Transient kinetic and dynamic interactions between verapamil and dofetilide, a class III antiarrhythmic.
Potential kinetic and dynamic interactions between the new class III antiarrhythmic dofetilide (D) and the calcium channel blocker verapamil (V) were determined in 12 young healthy male volunteers. A fixed sequence of V80 mg tid, placebo, D 0.5 mg bid, and D + V was given as matching active and placebo capsules. In steady-state conditions during combination treatment, a modest increase in mean (+/- SD) peak plasma concentration of dofetilide from 2.40 +/- 0.42 to 3.43 +/- 0.71 ng x ml(-1) (43% increase, p < 0.1) was noted. During the combination period, for the first 4 hours, mean AUC values for D increased from 7.4 +/- 1.0 (D alone) to 9.2 +/- 1.4 ng x h x ml(-1) (26% increase, p <0.1). No other significant pharmacokinetic interaction was seen. These transient changes were concurrent with trends for a dynamic interaction. The maximal mean increase in QT, over steady-state baseline values was 20 msec for D alone versus 26 msec during combination therapy. This relatively small interactive effect occurred only while peak plasma drug concentrations were developing at 1 to 3 hours after dosing and is probably caused by the known effect of verapamil to increase hepatic and portal bloodflow. In view of this interaction and the relationship between dofetilide plasma concentration and torsade, verapamil is contraindicated in patients receiving dofetilide.
Johnson
B F
BF
Pfizer Global Research & Development, Groton, Connecticut 06340, USA.
Cheng
S L
SL
Venitz
J
J
D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D004347:Drug Interactions; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D010627:Phenethylamines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D026902:Potassium Channel Blockers; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D014700:Verapamil / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*
D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; D014700:Verapamil; C063533:dofetilide