POPULATION PHARMACOKINETICS OF INTRAVENOUS AMIODARONE AND COMPARISON WITH 2-STAGE PHARMACOKINETIC ANALYSIS

The disposition of amiodarone, an antiarrhythmic agent was evaluated a fter a single intravenous infusion (5 mg/kg over 15 minutes) in patien ts of various ages and with various degrees of renal function and left ventricular function. The plasma concentration-time data were obtaine d from three clinical studies with similar protocols. The data were an alyzed by nonlinear mixed-effects modeling (NONMEM) to estimate the po pulation pharmacokinetic parameters of amiodarone and to determine the significant demographic covariates affecting these parameters. The ph armacokinetic parameters of amiodarone (weight-corrected) also were ca lculated using two-stage analysis and were compared with the results o btained from the mixed-effects analysis. The population plasma concent ration-time profile of amiodarone was best described by a four-compart ment model. Demographic covariates (i.e., creatinine clearance and eje ction fraction) did not improve the final pharmacostatistical model si gnificantly. The results from the two-stage analysis showed no signifi cant relationship between amiodarone pharmacokinetic parameters and ag e, gender, renal function, or ejection fraction. The results from one study, however, demonstrated that advanced age (greater than or equal to 65 years) resulted in reduced amiodarone clearance coupled with a p rolonged 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 validat ed the results obtained from the two-stage analysis.