Influence of coadministration on the pharmacokinetics of azimilide dihydrochloride and digoxin.
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.
Toothaker
Roger D
RD
Procter & Gamble Pharmaceuticals, Health Care Research Center, Mason, OH 45040-9462, USA.
Corey
Alfred E
AE
Valentine
Suzanne N
SN
Agnew
Jeff R
JR
Parekh
Nikhil
N
Moehrke
Werner
W
Thompson
Gary A
GA
Powell
James H
JH
D000293:Adolescent; D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D018592:Cross-Over Studies; D004077:Digoxin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004338:Drug Combinations; D004347:Drug Interactions; D004562:Electrocardiography; D006801:Humans; D006827:Hydantoins; D048289:Imidazolidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D004338:Drug Combinations; D006827:Hydantoins; D048289:Imidazolidines; D010879:Piperazines; D004077:Digoxin; C086123:azimilide