Mechanism of warfarin potentiation by amiodarone: Dose ? and concentration ? Dependent inhibition of warfarin elimination

Abstract

Potentiation of the anticoagulant-effect of warfarin by amiodarone was studied in 30 patients. Thirteen received both drugs concurrently, and 17 received warfarin alone and the combination sequentially. Warfarin doses were adjusted to maintain the prothrombin time between 25-30% of control and its kinetics were compared to those in 20 control patients who received warfarin alone. Potentiation occurred in 28/30 patients, presenting as a 35%-65% reduction in the required dose of warfarin, and was correlated with the dose of amiodarone (r = 0.77, p less than 0.01). The free warfarin fraction was not affected by amiodarone (1.8% vs 1.6% in the controls). Warfarin clearance was lower in amiodarone-treated patients than in the controls (1.4 vs 3.1 ml/min, p less than 0.01) with similar plasma concentrations (1.5 vs 1.2 micrograms/ml) despite administration of lower doses (23.3 vs 39 mg/week respectively). The amiodarone concentration was significantly correlated with the warfarin concentrations independent of the effect of amiodarone on the dose of warfarin. Amiodarone hat no effect on prothrombin other than through its actions on the dose and plasma concentration of warfarin. The mechanism of the amiodarone-warfarin interaction is pharmacokinetic through dose - and concentration - dependent inhibition of warfarin elimination.

Analysis of potential interactions between warfarin and prescriptions in Estonian outpatients aged 50 years or more

“…In our study, the frequency of concomitant use of amiodarone (7%) was also higher than in other studies 24,2530,32,33,39,41, especially in the initial phase of concomitant use of drugs42,43, and this interaction is considered to be clinically significant 25. In contrast, Hermann et al 39.…”

Anticoagulation in pulmonary arterial hypertension: a qualitative systematic review

“…There is also concern regarding increased risk of gastrointestinal haemorrhage among patients with scleroderma-associated pulmonary hypertension due to the presence of luminal telangiectasia [34]. Many medications have been implicated in potentiation of the effect of warfarin, including azole antibiotics [35,36], macrolides [37], quinolones [38], selective serotonin reuptake inhibitors [39] and amiodarone [40][41][42]. Caution should also be exercised with the concomitant use of other PH therapies and warfarin.…”

Are Evidence Standards Different for Genomic‐ vs. Clinical‐Based Precision Medicine? A Quantitative Analysis of Individualized Warfarin Therapy

“…The dose of warfarin can be individualized based on the presence of genetic variants in the two genes ( CYP2C9 and VKORC1 ), which are responsible for the metabolism and function of warfarin (10). Analogously, warfarin dose also can be individualized based on knowledge of an interacting drug, amiodarone, which exerts its effect through inhibition of the CYP2C9 enzyme (11). Notably, clinical guidelines recommended against the use of pharmacogenetics-based initial dosing of warfarin, (12, 13) yet recommended use of lower initiation dose (≤ 5 mg) for warfarin in patients taking amiodarone (13).…”