Ability of Late Sodium or Calcium Current Block to Balance the ECG Effects of Potassium Current Block
Condition: Drug-induced QT Prolongation; Pharmacokinetics; Pharmacodynamics
MeSH terms: Long QT Syndrome
Intervention: Dofetilide; Mexiletine; Lidocaine; Moxifloxacin; Diltiazem; Placebo
Intervention description: 8 am: Placebo
12 pm (noon): 250 µg
5:30 pm: 250 µg; 8 am: weight x 4 mg/kg
12 pm (noon): Same as at 8 am
5:30 pm: Same as at 8 am; 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; 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); • 7:30 pm: 330 µg/h per kg (loading) for 60 minutes and 61 µg/h per kg (maintenance) for 30 minutes; Placebo (#2 Gelcap or IV saline)
Intervention MeSH terms: Moxifloxacin; Lidocaine; Mexiletine; Dofetilide; Diltiazem
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 22.0
Sex: All
Minimum age: 18 Years
Maximum age: 35 Years
Healthy volunteers: Accepts Healthy Volunteers

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).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Subject is a healthy man or woman, 18 to 35 years of age, inclusive, who weighs at
             least 50 kg (110 pounds), no more than 85 kg (197 pounds) and has a body mass index of
             18 to 27 kg/m2, inclusive, at Screening.

          2. Subject has normal medical history findings, clinical laboratory results, vital sign
             measurements, 12 lead ECG results, and physical examination findings at Screening or,
             if abnormal, the abnormality is not considered clinically significant (as determined
             and documented by the investigator or designee).

          3. Male or female subjects must agree to practice 2 highly effective methods of birth
             control (as determined by the investigator or designee; one of the methods must be a
             barrier technique) from Screening until 30 days after the last dose of study drug.

        Exclusion Criteria:

          -  1. Subject has a 12 lead safety ECG result at Screening or Check in of Period 1 with
             evidence of any of the following abnormalities:

               -  QT corrected interval (QTc) using Fridericia correction (QTcF) >430 milliseconds
                  (ms)

               -  PR interval >220 ms or <120 ms

               -  QRS duration >110 ms

               -  Second- or third-degree atrioventricular block

               -  Complete left or right bundle branch block or incomplete right bundle branch
                  block

               -  Heart rate <50 or >90 beats per minute

               -  Pathological Q-waves (defined as Q wave >40 ms)

               -  Ventricular pre-excitation

                  2. Subject has more than 12 ectopic beats during the 3 hour Holter ECG at
                  Screening.

                  3. Subject has a history of unexplained syncope, structural heart disease, long
                  QT syndrome, heart failure, myocardial infarction, angina, unexplained cardiac
                  arrhythmia, torsades de pointes, ventricular tachycardia, or placement of a
                  pacemaker or implantable defibrillator. Subjects will also be excluded if there
                  is a family history of long QT syndrome (genetically proven or suggested by
                  sudden death of a close relative due to cardiac causes at a young age) or Brugada
                  syndrome.

                  4. Subject has a history or current evidence of any clinically significant (as
                  determined by the investigator) cardiovascular, dermatologic, endocrine,
                  gastrointestinal, hematologic, hepatic, immunologic, metabolic, neurologic,
                  psychiatric, pulmonary, renal, urologic, and/or other major disease or malignancy
                  (excluding nonmelanoma skin cancer). The investigator may allow exceptions to
                  these criteria (e.g., stable mild joint disease [that will not interfere with or
                  influence the activities required by the protocol, in the opinion of the
                  investigator], cholecystectomy, childhood asthma) following discussion with the
                  medical monitor.

                  5. Subject has a history of thoracic surgery.

                  6. Subject has any condition possibly affecting study drug absorption (e.g.,
                  gastrectomy, Crohn's disease, irritable bowel syndrome).

                  7. Subject has a skin condition likely to compromise ECG electrode placement.

                  8. Subject is a female with breast implants.

                  9. Subject's laboratory test results at Screening or Check in of Period 1 are
                  outside the reference ranges provided by the clinical laboratory and considered
                  clinically significant (as determined and documented by the investigator or
                  designee).

                  10. Subject's laboratory test results at Screening or Check in of Period 1
                  indicate hypokalemia, hypocalcemia, or hypomagnesemia according to lower limits
                  of the reference ranges provided by the clinical laboratory.

                  11. Subject's laboratory test results at Screening or Check in of Period 1 are >2
                  × the upper limit of normal (ULN) for alanine aminotransferase or aspartate
                  aminotransferase, >1.5 × ULN for bilirubin, or >1.5 × ULN for creatinine.

                  12. Subject has a positive test result at Screening for human immunodeficiency
                  virus, hepatitis C antibodies, or hepatitis B surface antigen.

                  13. Subject has a mean systolic blood pressure <90 or >140 mmHg or a mean
                  diastolic blood pressure <50 or >90 mmHg at either Screening or Check in of
                  Period 1.