RESUMEN
The influence of coadministration on digoxin and azimilide pharmacokinetics/pharmacodynamics was assessed in a randomized, 3-way crossover study in 18 healthy men. Serial blood and urine samples were obtained for azimilide and digoxin quantitation. Treatment effects on pharmacokinetics were assessed using analysis of variance. The relationship between azimilide blood concentrations and QT(c) prolongation was characterized by an E(max) model. Effects of coadministration on pharmacodynamics were assessed using a mechanistic-based inhibition model. Azimilide pharmacokinetics was unaffected by digoxin, except for a 36% increase in CL(r) (P = .0325), with no change in CL(o). Digoxin pharmacokinetics was unaffected by azimilide, except for a 21% increase in C(max) (P = .0176) and a 10% increase in AUC(tau) (P = .0121). Digoxin coadministration increased the apparent EC(50) with no effect on E(max), consistent with competitive inhibition (K(i) = 0.899 ng/mL). The pharmacokinetic and pharmacodynamic changes observed upon coadministration were small and are not expected to be clinically important.
Asunto(s)
Antiarrítmicos/farmacocinética , Cardiotónicos/farmacocinética , Digoxina/farmacocinética , Imidazolidinas/farmacocinética , Piperazinas/farmacocinética , Adolescente , Adulto , Antiarrítmicos/administración & dosificación , Antiarrítmicos/sangre , Antiarrítmicos/orina , Cardiotónicos/administración & dosificación , Cardiotónicos/sangre , Cardiotónicos/orina , Estudios Cruzados , Digoxina/administración & dosificación , Digoxina/sangre , Digoxina/orina , Combinación de Medicamentos , Interacciones Farmacológicas , Electrocardiografía , Humanos , Hidantoínas , Imidazolidinas/administración & dosificación , Imidazolidinas/sangre , Imidazolidinas/orina , Masculino , Piperazinas/administración & dosificación , Piperazinas/sangre , Piperazinas/orinaRESUMEN
AIMS: To assess the influence of severe renal impairment on azimilide pharmacokinetics. METHODS: A single oral dose of 125 mg azimilide dihydrochloride was administered to subjects with normal and severely impaired renal function. Blood and urine samples were collected for 22-28 and 10 days, respectively. RESULTS: Azimilide renal clearance decreased in subjects with renal impairment (mean 14 vs 4.8 ml h-1 kg-1, 95% confidence interval on the ratio 0.23, 0.50). However, no change in any other pharmacokinetic parameter including oral clearance (mean 109 vs 104 ml h-1 kg-1, 95% confidence interval on the ratio 0.67, 1.36) was observed. CONCLUSIONS: Since azimilide blood concentrations are essentially unaffected by renal function, an a priori dosage regimen adjustment is not required in patients with renal impairment.