Population pharmacokinetics of intravenous amiodarone and comparison with two-stage pharmacokinetic analysis

The disposition of amiodarone, an antiarrhythmic agent was evaluated after a single intravenous infusion (5 mg/kg over 15 minutes) in patients of various ages and with various degrees of renal function and left ventricular function. The plasma concentration-time data were obtained from three clinical studies with similar protocols. The data were analyzed by nonlinear mixed-effects modeling (NONMEM) to estimate the population pharmacokinetic parameters of amiodarone and to determine the significant demographic covariates affecting these parameters. The pharmacokinetic parameters of amiodarone (weight-corrected) also were calculated using two-stage analysis and were compared with the results obtained from the mixed-effects analysis. The population plasma concentration-time profile of amiodarone was best described by a four-compartment model. Demographic covariates (i.e., creatinine clearance and ejection fraction) did not improve the final pharmacostatistical model significantly. The results from the two-stage analysis showed no significant relationship between amiodarone pharmacokinetic parameters and age, gender, renal function, or ejection fraction. The results from one study, however, demonstrated that advanced age (> or = 65 years) resulted in reduced amiodarone clearance coupled with a prolonged elimination half-life. No such correlation was detected with NONMEM analysis, which may be partly attributable to the small number of elderly patients. Overall, the results from NONMEM analysis validated the results obtained from the two-stage analysis.