Population pharmacokinetic analysis of the interaction of digoxin with N‐desethylamiodarone in patients with atrial fibrillation and heart failure.

Aims: To evaluate the effects of amiodarone and/or N‐desethylamiodarone concentrations on digoxin pharmacokinetics and determine the optimal dose of digoxin combined with amiodarone in Japanese patients with atrial fibrillation and heart failure. Methods: A population pharmacokinetic analysis of 3288 points from 368 patients receiving oral digoxin, including 48 (13%) who were coadministered amiodarone, was performed. A 1‐compartment model with first‐order absorption with amiodarone or N‐desethylamiodarone as time‐varying covariates for apparent digoxin clearance was constructed using stepwise forward inclusion and backward elimination approaches. The percentage of patients with digoxin values in the toxic range (≥0.9 ng/mL) was evaluated with Monte Carlo simulation. Results: The median serum digoxin concentration was 0.75 ng/mL; the median plasma concentrations of amiodarone and N‐desethylamiodarone were 610 and 644 ng/mL, respectively. The final model for oral clearance of digoxin was explained by creatinine clearance (CLcr) and the N‐desethylamiodarone concentration. Digoxin clearance increased by 21% when CLcr was doubled and decreased by 3% when the N‐desethylamiodarone concentration increased by 100 ng/mL. In the simulation, the proportion of patients with values in the toxic range was high at 0.125 mg daily among patients taking amiodarone. A daily dose of 0.0625 mg is recommended for patients with a CLcr >30 mL/min. For patients with a CLcr ≤30 mL/min and an N‐desethylamiodarone concentration >600 ng/mL, a daily dose of 0.03125 mg is recommended because of reduced digoxin clearance. Conclusions: This study revealed that renal impairment and high plasma N‐desethylamiodarone concentrations reduce digoxin clearance in patients with atrial fibrillation and heart failure. [ABSTRACT FROM AUTHOR]