Effects of itraconazole and rifampicin on the single‐dose pharmacokinetics of the nonsteroidal mineralocorticoid receptor blocker esaxerenone in healthy Japanese subjects

Abstract

Aims To investigate the effects of the strong cytochrome P450 (CYP) 3A inhibitor itraconazole and the strong CYP3A inducer rifampicin on the pharmacokinetics of single‐dose esaxerenone, a nonsteroidal mineralocorticoid receptor blocker, in healthy Japanese subjects. Methods Two open‐label, single‐sequence, crossover studies were conducted in healthy Japanese males aged 20–45 years. In Study 1 (n = 20), subjects received a single oral 2.5 mg dose of esaxerenone (Days 1, 13), with itraconazole 200 mg twice daily (Day 8) and once daily (Days 9–16). In Study 2 (n = 12), subjects received a single oral 5 mg dose of esaxerenone (Days 1, 13), with rifampicin 600 mg once daily (Days 8–16). The plasma concentration of esaxerenone and esaxerenone metabolites were measured using liquid chromatography–tandem mass spectrometry. Pharmacokinetic parameters were calculated using noncompartmental analysis, and safety was assessed. Results Esaxerenone exposure increased when coadministered with itraconazole. Geometric least‐square mean ratios (90% confidence interval) of peak plasma esaxerenone concentration (Cmax), area under the plasma concentration–time curve (AUC) from zero until the last measurable concentration (AUClast) and AUC from zero until infinity (AUCinf) were 1.13 (1.05, 1.20) ng mL−1, 1.47 (1.40, 1.54) ng h mL−1 and 1.53 (1.45, 1.62) ng h mL−1, respectively. Esaxerenone exposure decreased when coadministered with rifampicin. Geometric least‐squares mean ratios (90% confidence interval) of esaxerenone Cmax, AUClast and AUCinf were 0.659 (0.599, 0.724), 0.315 (0.300, 0.332) and 0.312 (0.297, 0.328), respectively. Conclusion Itraconazole increased esaxerenone AUCinf by 53.1%, and rifampicin decreased esaxerenone AUCinf by 68.8%. These results suggest that caution is recommended when coadministering esaxerenone with strong inhibitors and inducers of CYP3A.

Physiologically based pharmacokinetic modelling to predict the clinical effect of CYP3A inhibitors/inducers on esaxerenone pharmacokinetics in healthy subjects and subjects with hepatic impairment

“…An open-label, single-sequence, crossover study conducted in healthy Japanese subjects provided PK data for DDIs with CYP3A inhibitors and inducers (itraconazole and rifampicin, respectively) [ 9 ]. Each subject received an oral dose of esaxerenone (2.5 mg) on day 1 (single-dose administration phase), followed by oral itraconazole (200 mg twice daily on day 8 and once daily from day 9 to 16), in conjunction with a second oral dose of esaxerenone (2.5 mg) on day 13 (coadministration phase).…”

“…Each subject received an oral dose of esaxerenone (2.5 mg) on day 1 (single-dose administration phase), followed by oral itraconazole (200 mg twice daily on day 8 and once daily from day 9 to 16), in conjunction with a second oral dose of esaxerenone (2.5 mg) on day 13 (coadministration phase). A similar study design was conducted with rifampicin, with each subject administered an oral dose of esaxerenone (5 mg) on days 1 and 13, with oral rifampicin (600 mg) co-administered once daily on days 8 to 16 [ 9 ].…”

“…CYP3A inhibitors and inducers have been used to investigate the potential victim DDI risks of esaxerenone. Itraconazole, a strong CYP3A inhibitor, increased the area under the curve (AUC) by 1.5 times when co-administered with esaxerenone, while rifampicin, a strong CYP3A inducer, reduced the AUC by a third and shortened the t 1/2 ; thus, considerations should be taken when administering esaxerenone alongside both strong CYP3A inhibitors and inducers [ 9 ].…”

Drug–Drug Interactions of the Nonsteroidal Mineralocorticoid Receptor Antagonist Apararenone With Midazolam, Warfarin, and Digoxin: A Phase 1 Studies in Healthy Volunteers

“…In terms of DDIs as a victim drug, the approved MR antagonists eplerenone and esaxerenone are primarily metabolized by CYP3A4 21,22 ; therefore, caution is advised when these drugs are administered in combination with CYP3A4 inhibitors/inducers. In contrast, apararenone is not considered to be metabolically sensitive to other drugs.…”

Drug-Drug Interaction Risk Assessment of Esaxerenone as a Perpetrator by In Vitro Studies and Static and Physiologically Based Pharmacokinetic Models

“…Because of its high membrane permeability (Yamada et al, 2019), esaxerenone is rapidly absorbed after oral administration with high bioavailability (Kurata et al, 2019). Although its major elimination route is metabolism, esaxerenone is considered to have limited potential to be a victim of drug-drug interactions (DDIs) with enzyme inhibitors because it is metabolized via multiple routes, such as oxidation, hydrolysis, and glucuronidation (Yamada et al, 2019;Kirigaya et al, 2020a). s This article has supplemental material available at dmd.aspetjournals.org.…”