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  3. Physiologically based pharmacokinetic model analysis of the inhibitory effect of vonoprazan on the metabolic activation of proguanil

Physiologically based pharmacokinetic model analysis of the inhibitory effect of vonoprazan on the metabolic activation of proguanil

  • Drug Metab Pharmacokinet. 2024 Feb:54:100537. doi: 10.1016/j.dmpk.2023.100537.
Kenjiro Okubo 1,  Toshiyuki Kudo 2,  Sae Yoshihara 1,  Yu Nakabayashi 1,  Kana Nakauchi 1,  Akimi Tanaka 1,  Moe Saito 1,  Ayumi Tsujisawa 1,  Hitomi Goda 3,  Yoshiaki Yamagishi 4,  Chinatsu Otake 5,  Kosho Makino 6,  Hideyo Takahashi 7,  Kiyomi Ito 8
Affiliations

Affiliations

  • 1 Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo, 202-8585, Japan.
  • 2 Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo, 202-8585, Japan; Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo, 202-8585, Japan. Electronic address: [email protected].
  • 3 Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo, 202-8585, Japan.
  • 4 Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo, 202-8585, Japan; Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo, 202-8585, Japan. Electronic address: [email protected].
  • 5 Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba, 278-8510, Japan.
  • 6 Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba, 278-8510, Japan. Electronic address: [email protected].
  • 7 Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba, 278-8510, Japan. Electronic address: [email protected].
  • 8 Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo, 202-8585, Japan; Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo, 202-8585, Japan. Electronic address: [email protected].
PMID: 38086197 DOI: 10.1016/j.dmpk.2023.100537
Abstract

We previously reported that repeated oral administration of vonoprazan (VPZ) followed by oral administration of proguanil (PG) in healthy adults increased blood concentration of PG and decreased blood concentration of its metabolite cycloguanil (CG) compared with administration of PG alone. In this study, we investigated whether this interaction can be quantitatively explained by VPZ inhibition of PG metabolism. In an in vitro study using human liver microsomes, VPZ inhibited CG formation from PG in a concentration-dependent manner, and the inhibition was enhanced depending on preincubation time. Then, a physiologically based pharmacokinetic (PBPK) model analysis was performed incorporating the obtained inhibition parameters. By fitting the blood concentration profiles of VPZ and PG/CG after VPZ and PG were orally administered alone to our PBPK model, parameters were obtained which can reproduce their concentration profiles. In contrast, when the VPZ inhibition parameters for CG formation from the in vitro study were incorporated, the predicted blood PG and CG concentrations were unchanged; the apparent dissociation constant had to be set to about 1/23 of the obtained in vitro value to reproduce the observed interaction. Further comprehensive evaluation is required, including the possibility that mechanisms Other than metabolic inhibition may be involved.

Keywords

Drug interaction; Physiologically based pharmacokinetic model; Proguanil; Time-dependent inhibition; Vonoprazan.

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