Effect of Clarithromycin, a Strong CYP3A and P-glycoprotein Inhibitor, on the Pharmacokinetics of Edoxaban in Healthy Volunteers and the Evaluation of the Drug Interaction with Other Oral Factor Xa Inhibitors by a Microdose Cocktail Approach

Alexander Lenard; Simon A Hermann; Felicitas Stoll; Juergen Burhenne; Kathrin I Foerster; Gerd Mikus; Andreas D Meid; Walter E Haefeli; Antje Blank

doi:10.1007/s10557-023-07443-2

Effect of Clarithromycin, a Strong CYP3A and P-glycoprotein Inhibitor, on the Pharmacokinetics of Edoxaban in Healthy Volunteers and the Evaluation of the Drug Interaction with Other Oral Factor Xa Inhibitors by a Microdose Cocktail Approach

Cardiovasc Drugs Ther. 2023 Mar 4. doi: 10.1007/s10557-023-07443-2. Online ahead of print.

Authors

Alexander Lenard^{1

2}, Simon A Hermann^{1

2}, Felicitas Stoll^{1

2}, Juergen Burhenne^{1

2}, Kathrin I Foerster^{1

2}, Gerd Mikus^{1

2}, Andreas D Meid^{1

2}, Walter E Haefeli^{1

2}, Antje Blank^{3

4}

Affiliations

¹ Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
² Partner Site Heidelberg, German Center for Infection Research, Heidelberg, Germany.
³ Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany. antje.blank@med.uni-heidelberg.de.
⁴ Partner Site Heidelberg, German Center for Infection Research, Heidelberg, Germany. antje.blank@med.uni-heidelberg.de.

PMID: 36870039
DOI: 10.1007/s10557-023-07443-2

Abstract

Purpose: We assessed the differential effect of clarithromycin, a strong inhibitor of cytochrome P450 (CYP) 3A4 and P-glycoprotein, on the pharmacokinetics of a regular dose of edoxaban and on a microdose cocktail of factor Xa inhibitors (FXaI). Concurrently, CYP3A activity was determined with a midazolam microdose.

Methods: In an open-label fixed-sequence trial in 12 healthy volunteers, the pharmacokinetics of a microdosed FXaI cocktail (μ-FXaI; 25 μg apixaban, 50 μg edoxaban, and 25 μg rivaroxaban) and of 60 mg edoxaban before and during clarithromycin (2 x 500 mg/d) dosed to steady-state was evaluated. Plasma concentrations of study drugs were quantified using validated ultra-performance liquid chromatography-tandem mass spectrometry methods.

Results: Therapeutic clarithromycin doses increased the exposure of a therapeutic 60 mg dose of edoxaban with a geometric mean ratio (GMR) of the area under the plasma concentration-time curve (AUC) of 1.53 (90 % CI: 1.37-1.70; p < 0.0001). Clarithromycin also increased the GMR (90% CI) of the exposure of microdosed FXaI apixaban to 1.38 (1.26-1.51), edoxaban to 2.03 (1.84-2.24), and rivaroxaban to 1.44 (1.27-1.63). AUC changes observed for the therapeutic edoxaban dose were significantly smaller than those observed with the microdose (p < 0.001).

Conclusion: Clarithromycin increases FXaI exposure. However, the magnitude of this drug interaction is not expected to be clinically relevant. The edoxaban microdose overestimates the extent of the drug interaction with the therapeutic dose, whereas AUC ratios for apixaban and rivaroxaban were comparable to the interaction with therapeutic doses as reported in the literature.

Trial registration: EudraCT Number: 2018-002490-22.

Keywords: Clarithromycin; Drug-drug interaction; Factor Xa inhibitors; Healthy volunteers; Microdose.