Evaluation of vardenafil and sildenafil on cardiac repolarization.

This novel study evaluated the effects of vardenafil and sildenafil on QT and corrected QT (QTc) duration using a model that minimizes experimental error to obtain the most accurate assessment of observed QTc effects. A placebo-controlled and positive-controlled, period-balanced, double-blinded, 6-way crossover study evaluated therapeutic and supratherapeutic oral doses of vardenafil (10 and 80 mg, respectively) and sildenafil (50 and 400 mg, respectively), therapeutic doses of moxifloxacin (400 mg), and a placebo in 58 healthy men (mean age 53 years), with dosing every 3 days. Six replicate, 12-lead, digital electrocardiograms (ECGs) were recorded at 3 time points before and 5 time points after dosing to cover the time course of maximum exposure to study drugs and their metabolites. An independent laboratory blindly analyzed approximately 17,000 ECGs. For the placebo, mean change in QTcF (Fridericia) duration 1 hour after dose (approximate Tmax of vardenafil and sildenafil) was 0 ms (+/-0.7 SD). QT/QTc variability was small across regimens, indicating statistically powerful results. Moxifloxacin demonstrated an expected 8-ms mean change and was the only drug to prolong absolute QT. Placebo-corrected mean changes in QTcF duration (90% confidence interval) at 1 hour after dose were 8 ms (range 6 to 9) for vardenafil 10 mg and 6 ms (range 5 to 8) for sildenafil 50 mg. QTci (linear and nonlinear per patient) yielded similar trends: 4 ms (range 3 to 6) for vardenafil 10 mg and 4 ms (range 2 to 5) for sildenafil 50 mg. Dose response demonstrated very shallow QTc relations for study drugs. Therapeutic and supratherapeutic doses produced only small increases in the QTcF interval, which were considered to be clinically irrelevant. This well-controlled, statistically powerful study in middle-aged men demonstrated that vardenafil and sildenafil produced no increase of absolute QT and only similar, small increases of the QTc interval, with a shallow dose-response curve. The study design and conduct may serve as a guide for future QT assessment of new drugs.

Cardiovascular Monitoring in Normal Healthy Adults: A Literature Review and Recommendations for the Reporting of Disturbances of Cardiac Rhythm.

Continuous monitoring of the electrocardiogram has become a commonly used technique in the safety assessment of new drugs when these are administered to human beings for the first time. Disturbances of cardiac rhythm have been observed with cardiac monitoring during clinical pharmacology studies in normal healthy volunteers. It is often difficult to assess the clinical significance of these rhythms especially when these rhythms occur following the administration of new drugs to human beings for the first time. Certain arrhythmias are frequently noted in normal healthy adults, including sinus bradycardia, sinus arrhythmia, the Wenckebach type of second-degree AV block (Mobitz I), atrioventricular junctional rhythm, PAC's, and PVC's. PAC's and PVC's are commonly observed, although greater than 50 PVC's/24 hr and greater than 100 PAC's/hr are relatively rare. Atrial couplets/atrial tachycardia and ventricular couplets/nonsustained ventricular tachycardia are relatively rare, but nevertheless do occur on occassion in normal healthy adults. With these consideration in mind, a guideline for the interpretation and reporting of cardiac arrhythmias occurring during clinical pharmacology studies in normal healthy adults is presented. The absence of symptoms or structural heart disease are important considerations in the evaluation of arrhythmias in normal healthy adults. The severity and seriousness of the adverse experience should be left up to the investigator's discretion. Rechallenge with active drug or placebo should be considered on a case-by-case basis.