Onset and duration of action of sildena l citrate for the treatment of erectile dysfunction

Transcription

1 Onset and duration of action of sildena l citrate for the treatment of erectile dysfunction Ian Eardley, 1 Peter Ellis, 2 Mitradev Boolell 2 & Maria Wulff 2 1 Department of Urology, St James University Hospital, Leeds, West Yorkshire and 2 P zer Ltd, Sandwich, Kent, UK Aims To determine the onset and duration of action of sildena l in patients with erectile dysfunction ED). Methods Two randomised, double-blind, placebo-controlled, two-way crossover studies were conducted in men with ED of no known organic cause. Study I: The time to onset of erections after sildena l 5 mg) or placebo dosing following visual sexual stimulation VSS) was assessed in 17 patients. Patients not achieving >6% penile rigidity by 7 min postdose as measured by a RigiScan 1 monitoring device were assigned an onset time of 7 min. Study II: The duration of grade 3 hard enough for penetration) and grade 4 fully hard) erections, determined by self-assessment during 6 min of VSS starting 2 and 4 h after sildena l 1 mg) or placebo dosing, was measured in 16 patients. Results Study I: The median time range) to onset of erections was 27 min in a range of 12±7) after receiving sildena l 5 mg. In the sildena l group, 71% of patients experienced onset of erections within 3 min of dosing, and 82% responded within 45 min. Of the patients who achieved >6% penile rigidity after sildena l, 86% had done so by 3 min after dosing. Study II: When VSS began 2 h postdose, the median duration of grade 3 or 4 erections was 19.5 min ±55) for sildena l vs min ±23) for placebo. When VSS began 4 h postdose, the median duration was 5 min ±45) for sildena l compared with min for placebo ±27). Conclusions Sildena l is an effective oral treatment for ED that produces a penetrative erection as early as 12 min and for most patients, within 3 min after dosing, and a duration of action lasting at least 4 h. Keywords: erectile dysfunction, sildena l citrate, duration of action, onset of action Introduction The ability to achieve penile erection is dependent on several factors, including relaxation of corpus cavernosal smooth muscle, increased vascular blood in ow and restricted venous out ow in the penis [1]. The physiological mechanism is mediated via a nitric oxide NO)- cyclic guanosine monophosphate cgmp) pathway [2±4]. During stimulation, nonadrenergic-noncholinergic neurones and vascular endothelial cells release NO, which activates guanylate cyclase, thereby increasing the level of cgmp in the corpus cavernosum [2]. Sildena l citrate Viagra 1, P zer) is a selective inhibitor of cgmp-speci c phosphodiesterase type 5 PDE5), a Correspondence: Ian Eardley, Department of Urology, St James University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7 TF, UK, Tel.: PDE isozyme found in high concentration within the corpus cavernosum [3]. By inhibiting the breakdown of cgmp, sildena l enhances the natural NO-cGMP mechanism of penile erection following sexual stimulation. Clinical studies have demonstrated that for men with erectile dysfunction ED) of organic, psychogenic and mixed organic/psychogenic aetiologies, sildena l is associated with signi cant improvement in the ability to achieve and maintain erections [5±11]. Pharmacokinetic studies have supported the suitability of single oral doses of sildena l for an as-needed and on-demand treatment for ED. In healthy volunteers, sildena l doses are absorbed rapidly, with maximum plasma concentrations achieved within a median time of 1 h range,.5±2 h) after dosing [3]. The terminal half-life of sildena l is 3±5 h; therefore, the drug's therapeutic response is expected to be sustained for at least 3 h following a dose of 1 mg. The two studies reported f 22 Blackwell Science Ltd Br J Clin Pharmacol, 53, 61S±65S 61S

2 I. Eardley et al. here were conducted to determine the time to onset Study I) and duration of penile erection of suf cient rigidity for penetrative sexual intercourse Study I and II), and duration of action Study II) following a single oral dose of sildena l in patients with ED. Patients with ED of no known organic cause were chosen because they represent a signi cant portion of patients with ED, and they exhibit high response rates to treatment. Methods Patients aged 35±7 years with a clinical diagnosis of ED of no known organic cause as evidenced by the presence of nocturnal erections, erections of penetrative rigidity under any circumstance or a positive response to an intracavernosal prostaglandin E 1 dose of j2 mg or a papaverine dose of j4 mg) of at least 6 months' duration were included in the studies. Major exclusion criteria included a history of serious medical conditions diabetes or untreated hypogonadism, signi cant arterial disease, migraine headaches and alcohol or substance abuse) or current treatment with nitrates, antidepressants, tranquillisers or anticoagulants. Other therapies for ED e.g. intracavernosal injections) had to be discontinued 2 weeks before the start of the study. Before enrolment, patients underwent a physical examination, a 12-lead electrocardiogram and standard laboratory tests. They were also required to provide written informed consent. Study design Both studies used a randomized, double-blind, placebocontrolled, two-way crossover design. In the rst study, fasted patients received a single oral 5-mg dose of sildena l, the recommended therapeutic starting dose, or matching placebo, followed by a 7-day washout period, after which they received a single dose of the alternate study drug. Visual sexual stimulation VSS) began 1 min after dosing with study medication and lasted for 6 min. For VSS, subjects were given a free choice from a selection of sexually explicit magazines and videos and were to view similar materials on each occasion. To ensure immediate sexual stimulation, videos were to be set by the investigator to start with a sexually explicit scene. Penile rigidity at the base of the penis was measured using the RigiScan 1 monitoring device Dacomed Corporation) [12], and data were recorded continuously from 15 min before dosing to 7 min after dosing. Rigidity measurements made using the RigiScan 1 were shown to be reproducible over a 3-night span in healthy volunteers [13]. In the second study, fasted patients received four treatments and underwent four assessments. The study consisted of two parts; each part was divided into two treatment periods in which the patients received a single oral 1-mg dose of sildena l, the maximum recommended therapeutic dose, or placebo. VSS, which lasted for 6 min, commenced 2 h after dosing with study drug during the treatment periods in part one and 4 h after dosing with study drug during the treatment periods in part two. Ef cacy evaluation Patients who had either at least one erection with >6% rigidity or a grade 3 or 4 erection were de ned as responders. The time to onset of erections with >6% rigidity considered hard enough for penetrative sexual intercourse) at the base of the penis was calculated from the RigiScan 1 data [14]. The patients were asked to record all erections during VSS and to grade the degree of hardness on a scale of 1±4: grade 1=an increase in penis size but not hardness; grade 2=hard but not hard enough for penetration; grade 3=hard enough for penetration but not completely hard; grade 4=completely hard. Patients in Study I who did not achieve an erection with >6% rigidity at the base of the penis at 7 min after dosing were assigned a default onset time of 7 min and a default value of for duration of erection in the calculation of means and medians of these parameters. The total duration of erections recorded during RigiScan 1 monitoring or from the patients' self-assessments during 6 min of VSS was determined in both studies. Statistical analyses Median values for assessments of time to onset and duration of erections were calculated. Means were also calculated for those assessments in which data were normally distributed. Patients' self-assessments of total mean durations of grade 3 and 4 erections were analysed using an analysis of variance ANOVA) model appropriate for a two-treatment, two-period crossover design Study I). The duration of grade 3 or 4 erections Study 2) was analysed using an ANOVA model, with terms for sequence, patient, period and treatment. The proportion of responders was calculated for the sildena l and placebo treatment groups and was analysed Study II) using the Mainland-Gart test for treatment effect. Results Patient demographics A total of 17 patients entered Study I. The mean age was 52 years range 37±7 years), and the mean duration of ED was 3.1 years range.5±19. years) for the patients in Study I. Of these 17 patients, three had a vasectomy, one had a unilateral orchidectomy, one had prostatitis 62S f 22 Blackwell Science Ltd Br J Clin Pharmacol, 53, 61S±65S

3 Onset and duration of sildena l and one had varicosities. Seven patients had received previous treatments for ED: four received prostaglandin, two yohimbine and one an investigational drug. One patient in Study I discontinued the study after completing treatment and was lost to follow-up. Sixteen patients, none of whom had participated in Study I, entered Study II. The mean age was 57 years range 35±68 years), and the mean duration of ED was 1.9 years range.3±8. years) for the patients in Study II. Of the 16 patients, seven had a vasectomy, one had an undescended right testicle, one had redundant prepuce, one had a scrotal cyst and one had hyperplasia of the prostate. None of the patients had received previous treatment for ED. Due to malfunction in the RigiScan 1 equipment while downloading penile plethysmography data, the 2-h post placebo dosing data for one patient in Study II was not available for assessment of ef cacy. Onset and duration of actionðstudy I The onset of all erections occurred only after the start of VSS. The proportion of responders patients with >6% penile rigidity) was 82% 14 of 17 patients) after sildena l treatment and 53% 9 of 17 patients) after placebo treatment. Eight of 17 patients 47%) responded to both sildena l and placebo. A grade 3 or 4 erection was reported by 12 of 17 71%) patients receiving sildena l compared with 6 of 17 35%) patients receiving placebo. The overall median time to onset of erections with >6% rigidity for the 17 patients was 27 min range 12±7 min) after receiving sildena l 5 mg) and 5 min range 15±7 min) after receiving placebo Figure 1). Analysis of data from the sildena l-treated patients showed that the onset of erection occurred within 3 min postdose in 12 patients 71%) and between 31 and 44 min in two patients 12%); three patients 18%) did not achieve an erection with >6% rigidity within 7 min of dosing. Of the 14 patients who responded to sildena l, 12 86%) achieved an erection with >6% penile rigidity within 3 min postdose, and the other two responders did so by 37 min postdose. In comparison, for the group of placebo-treated patients, the onset of erection occurred within 3 min postdose in seven patients 41%), between 31 and 44 min in one patient 6%) and between 45 and 7 min in one patient 6%); eight patients 47%) did not respond to treatment. Of the nine placebo responders, seven 78%) responded within 3 min postdose, one 6%) within 31±44 min postdose and one 6%) within 45±7 min postdose. Sildena l also signi cantly increased the duration of erections with >6% penile rigidity, compared with placebo. The ANOVA showed a statistically signi cant treatment effect P=.6) and the ratio of geometric Median time to onset of erections with >6% rigidity (min) means sildena l : placebo) was % con dence interval: 1.57, 8.94), suggesting that sildena l increased the duration of rigidity by three- to fourfold, compared with placebo. The median total duration of erections with >6% rigidity, as determined by RigiScan 1 monitoring during the 7 min after dosing, was 8.5 min range ±48 min) for the sildena l recipients, compared with min range ±16 min) for the placebo recipients. Among the 14 sildena l responders, the median duration of erections was 11.8 min range.5±47.5 min). Among the nine placebo responders, the median duration of erections was 7.5 min range 1.±16. min). Results of the patients' self-assessments of the median duration of grade 3 or 4 erections were similar to those derived from the RigiScan 1 data. Among all patients treated with sildena l, the median duration of grade 3 or 4 erections was 1. min range ±6 min) and the adjusted mean was 15.8 min, compared with a median of min range ±2 min) and an adjusted mean of 2.4 min for patients treated with placebo ANOVA, P<.1 for treatment effect). Duration of actionðstudy II, all patients, responders (5 mg), all pateints (5 mg), responders Number of patients per group Figure 1 Median time to onset of erections with >6% rigidity during visual sexual stimulation as determined using data derived from RigiScan 1 monitoring of penile rigidity in Study I. Bars indicate the range between minimum and maximum values. Treatment with a single 1-mg dose of sildena l was associated with signi cantly greater mean duration of grade 3 or 4 erections compared with single-dose placebo treatment regardless of whether VSS commenced 2 ANOVA, P<.1) or 4 h ANOVA, P<.1) after dosing. The median and mean durations of grade 3 or 4 erections for the treatment groups as a whole and for the responder subsets are shown in Figure 2. f 22 Blackwell Science Ltd Br J Clin Pharmacol, 53, 61S±65S 63S

4 Mean duration of grade 3/4 erection (min) Median duration of grade 3/4 erection (min) I. Eardley et al. a 6 2 c 4 2 2h after dosing n = (1mg) 2h after dosing b n = 16 5 d 4 n = n = 16 5 (1mg) (1mg) When VSS commenced 2 h after dosing, the median total duration of grade 3 or 4 erections for patients receiving sildena l was 19.5 min range ±55 min), and the mean duration ts.e. mean) was 19.4t4.1 min. In contrast, the median duration for patients receiving placebo was min range ±23 min), and the mean duration was 3.9t2.1 min P<.1; Figure 2a, c). The proportion of treatment responders was 75% 12 patients) for those receiving sildena l and 31% ve patients) for those receiving placebo P<.5). Among the sildena l responders, the median total duration of grade 3 or 4 erections was 24. min range ±55 min), and the mean was 23.8t4.2 min, whereas the median duration for placebo responders was min range ±23 min), and the mean was 4.8t2.5 min P<.1). When VSS commenced 4 h after dosing, the median total duration of grade 3 or 4 erections in patients receiving sildena l was 5. min range ±45 min), and 2 2 4h after dosing (1mg) 4h after dosing Figure 2 Total duration of grade 3 hard enough for penetration) and grade 4 fully hard) erections, determined from patient self-assessment during 6 min of visual sexual stimulation in Study II. a) and b) show median values determined starting 2 and 4 h after dosing, respectively; bars indicate the range between minimum and maximum values. c) and d) show mean values determined starting 2 and 4 h after dosing, respectively. All patients %); responders &). Bars indicate s.e. mean. *P<.1 vs placebo; {P<.1 vs placebo. the overall mean was 13.9t4. min, whereas in patients receiving placebo, the median total duration was min range ±27 min), and the mean was 2.9t1.9 min P<.1; Figure 2b, 2d). The proportion of treatment responders was signi cantly greater among patients receiving sildena l 13 of 16 patients, 81%) compared with patients receiving placebo ve of 16 patients, 31%; P<.5). For the sildena l responders, the median total duration of grade 3 or 4 erections was 1 min range 2±45 min), and the mean was 17.2t4 min. For the placebo responders, the median total duration of grade 3 or 4 erections was min range ±27 min) and the mean was 3.6t2 min P<.1). Discussion Desirable characteristics of an oral treatment for ED include pharmacokinetic properties that allow a prompt onset of clinical effect and several hours of clinical activity after administration of a single dose, in addition to reliable ef cacy and a favourable safety pro le at recommended doses. The results of the present studies demonstrate that in men with ED of no known organic cause, treatment with 5- or 1-mg oral doses of sildena l facilitated the achievement of erections in the presence of VSS that were rigid enough for penetrative sexual intercourse. Furthermore, the onset of action was achieved within a median time of 27 min after sildena l dosing. Such erections were achieved as quickly as 12 min and, for most patients 71%), within 3 min. This nding re ects the time to peakplasma concentration of sildena l after oral dosing 3±12 min) [3] and is consistent with the results of other clinical trials [5±11]. Erections also were achieved when VSS was delayed for 2 or 4 h after patients received 1-mg doses of sildena l. Patients were able to maintain erections for a mean duration of 19 min 2 h after dosing) and 14 min 4 h after dosing). These data suggest that suf cient sildena l remains systemically available to allow for adequate erections 4 h postdose and are consistent with a sildena l half-life of 3±5 h [3]. This is an appropriate period of therapeutic activity that is realistic and convenient for most couples. In Study I, more than one-half 53%, 9/17) of the study patients responded >6% penile rigidity) to placebo. Furthermore, among the nine patients who responded to placebo, seven 78%) did so within 3 min after dosing, similar to the proportion of sildena l responders 86%, 12/14) who responded during the same time interval. In addition, a high percentage of patients responded to both sildena l and placebo in Study I 47%) and in the rst part of Study II when VSS started 2 h after dosing 42%). These ndings suggest that a large proportion of the patients enrolled in these two 64S f 22 Blackwell Science Ltd Br J Clin Pharmacol, 53, 61S±65S

5 Onset and duration of sildena l studies appeared to have had a signi cant psychogenic component to their ED. In clinical practice, it would be worthwhile to perform nocturnal penile tumescence and rigidity testing [12] in patients presenting with ED of no organic cause and a history suggestive of psychogenic causes. An objective evaluation of psychogenic factors leading to ED may serve to direct the patient to the appropriate therapy, such as psychological treatment with or without pharmacological treatment. Although this report supplies speci c and detailed information related to the onset and duration of action of sildena l, several limitations are inherent in the study design. The use of 6 min of continuous VSS may have confounded the results as, on its own, prolonged continuous VSS may produce some effects. Without suitable controls, the contribution of this variable to treatment outcome is not known. Even though the number of patients is small, reasonable means and medians were generated. Although direct comparisons between the two different sildena l doses from the two studies are not possible, we felt it was important to investigate the onset of the recommended starting dose 5 mg) and the duration of the recommended highest dose 1 mg) [5]. The lowest recommended dose of sildena l 25 mg) is generally reserved for special populations e.g. elderly or those with hepatic or renal impairment) or those patients who experience side-effects at a higher dose [15]. Thus, the ndings presented have great relevance to clinical practice and suggest that the majority of patients with ED of no known organic cause can expect to have erections rigid enough for penetrative sexual intercourse within 3 min and as late as 4 h after taking sildena l. In conclusion, oral sildena l at recommended doses has a rapid onset of action and is effective for several hours after dosing, allowing couples to engage in sexual activity within a natural time frame. References 1 Andersson K-E, Wagner G. Physiology of penile erection. Physiol Rev 1995; 75: 191± Rajfer J, Aronson WJ, Bush PA, Dorey FJ, Ignarro LJ. Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to nonadrenergic, noncholinergic neurotransmission. N Engl J Med 1992; 326: 9±94. 3 Boolell M, Allen MJ, Ballard SA, et al. Sildena l: an orally active type 5 cyclic GMP-speci c phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res 1996; 8: 47±52. 4 Burnett AL. Nitric oxide in the penis. physiology and pathology. J Urol 1997; 157: 32 ± Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildena l in the treatment of erectile dysfunction. N Engl J Med 1998; 338: 1397± Morales A, Gingell C, Collins M, Wicker PA, Osterloh IH. Clinical safety of oral sildena l citrate Viagra 1 ) in the treatment of erectile dysfunction. Int J Impot Res 1998; 1: 69±74. 7 Padma-Nathan H, Steers WD, Wicker PA, for the Sildena l Study Group. Ef cacy and safety of oral sildena l in the treatment of erectile dysfunction: a double-blind, placebo-controlled study of 329 patients. Int J Clin Pract 1998; 52: 375±38. 8 Conti CR, Pepine CJ, Sweeney M. Ef cacy and safety of sildena l citrate in the treatment of erectile dysfunction in patients with ischemic heart disease. Am J Cardiol 1999; 83 Suppl 5A): 29C±34C. 9 Montorsi F, McDermott TED, Morgan R, et al. Ef cacy and safety of xed-dose oral sildena l in the treatment of erectile dysfunction of various etiologies. Urology 1999; 53: 111± Rendell MS, Rajfer J, Wicker PA, Smith MD, for the Sildena l Study Group. Sildena l for treatment of erectile dysfunction in men with diabetes. JAMA 1999; 281: 421± Giuliano F, Hultling C, El Masry WS, et al. Randomized trial of sildena l for the treatment of erectile dysfunction in spinal cord injury. Ann Neurol 1999; 46: 15± Levine LA, Lenting EL. Use of nocturnal penile tumescence and rigidity in the evaluation of male erectile dysfunction. Urol Clin North Am 1995; 22: 775± Hatzichristou DG, Hatzimouratidis K, Ioannides E, Yannakoyorgos K, Dimitriadis G, Kalinderis A. Nocturnal penile tumescence and rigidity monitoring in young potent volunteers: reproducibility, evaluation criteria and the effect of sexual intercourse. J Urol 1998; 159: 1921± Ogrinc FG, Linet OI. Evaluation of real-time RigiScan 1 monitoring in pharmacological erection. J Urol 1995; 154: 1356± Zusman RM, Morales A, Glasser DB, Osterloh IH. Overall cardiovascular pro le of sildena l citrate. Am J Cardiol 1999; 83: 35C± 44C. f 22 Blackwell Science Ltd Br J Clin Pharmacol, 53, 61S±65S 65S