Population pharmacokinetics of long-term oral amiodarone therapy

Background: Amiodarone is an increasingly popular and uniquely effective an tiarrhythmic agent for which population pharmacokinetic parameters in patie nts receiving long-term oral therapy have not been defined previously. Methods: We collected 605 observations of serum amiodarone and desethylamio darone metabolite concentrations from 77 patients (mean follow-up, 2 years) . Mixed-effects modeling (NONMEM) was used to determine the typical populat ion pharmacokinetic parameters, their respective variabilities, and a simpl e oral dosing regimen to rapidly achieve and maintain a target concentratio n of 1.5 mg/L, Individual serum concentration versus time curves were simul ated for the study population based on regimens outlined in the product mon ograph and were compared with those for the proposed dosing regimen. The re lationship between the duration of amiodarone therapy and the rate of decre ment in serum concentration after discontinuation was explored. Results: Amiodarone concentrations were best described by a two-compartment model with the typical parameters +/- interindividual coefficients of vari ation (where applicable) as follows: volumes of distribution/bioavailabilit y (V-1/F = 882 L; V-2/F = 12,700 L +/- 58%) and clearances/bioavailability (CL1/F = 229 L/day +/- 31%; and CL2/F = 599 L/day +/- 56%). Rapid distribut ion half-life was 17 hours, and terminal half-life was 55 days. A practical dosing regimen of 1600 mg/d for 2 days, 1200 mg/d for 5 days, 1000 mg/d fo r 7 days, 800 mg/d for 7 days, 600 mg/d for 7 days, and 400 mg/d for 62 day s followed by a maintenance dose of 343 mg/d (400 mg/d for 6 of 7 days) is proposed. After steady state is reached, cessation of dosing produces a 25% serum concentration decrement in 3 days and 50% in 36 days. Conclusions: Population pharmacokinetics confirm that amiodarone has an ext raordinarily long half-life. The slow elimination rate makes anticipating t he timing of adjustments in amiodarone therapy to avoid toxicity unusually perplexing. However, based on the estimated variability; the proposed dosin g regimen would produce steady-state concentrations within the therapeutic window for 90% of patients.