Drug–Drug Interactions with Direct Oral Anticoagulants

Figures

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  Fig. 1. Primary direct oral anticoagulant (DOAC) clearance/elimination pathways. Data were extracted from per oral (po; apixaban, edoxaban, and rivaroxaban) and intravenous (iv; betrixaban and dabigatran) mass balance studies [2, 38, 48, 57]. The rivaroxaban pie chart is a modification from Mueck and co-workers [63]. BCRP breast cancer resistance protein, CES carboxylesterase, CYP cytochrome P450, P-gp P-glycoprotein

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  Fig. 2. Area under the concentration–time curve ratios (AUCR) and maximum (peak) concentration ratios (CmaxR) of apixaban with and without concomitantly taken drugs. Results of drug–drug interaction trials that have been conducted and published up to January 2020 are depicted [22, 32, 36, 40, 43, 85, 98–101]. A ratio equals 1 if the co-administered drug statistically insignificantly influenced direct oral anticoagulant (DOAC) pharmacokinetics. Green bars: AUCR and CmaxR > 0.5 and < 2. Yellow bars: AUCR and CmaxR ≤ 0.5 and ≥ 2. 1Ketoconazole 400 mg investigated. 2DOAC microdoses administered. 3Rifampicin was given repeatedly

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  Fig. 3. Area under the concentration–time curve ratios (AUCR) and maximum (peak) concentration ratios (CmaxR) of betrixaban with and without concomitantly taken drugs. Results of drug–drug interaction trials that have been conducted and published up to January 2020 are depicted [2]. A ratio equals 1 if the co-administered drug statistically insignificantly influenced direct oral anticoagulant pharmacokinetics. Green bars: AUCR and CmaxR > 0.5 and < 2. Yellow bars: AUCR and CmaxR ≤ 0.5 and ≥ 2. 1Verapamil provided in an extended-release formulation. 2Ketoconazole 200 mg investigated. 3The antacid mixture was composed of aluminium hydroxide and magnesium hydroxide

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  Fig. 4. Area under the concentration–time curve (AUC) ratios (AUCR) and maximum (peak) concentration (Cmax) ratios (CmaxR) of dabigatran with and without concomitantly taken drugs. Results of drug–drug interaction (DDI) trials that have been conducted and published up to January 2020 are depicted [23, 52, 70, 71, 102–113]. A ratio equals 1 if the co-administered drug statistically insignificantly influenced direct oral anticoagulant (DOAC) pharmacokinetics. Green bars: AUCR and CmaxR > 0.5 and < 2. Yellow bars: AUCR and CmaxR ≤ 0.5 and ≥ 2. Red bars: AUCR and CmaxR ≥ 5. 1DOAC microdoses administered. 2Ketoconazole 200 mg investigated. 3A single dose of rifampicin was provided. 4The figure depicts the greatest effect of clarithromycin on dabigatran pharmacokinetics that has been reported. Results from DDI trials are ambiguous. Although the same dose of clarithromycin was administered, one trial did not observe any change in dabigatran exposure and the other reported a smaller AUCR than depicted (AUCR 1.49) [103, 105]. 5Verapamil was provided in an extended-release formulation. Immediate-release verapamil given 1 h before dabigatran etexilate had greater impact on dabigatran exposure.…

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  Fig. 5. Area under the concentration–time curve ratios (AUCR) and maximum (peak) concentration ratios (CmaxR) of edoxaban with and without concomitantly taken drugs. Results of drug–drug interaction trials that have been conducted and published up to January 2020 are depicted [59, 76, 84, 98, 114–117]. A ratio equals 1 if the co-administered drug statistically insignificantly influenced direct oral anticoagulant (DOAC) pharmacokinetics. Green bars: AUCR and CmaxR > 0.5 and < 2. Yellow bars: AUCR and CmaxR ≤ 0.5 and ≥ 2. Red bars: AUCR and CmaxR ≥ 5. 1DOAC microdoses administered. 2Ketoconazole 400 mg investigated. 3Verapamil provided in an extended-release formulation. 4Acetylsalicylic acid (ASA) 325 mg/day administered. 5ASA 100 mg/day administered. 6Rifampicin was given repeatedly

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  Fig. 6. Area under the concentration–time curve ratios (AUCR) and maximum (peak) concentration ratios (CmaxR) of rivaroxaban with and without concomitantly taken drugs. Results of drug–drug interaction trials that have been conducted and published up to January 2020 are depicted [62, 63, 69, 74, 81–83, 98, 104, 118–122]. A ratio equals 1 if the co-administered drug statistically insignificantly influenced direct oral anticoagulant (DOAC) pharmacokinetics. Green bars: AUCR and CmaxR > 0.5 and < 2. Yellow bars: AUCR and CmaxR ≤ 0.5 and ≥ 2. 1Ketoconazole 400 mg investigated. 2DOAC microdoses administered. 3Trial was performed in patients with moderate renal impairment. 4Rivaroxaban 40 mg administered. 5Ketoconazole 200 mg investigated. 6Trial was performed in patients with mild renal impairment. 7Rivaroxaban 10 mg administered. 8The antacid mixture was composed of aluminium hydroxide and magnesium hydroxide. 9Rifampicin was given repeatedly