RT Journal Article
SR Electronic
T1 The enhancement of subcutaneous first-pass metabolism causes non-linear pharmacokinetics of TAK-448 after a single subcutaneous administration to rats
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.119.087148
DO 10.1124/dmd.119.087148
A1 Yuu Moriya
A1 Akifumi Kogame
A1 Yoshihiko Tagawa
A1 Akio Morohashi
A1 Takahiro Kondo
A1 Satoru Asahi
A1 Leslie Z. Benet
YR 2019
UL http://dmd.aspetjournals.org/content/early/2019/06/14/dmd.119.087148.abstract
AB 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 non-linear pharmacokinetics of TAK-448 after subcutaneous (SC) administration to rats. Plasma pharmacokinetics of TAK-448 and radiolabeled TAK-448 ([14C]TAK-448) were examined after SC and intravenous (IV) administration 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 an dose ascending study, less than dose-proportional non-linear pharmacokinetics were observed after SC administration with limited absorption of TAK-448 at the highest dose level contrary to the linear pharmacokinetics following IV dosing, indicating an enhancement of SC metabolism with dose escalation. The systemic absorption of unchanged TAK-448 recovered when protease inhibitors were subcutaneously co-administered, suggested the involvement of SC proteases in the first-pass metabolism. An in vitro metabolism study suggests that serine protease could be responsible for the SC metabolism of TAK-448. A dose-dependent enhancement of first-pass metabolism appears to contribute to the less than dose-proportional non-linear pharmacokinetics of TAK-448 after SC administrations to rats.SIGNIFICANCE STATEMENT N/A