Vivus sees promising results with avanafil nitrate
Results of a clinical pharmacology study conducted to evaluate the hemodynamic responses (blood pressure and heart rate) to glyceryl trinitrate (GTN) in subjects pretreated with placebo, avanafil nitrate, US biotech company Vivus' investigational PDE5 inhibitor, and sildenafil citrate (Viagra) showed that there was a trend at all time points evaluated toward a greater decrease in the mean maximal standing systolic blood pressure over a 12 hour period following GTN administration in subjects pretreated with sildenafil as compared with those pretreated with avanafil or placebo.
Results of a clinical pharmacology study conducted to evaluate the hemodynamic responses (blood pressure and heart rate) to glyceryl trinitrate (GTN) in subjects pretreated with placebo, avanafil nitrate, US biotech company Vivus' investigational PDE5 inhibitor, and sildenafil citrate (Viagra) showed that there was a trend at all time points evaluated toward a greater decrease in the mean maximal standing systolic blood pressure over a 12 hour period following GTN administration in subjects pretreated with sildenafil as compared with those pretreated with avanafil or placebo.
When results from all time points were combined, the mean maximal decreases in standing systolic blood pressure following GTN administration were 21.5mmHg for placebo, 20.6 mmHg for avanafil and 25.5 mmHg for sildenafil. The difference between avanafil and placebo was not statistically different (p=0.29), while sildenafil produced a decrease in blood pressure, which approached significance when compared with avanafil (p=0.07), and was significantly different compared to placebo (p<0.05). The mean maximal increases in heart rate following GTN administration were 18.8 beats per minute for placebo, 17.6 beats per minute for avanafil, which were both statistically different than 22.9 beats per minute for sildenafil. Increased heart rate is the body's compensatory response to decreases in blood pressure.
A total of 101 healthy males (mean age of 43) were treated in this double- blind, randomised, crossover design study. The objective of the study was to evaluate the hemodynamic response to a sublingual dose of gylceryl trinitrate in subjects receiving oral avanafil, sildenafil citrate, and placebo. All subjects were administered 0.4 mg of GTN sublingually on three separate occasions in random order, once where GTN was administered following a dose of avanafil (200mg), once where GTN was administered following a dose of sildenafil (100mg) and once where GTN was administered following a dose of placebo. Different groups of subjects received GTN at pre-specified time intervals after study medication ranging from 30 minutes to 12 hours. Sitting and standing blood pressure and heart rate measurements were intensively monitored for two hours following nitrate administration.
The combined effects of GTN and study drugs on hemodynamic responses were also evaluated over a 12-hour period. Results from this analysis demonstrated that the combined effect of GTN and either avanafil or sildenafil as measured by the mean maximal decrease in standing systolic blood pressure over GTN alone, was 4.1 mmHg for avanafil and 7.8 mmHg for sildenafil (p=0.11). The mean maximal increase in standing heart rate over the similar increase produced by GTN alone in the same evaluation period was 1.8 beats per minute for avanafil and 6.9 beats per minute for sildenafil (p<0.001).
Clinically significant hypotension was also evaluated in this study and was prospectively defined in the study protocol as a decrease in standing systolic blood pressure of greater than 30 mmHg. The number of patients who developed clinically significant orthostatic hypotension on GTN after pretreatment with placebo, avanafil and sildenafil were 11, 14, and 28 respectively. The study also showed that the hemodynamic interaction between avanafil and GTN was no longer detectable at 12 hours after administration of avanafil. In contrast, the interaction between sildenafil and GTN persisted for at least 12 hours after administration of sildenafil.
Avanafil is Vivus' investigational oral phosphodiesterase type 5 (PDE5) inhibitor being developed for the treatment of erectile dysfunction. Nitrates, such as GTN, are commonly used to treat angina pectoris, or chest pain, and are known to lower blood pressure. When nitrates and PDE5 inhibitors are administered together, profound and sometimes life-threatening decreases in blood pressure have occurred.
'Results of this study demonstrate that avanafil, which has a shorter plasma half-life and a greater selectivity for the phosphodiesterase type 5 enzyme, had less effect versus sildenafil on heart rate and blood pressure when taken prior to nitrates,' said Professor Dr Christian Stief, a recognised expert on PDE5 inhibitors and director of the urology clinical division, Ludwigs-Maximilians-Universitat Munchen, Klinikum der Universitat, Munich, Germany. 'These results offer encouragement that avanafil may provide an improved cardiovascular profile in the treatment of men with erectile dysfunction.'
'In this study, mean decreases in blood pressure and increases in heart rate were numerically but not statistically less for avanafil when compared with sildenafil at all time points monitored with only one exception,' said Dr John Dietrich, vice president of r&d of Vivus. 'In the group receiving GTN 30 minutes after PDE5 inhibitors were administered, avanafil plus GTN produced a numerically but not statistically greater decrease in blood pressure than sildenafil plus GTN. This result is an indication of the more rapid onset of action of avanafil with peak plasma levels achieved in approximately 30 minutes. While these results are encouraging, additional studies are necessary to define the clinical relevance of these differences. We plan to present the complete study data at an upcoming scientific meeting.'