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

Abstract

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.