Syunsuke Yamamoto1, Masatoshi Karashima2, Noriyasu Sano3, Chiharu Fukushi3, Kimio Tohyama3, Yuta Arai2, Hideki Hirabayashi3, Nobuyuki Amano3. 1. Drug Metabolism and Pharmacokinetics Research Laboratories, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, Japan. syunsuke.yamamoto@takeda.com. 2. Analytical Development, Pharmaceutical Sciences, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, Japan. 3. Drug Metabolism and Pharmacokinetics Research Laboratories, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, Japan.
Abstract
PURPOSE: Although Göttingen minipigs have been widely used for the evaluation of skin absorption, the correlation of minipig skin permeability with human skin absorption remains unclear. This study was designed to investigate the prediction of human plasma concentrations after dermal application of drug products using skin permeability data obtained from minipigs. METHODS: First, in vitro skin permeabilities of seven marketed transdermal drug products were evaluated in minipigs, and compared with in vitro human skin permeability data. Next, plasma concentration-time profiles in humans after dermal applications were simulated using the in vitro minipig skin permeability data. Finally, the in vitro-in vivo correlation of minipig skin permeability was assessed. RESULTS: The in vitro skin permeabilities in minipigs were correlated strongly with in vitro human skin permeability data for the same drug products, indicating the utility of minipig skin as an alternative to human skin for in vitro studies. The steady-state plasma concentration or the maximum concentration of drugs was within 2-fold of the clinical data. Bioavailability was approximately 3-fold lower than in vitro permeated fraction. CONCLUSIONS: Predictions using in vitro skin permeability data in Göttingen minipig skin can reproduce the human pharmacokinetic profile, although the prediction of in vivo skin absorption underestimates human absorption.
PURPOSE: Although Göttingen minipigs have been widely used for the evaluation of skin absorption, the correlation of minipig skin permeability with human skin absorption remains unclear. This study was designed to investigate the prediction of human plasma concentrations after dermal application of drug products using skin permeability data obtained from minipigs. METHODS: First, in vitro skin permeabilities of seven marketed transdermal drug products were evaluated in minipigs, and compared with in vitro human skin permeability data. Next, plasma concentration-time profiles in humans after dermal applications were simulated using the in vitro minipig skin permeability data. Finally, the in vitro-in vivo correlation of minipig skin permeability was assessed. RESULTS: The in vitro skin permeabilities in minipigs were correlated strongly with in vitro human skin permeability data for the same drug products, indicating the utility of minipig skin as an alternative to human skin for in vitro studies. The steady-state plasma concentration or the maximum concentration of drugs was within 2-fold of the clinical data. Bioavailability was approximately 3-fold lower than in vitro permeated fraction. CONCLUSIONS: Predictions using in vitro skin permeability data in Göttingen minipig skin can reproduce the human pharmacokinetic profile, although the prediction of in vivo skin absorption underestimates human absorption.
Entities:
Keywords:
Göttingen minipig; absorption; in vitro/in vivo correlations (IVIVC); pharmacokinetics; skin; transdermal
Authors: Iris Ribitsch; Pedro M Baptista; Anna Lange-Consiglio; Luca Melotti; Marco Patruno; Florien Jenner; Eva Schnabl-Feichter; Luke C Dutton; David J Connolly; Frank G van Steenbeek; Jayesh Dudhia; Louis C Penning Journal: Front Bioeng Biotechnol Date: 2020-08-13
Authors: Michele Schlich; Umberto M Musazzi; Virginia Campani; Marco Biondi; Silvia Franzé; Francesco Lai; Giuseppe De Rosa; Chiara Sinico; Francesco Cilurzo Journal: Drug Deliv Transl Res Date: 2021-11-09 Impact factor: 5.671