Conditions: Drug-induced QT Prolongation Pharmacokinetics Pharmacodynamics
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 22
Healthy volunteers: yes

Brief summary:
The primary objective of this research study is to test the hypothesis that late sodium current blocking drugs (mexiletine or lidocaine) can attenuate the effect of hERG potassium channel blocking drugs (dofetilide) on ventricular repolarization (QTc) by shortening early repolarization (J-Tpeakc). The secondary object is to assess the ability of calcium channel block (diltiazem) to reduce the QTc prolongation associated with hERG block (moxifloxacin).

Detailed description:
This is a randomized, double-blind, 5-period crossover study in healthy male and female subjects, 18 to 35 years of age, to compare the electrophysiological response of hERG potassium channel blocking drugs with and without the addition of late sodium or calcium channel blocking drugs. The 5 treatment periods are 1) dofetilide alone, 2) mexiletine with and without dofetilide, 3) lidocaine with and without dofetilide, 4) moxifloxacin with and without diltiazem and 5) placebo. During each treatment period, 12 blood samples for pharmacokinetic measurements are obtained with matched 12-lead ECG recordings.

Arms:
arm 1: Dofetilide alone arm arm 2: Dofetilide combined with mexiletine arm 3: Dofetilide combined with lidocaine arm 4: Moxifloxacin with and without diltiazem. arm 5: Placebo (#2 gelcap and intravenous saline)

Interventions: intervention 1: Dofetilide intervention 2: Mexiletine intervention 3: Lidocaine intervention 4: Moxifloxacin intervention 5: Diltiazem intervention 6: Placebo
Intervention descriptions: intervention 1: * 8 am: Placebo
* 12 pm (noon): 250 µg
* 5:30 pm: 250 µg intervention 2: * 8 am: weight x 4 mg/kg
* 12 pm (noon): Same as at 8 am
* 5:30 pm: Same as at 8 am intervention 3: * 9 am : 30 µg/min per kg (loading) for 60 minutes and 10 µg/min per kg (maintenance) for 30 minutes
* 2 pm: 55 µg/min per kg (loading) for 60 minutes and 20 µg/min per kg (maintenance) for 30 minutes
* 7:30 pm: 52 µg/min per kg (loading) for 60 minutes and 20 µg/min per kg (maintenance) for 30 minutes intervention 4: * 9 am: 5.63 mg/h per kg (loading) for 1 hour and 0.26 mg/h per kg (maintenance for 30 minutes)
* 2 pm: 6.14 mg/h per kg (loading) for 1 hour and 0.49 mg/h per kg (maintenance for 30 minutes)
* 7:30 pm: 2.23 mg/h per kg (loading) for 1 hour and 0.49 mg/h per kg (maintenance for 30 minutes) intervention 5: • 7:30 pm: 330 µg/h per kg (loading) for 60 minutes and 61 µg/h per kg (maintenance) for 30 minutes intervention 6: Placebo (#2 Gelcap or IV saline)

Protocol document: