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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.
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.
Brain natriuretic peptide (BNP) is a powerful neurohormonal marker of left ventricular function and prognosis. Amiodarone either has no effect or improves the haemodynamics in patients with left ventricular dysfunction, but its effect on BNP is unknown. This study evaluated the effect of amiodarone on plasma BNP level in patients with heart failure and ventricular tachyarrhythmia. Plasma BNP level was studied in 46 patients with heart failure ventricular tachyarrhythmia, before (baseline) and at week 2 and months 1, 3 and 6 of amiodarone treatment. In addition, 21 patients with heart failure and ventricular tachyarrhythmia, who received an implantable cardioverter defibrillator, but not amiodarone, were studied on the same schedule. All patients had previously received potent vasodilator and beta-blocker therapy. Echocardiography and Holter monitoring were also performed. Amiodarone significantly decreased plasma BNP levels at week 2 to month 6 during therapy. Heart rates and frequencies of premature ventricular complexes were markedly reduced by amiodarone. Echocardiographic findings did not show a change in left ventricular end-diastolic dimensions, despite a slight increase in fraction shortening at month 6 during amiodarone therapy. The above parameters showed no change in patients without amiodarone. The effect of heart rate, premature ventricular complexes, fraction shortening, serum creatinine or thyroid stimulating hormone level was not significantly associated with decrease in BNP level during amiodarone therapy by a multivariate analysis. Among amiodarone-treated patients, mortality was higher in 24 with BNP levels >/=100 pg/ml at month 6 than in 22 with BNP levels <100 pg/ml during a mean follow-up period of 31 months. Amiodarone appears to have a decreasing effect on plasma BNP level, as well as an antiarrhythmic effect, in patients with heart failure and ventricular tachyarrhythmia.
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