Physiologically based pharmacokinetic modelling to predict the clinical effect of CYP3A inhibitors/inducers on esaxerenone pharmacokinetics in healthy subjects and subjects with hepatic impairment.
Purpose: Esaxerenone is a novel, oral, nonsteroidal treatment for hypertension. Physiologically based pharmacokinetic (PBPK) modelling was performed to predict the drug–drug interaction (DDI) effect of cytochrome P450 (CYP)3A modulators on esaxerenone pharmacokinetics in healthy subjects and subject...
| Publicado en: | European Journal of Clinical Pharmacology Vol. 78; no. 1; pp. 65 - 74 |
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| Autores principales: | , , , , , |
| Formato: | research tables/charts Journal Article |
| Publicado: |
Springer Nature
Jan2022
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=154457794&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 154457794 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00316970 NP9 jtl: European Journal of Clinical Pharmacology issn: 00316970 maglogo: N pubinfo: dt: Jan2022 vid: 78 iid: 1 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 154457794 154457794 154457794 10.1007/s00228-021-03211-z 154457794 ppf: 65 ppct: 9 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: Physiologically based pharmacokinetic modelling to predict the clinical effect of CYP3A inhibitors/inducers on esaxerenone pharmacokinetics in healthy subjects and subjects with hepatic impairment. aug: au: Watanabe, Akiko Ishizuka, Tomoko Yamada, Makiko Igawa, Yoshiyuki Shimizu, Takako Ishizuka, Hitoshi affil: Quantitative Clinical Pharmacology Department, Daiichi Sankyo Co., Ltd., Tokyo, Japan sug: subj: Cytochrome P-450 Enzyme System Antagonists and Inhibitors Cytochrome P-450 Enzyme System Pharmacokinetics Heterocyclic Compounds Pharmacokinetics Liver Diseases Drug Interactions Antihypertensive Agents Heterocyclic Compounds Administration and Dosage Human Biological Availability Itraconazole Rifampin Clarithromycin Fluconazole Verapamil Drug Therapy, Combination ab: Purpose: Esaxerenone is a novel, oral, nonsteroidal treatment for hypertension. Physiologically based pharmacokinetic (PBPK) modelling was performed to predict the drug–drug interaction (DDI) effect of cytochrome P450 (CYP)3A modulators on esaxerenone pharmacokinetics in healthy subjects and subjects with hepatic impairment. Methods: In our PBPK model, the fraction of esaxerenone metabolised by CYP3A was estimated from mass-balance data and verified and optimised by clinical DDI study results with strong CYP3A modulators. The model was also verified by the observed pharmacokinetics after multiple oral dosing and by the effect of hepatic impairment on esaxerenone pharmacokinetics. The model was applied to predict the DDI effects on esaxerenone pharmacokinetics with untested CYP3A modulators in healthy subjects and with strong CYP3A modulators in subjects with hepatic impairment. Results: The PBPK model well described esaxerenone pharmacokinetics after multiple oral dosing. The predicted fold changes in esaxerenone plasma exposure after coadministration with strong CYP3A modulators were comparable with the observed data (1.53-fold with itraconazole and 0.31-fold with rifampicin). Predicted DDIs with untested moderate CYP3A modulators were less than the observed DDI with strong CYP3A modulators. The PBPK model also described the effect of hepatic impairment on esaxerenone plasma exposure. The predicted DDI results with strong CYP3A modulators in subjects with hepatic impairment indicate that, for concomitant use of CYP3A modulators, caution is advised for subjects with hepatic impairment, as is for healthy subjects. Conclusion: The PBPK model developed predicted esaxerenone pharmacokinetics and DDIs and informed concurrent use of esaxerenone with CYP3A modulators. pubtype: Academic Journal doctype: research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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