Optimizing Amiodarone Maintenance Dose to Minimize N-Desethylamiodarone Accumulation and Pulmonary Toxicity: Insights...

The accumulation of N-desethylamiodarone (DEA), an active metabolite of amiodarone, is a recognized risk factor for interstitial pneumonia. However, predictors of DEA accumulation, particularly during the initiation phase of amiodarone therapy, remain unclear. We aimed to identify predictors of DEA accumulation using classification and regression tree analysis and to verify their association with interstitial pneumonia in patients receiving amiodarone.

We conducted a retrospective analysis of 80 patients who underwent therapeutic drug monitoring of amiodarone and DEA levels at Kitasato University Hospital. Potential risk factors for elevated DEA levels (≥ 0.6 mg/L) were identified using classification and regression tree analysis with 20 variables. To prevent overfitting, strict pruning parameters were implemented (minimum bucket size = 7, maximum depth = 2). N-desethylamiodarone levels were compared between patients with and without interstitial pneumonia, and the findings were validated through Monte Carlo simulations based on published pharmacokinetic models.

Elevated DEA levels (≥ 0.6 mg/L) were observed in 23 patients (29%). Classification and regression tree analysis identified treatment duration (cutoff: 47 days) and weight-adjusted dose (cutoff: 2.15 mg/kg/day) as primary determinants of DEA accumulation (accuracy: 0.88; area under the curve: 0.90 [95% confidence interval 0.84-0.95]). Among the five patients who developed interstitial pneumonia, four (80%) exhibited elevated DEA levels, compared to 19 of 75 (25%) patients without interstitial pneumonia (p = 0.022). Pharmacokinetic simulations confirmed that the probability of toxic DEA accumulation increases substantially at doses exceeding 150 mg/day.

Treatment duration (≥ 47 days) and weight-adjusted dose (≥ 2.15 mg/kg/day) are significant predictors of DEA accumulation in this cohort of Japanese patients. Elevated DEA levels are significantly associated with the onset of interstitial pneumonia. To minimize the risk of toxicity, taking a maintenance dose of ≤ 100 mg/day (or < 2.15 mg/kg/day, which corresponds to ≤ 100 mg/day for a standard 50-kg patient) and monitoring DEA levels are recommended.