A definitive study of the effects of PDE-5 inhibitors on cardiac repolarization in middle-age males

Patients with erectile dysfunction may use PDE5 inhibitors such as vardenafil (V) and sildenafil (S), which alter the hERG channel of transfected cells only at suprapharmacologic nonclinical concentrations. This study evaluated effects of therapeutic and supratherapeutic doses of V and S on QT/QTc duration. A placebo- and active-control (moxifloxacin, M, at therapeutic dose), period balanced, double blinded, 6 way crossover study evaluated single oral doses of V 10 mg, V 80 mg, S 50 mg, S 400 mg, M 400 mg and placebo in 58 healthy men (mean age 53) with doses separated by 3 days. Six replicate 12-lead digital ECGs were recorded at 3 time points prior to and 5 time points post dose to cover the full exposure of drugs and metabolites. An independent lab blindly analyzed the ECGs. PK blood samples were drawn at the same 5 time points post dose. For placebo, mean change in QTcF (Fridericia) duration from baseline at 1 hour post dose (approximate Tmax of V and S) was 0 msec (+/- 0.7 SD). QT and QTc variability was small across regimens, indicating statistically powerful results due to large sample size and number (17,000) of ECGs. M demonstrated an expected 8 msec mean change and was the only drug to prolong absolute QT. Placebo-corrected values of mean change from baseline at 1 hour post-dose for each regimen are shown below. QT corrected using linear and nonlinear methods and each individual's QT/HR data (QTci) yielded similar trends of drug effect on QTc. PK/PD modeling demonstrated a very shallow QTc-concentration relationship for V and S. Therapeutic and supratherapeutic doses of V and S produced no increase of absolute QT and similar small increases in QTc interval. We conclude that these findings, and the absence of postmarketing reports of torsades de pointes with S, indicate that small increases in QTc for V and S are clinically insignificant. This study design may serve as a guide for future definitive QT assessment. (See Table) Clinical Pharmacology & Therapeutics (2004) 75, P47–P47; doi: 10.1016/j.clpt.2003.11.178 Table 1.  Treatment Treatment effect (placebo-corrected, 90% CI) HR (bpm) Absolute QT (msec) QTcF (msec) QTci, linear correction (msec) V 10 mg 5 (4,6) -2 (-4,0) 8 (6,9) 4(3,6) V 80 mg 6 (5,7) -2 (-4,0) 10 (8,11) 6 (4,7) S 50 mg 4 (3,5) -2 (-4,0) 6 (5,8) 4 (2,5) S 400 mg 5 (4,6) -1 (-3,1) 9 (8,11) 5 (4,7) M 400 mg 2 (1,3) 3 (1,5) 8 (6,9) 7 (5,8)