Key result
Clarithromycin increased the exposure of a therapeutic 60 mg dose of edoxaban by 53% (GMR 1.53), a magnitude of drug interaction that is not expected to be clinically relevant.
Why the study?
The study evaluated the differential effect of clarithromycin on the pharmacokinetics of a regular edoxaban dose versus a microdose factor Xa inhibitor cocktail.
Does clarithromycin alter the pharmacokinetics of edoxaban and other factor Xa inhibitors in healthy volunteers?
Does clarithromycin alter the pharmacokinetics of edoxaban and other factor Xa inhibitors in healthy volunteers?
Effect estimate: GMR 1.53 (95% CI 1.37-1.70)
Absolute Event Rate: 107% vs 70%
p-value: p=<0.0001
Clarithromycin increases factor Xa inhibitor exposure, though the magnitude is not expected to be clinically relevant, and edoxaban microdosing overestimates the interaction compared to therapeutic dosing.
Clarithromycin modestly increases edoxaban exposure without expected clinical relevance; leaves open optimal dosing strategies for factor Xa inhibitor interactions.
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.
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Lenard et al. (2023) studied Healthy volunteers (n=12). Clarithromycin vs. Baseline (before clarithromycin) was evaluated on Area under the plasma concentration-time curve (AUC 0-∞) of edoxaban 60 mg (GMR 1.53, 95% CI 1.37-1.70, p=<0.0001). Clarithromycin increased the exposure of a therapeutic 60 mg dose of edoxaban by 53% (GMR 1.53), a magnitude of drug interaction that is not expected to be clinically relevant.
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