolabeled TAK-448 suitable for pharmacokinetic study

Abstract

1. 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-¹⁴C]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.

2. 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.

3. After intravenous administration of [d-Tyr-¹⁴C]TAK-448 to rats, the radioactivity widely distributed to tissues with relatively higher concentrations in kidney and urinary bladder.

4. The radioactivity was decreased rapidly from the tissues.

5. After subcutaneous administration of [d-Tyr-¹⁴C]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.

6. These results suggest that TAK-448 has an acceptable pharmacokinetic profile for clinical evaluation and development, and demonstrate that the synthesized [D-Tyr-¹⁴C]TAK-448 used in this study represents a favorable labeling position to evaluate disposition properties of this compound.

Keywords:

• TAK-448 (RVT-602)
• disposition
• rat
• dog
• kisspeptin agonist

Disclosure statement

All studies reported here were supported and conducted by Takeda Pharmaceutical Company Limited. The authors declare no other conflicts of interest.

Table 7. Metabolic profiles of the radioactivity in urine, feces, and biles of rats and dogs after s.c. administration of [d-Tyr-¹⁴C]TAK-448 at a dose of 1 mg/kg.