Transient kinetic and dynamic interactions between verapamil and dofetilide, a class III antiarrhythmic

Potential kinetic and dynamic interactions between the new class III antiar rhythmic dofetilide (D) and the calcium channel blocker verapamil (V) were determined in 12 young healthy male volunteers. A fixed sequence of V 80 mg tid, placebo, D 0.5 mg bid, and D + V was given as matching active and pla cebo capsules. In steady-state conditions during combination treatment, a m odest increase in mean (+/-SD) peak plasma concentration of dofetilide from 2.40 +/- 0.42 to 3.43 +/- 0.71 ng.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.h.ml(-1) (26% inc rease, p < 0.1). No other significant pharmacokinetic interaction was seen. These transient changes were concurrent with trends for a dynamic interact ion. The maximal mean increase in QT, over steady-state baseline values was 20 msec for D alone versus 26 msec during combination therapy. This relati vely small interactive effect occurred only while peak plasma drug concentr ations were developing at 1 to 3 hours after dosing and is probably caused by the known effect of verapamil to increase hepatic and portal blood flow. In view of this interaction and the relationship between dofetilide plasma concentration and torsade, verapamil is contraindicated in patients receiv ing dofetilide.