PT  - JOURNAL ARTICLE
AU  - Makiko Yamada
AU  - Tomoko Ishizuka
AU  - Shin-ichi Inoue
AU  - Thomas Fischer
AU  - Veronika Rozehnal
AU  - Daisuke Sugiyama
TI  - Drug–drug interaction risk assessment of esaxerenone as a perpetrator by in vitro studies, and static and physiologically based pharmacokinetic models
AID  - 10.1124/dmd.120.090928
DP  - 2020 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.120.090928
4099  - http://dmd.aspetjournals.org/content/early/2020/07/02/dmd.120.090928.short
4100  - http://dmd.aspetjournals.org/content/early/2020/07/02/dmd.120.090928.full
AB  - Esaxerenone (CS-3150) is a novel, oral, nonsteroidal, selective mineralocorticoid receptor blocker approved for the treatment of hypertension in Japan. Here, the drug-drug interaction (DDI) potential of esaxerenone was evaluated in vitro and its impact in clinical practice was estimated. Esaxerenone exhibited time-dependent inhibition and induction of cytochrome P450 3A (CYP3A). When the clinical impacts of esaxerenone on the inhibition and induction of CYP3A were estimated separately by using a mechanistic static model, the predicted area under the curve ratios (AUCRs) of midazolam, a typical CYP3A substrate, were 1.89 and 0.33, respectively. This suggests that the DDI potential of esaxerenone cannot be neglected. In physiologically based pharmacokinetic (PBPK) modeling analysis using GastroPlus, the AUCR of midazolam was approximately 1.2, which is close to that in a clinical study, despite the difficulty of predicting DDIs for compounds with both inhibition and induction effects. Besides the models created using clinical pharmacokinetic (PK) data, the model created using predicted human PK from animal PK with allometric scaling showed good predictability, suggesting that GastroPlus can be utilized from the initial developmental stage to predict weak DDIs in the intestine. When only inhibition or induction was incorporated into a model, the AUCR of midazolam changed depending on the dosing period and dose of esaxerenone and the timing of midazolam administration. However, the AUCR calculated by incorporating both effects remained almost constant because of the offset of inhibition and induction. In summary, esaxerenone has low DDI potential as a perpetrator.SIGNIFICANCE STATEMENT Weak CYP3A inhibition and/or induction can sometimes predict DDIs in the intestine but not the liver. The predictability of intestinal DDIs has not been thoroughly investigated. Here, we simulate the DDIs of esaxerenone as a perpetrator by using PBPK modeling focusing on the intestine and discuss the offset of inhibition and induction.