The Enhancement of Subcutaneous First-Pass Metabolism Causes Nonlinear Pharmacokinetics of TAK-448 after a Single...

2-(N-acetyl-D-tyrosyl-trans-4-hydroxy-L-prolyl-L-asparaginyl-L-threonyl-L-phenylalanyl) hydrazinocarbonyl-L-leucyl-Nω-methyl-L-arginyl-L-tryptophanamide monoacetate (TAK-448, RVT-602), a kisspeptin analog, has been developed as a therapeutic agent for prostate cancer. The purpose of the present study is to clarify the mechanism of the less than dose-proportional nonlinear pharmacokinetics of TAK-448 after subcutaneous administration to rats. The plasma pharmacokinetics of TAK-448 and radiolabeled TAK-448 ([¹⁴C]TAK-448) were examined after subcutaneous and intravenous administrations to rats. [¹⁴C]TAK-448 was also subcutaneously injected together with protease inhibitors. The effects of the protease inhibitors on the in vitro metabolism of [¹⁴C]TAK-448 were investigated using rat skin homogenates. In a dose-ascending study, less than dose-proportional nonlinear pharmacokinetics were observed after subcutaneous administration with limited absorption of TAK-448 at the highest dose level contrary to the linear pharmacokinetics following intravenous dosing, indicating enhancement of subcutaneous metabolism with dose escalation. The systemic absorption of unchanged TAK-448 recovered when protease inhibitors were subcutaneously coadministered, suggested the involvement of subcutaneous proteases in the first-pass metabolism. An in vitro metabolism study suggests that serine protease could be responsible for the subcutaneous metabolism of TAK-448. Dose-dependent enhancement of first-pass metabolism appears to contribute to the less than dose-proportional nonlinear pharmacokinetics of TAK-448 after subcutaneous administrations to rats.