Efficacy of Sildenafil Citrate at 12 Hours after Dosing: Re-exploring thetherapeutic Window

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1 European Urology European Urology 46 (2004) Efficacy of Sildenafil Citrate at 12 Hours after Dosing: Re-exploring thetherapeutic Window Ignacio Moncada *, José Jara, David Subirá, Irene Castaño, Carlos Hernández Urology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain Accepted 14 April 2004 Available online 31 May 2004 Abstract Objective: This open-label study investigated the efficacy of sildenafil citrate at 12 hours postdose among prior treatment responders. Patients and Methods: Eight 100-mg doses of sildenafil were provided to 40 eligible patients with erectile dysfunction (ED), who were to record the results of each sexual attempt in a patient diary. Each patient was instructed to make a sexual attempt at 1 and 12 hours postdose on 4 occasions (part 1) and only at 12 hours postdose on 4 subsequent occasions (part 2). Results: Of 40 enrolled patients, 34 (85%) completed the study. In these evaluable patients, 97% and 74% of patients achieved erections that resulted in successful intercourse at 1 hour and 12 hours postdose, respectively. There was a nonsignificant reduction in the percentage of responders at 12 hours during part 1 versus part 2 of this study (71% versus 78%). Conclusions: This study demonstrates that, in the majority of these patients with ED, sildenafil remains clinically active 12 hours after administration. Larger studies may be necessary to confirm and clarify the therapeutic window # 2004 Elsevier B.V. All rights reserved. Keywords: Sildenafil; Erectile dysfunction; Pharmacokinetics; Onset of action; Duration of action 1.Introduction The development of pharmacological agents for the treatment of erectile dysfunction (ED) has introduced greater freedom in a couples ability to plan sexual activity. However, couples receiving any type of pharmacological treatment for ED invariably need to schedule sexual activity to some degree, potentially increasing sexual encounter-related anxiety [1,2]. In this regard, patient knowledge of specific pharmacological aspects, such as onset of action from time of administration and duration of the effect, is a prerequisite for optimal use of ED-directed therapies. Ascertaining the length of the therapeutic window that will allow patients with ED to successfully engage in sexual intercourse will contribute to this knowledge. * Corresponding author. Tel. þ ; Fax: þ address: imoncada@md.infonegocio.com (I. Moncada). To date, the most consistent data for the onset and duration of the effects of sildenafil citrate, the first oral phosphodiesterase type 5 (PDE5) inhibitor to be developed and marketed for ED [3], were obtained from two randomized clinical trials that used the RigiScan 1 (Dacomed Corporation, Minneapolis, MN, USA) device to monitor changes in penile rigidity during visual sexual stimulation in a controlled hospital setting [4]. In the first study, some patients reported onset of action as quickly as 12 minutes (median of 27 minutes) after receiving sildenafil 50 mg, with the majority of patients (71%) achieving erections within 30 minutes postdose. The design of the second study was intended to demonstrate the duration of action of sildenafil at 2 and 4 hours after a 100-mg dose. When visual sexual stimulation was initiated 4 hours after dosing, 86% of patients attained erections a response rate that was significantly higher than the corresponding rate of 31% in the placebo group. Additionally, mean duration of /$ see front matter # 2004 Elsevier B.V. All rights reserved. doi: /j.eururo

2 358 I. Moncada et al. / European Urology 46 (2004) erections at 4 hours postdose was 17.2 minutes and 3.6 minutes for responders in the sildenafil and placebo groups, respectively [4]. The therapeutic window of sildenafil could be framed at approximately 30 minutes (median onset of action) and 4 hours (plasma half-life [t 1=2 ]) postdose [4 6]. In clinical practice, however, we have found that patients frequently report an ability to respond to sexual stimulation >12 hours after taking sildenafil; however, the effectiveness of sildenafil beyond a 4- hour period has not been prospectively studied. Although experience with sildenafil has shown that efficacy at 4 hours postdose is adequate in most instances, a wider therapeutic window may be desirable for a minority of patients. The objective of this open-label study was to assess the clinical activity of a single 100-mg dose of sildenafil at 12 hours postdose in patients known to respond to this therapy. 2.Patients and methods 2.1. Eligibility and treatment This prospective observational open-label study recruited 40 patients from a single site. Eligible patients were men older than 18 years of age who had a documented clinical diagnosis of ED based on clinical history, physical exam, and laboratory findings. The diagnosis was confirmed by a score of 21 or less on the Sexual Health Inventory for Men [7]. All patients provided informed consent to participate. All patients were undergoing sildenafil therapy for at least 3 months before entering the study and were categorized as sildenafil responders. Accordingly, patients in whom >80% of sexual attempts with prior sildenafil therapy were deemed successful were eligible for enrollment; no other criteria regarding etiology, severity, or duration of ED were used. Eight 100-mg doses of sildenafil were provided to eligible patients in this 2-part study, with both parts intended to include 4 sexual attempts using a single dose In the first part, patients were instructed to attempt sexual intercourse 1 hour and again 12 hours after taking a dose With regards to specific timing for part 1, it was recommended that patients take the drug at 20:00 hours and make the first sexual attempt at 21:00 hours and the second at 08:00 the following morning. In the second part, patients were to make a sexual attempt only 12 hours after dosing. All patients participated in parts 1 and 2 of this study and were asked to complete both parts within an 8-week period. There were no food or alcohol restrictions given to the patients in relation to the timing of sildenafil dosing Efficacy assessment The timing of sildenafil dosing as well as the timing and results of each sexual attempt were to be recorded in a patient diary. The primary efficacy endpoint for this study was the percentage of positive responses to the question Did the erection last long enough to have successful intercourse? This question is equivalent to the third question of the sexual encounter profile (SEP) diary that was provided to patients in most randomized clinical trials assessing the efficacy of drug therapy for ED. Patients who did not comply with the protocol instructions were considered unevaluable and were not included in the efficacy analysis. McNemar s test was used for comparisons of percentages, with a level of p 0.05 (two-sided) considered statistically significant. 3.Results The 40-patient target accrual was reached. The mean standard deviation (S.D.) age was 54 6 years, with ages ranging from 30 to 62 years. The mean S.D. time in treatment before entering the study was 17 9 months (range 6 48 months). Most patients had mild to moderate ED (81%), and the remaining patients had severe ED (19%). In 89% of the cases, the ED etiology was considered to be organic or mixed, and 84% of patients had concomitant diseases or conditions. None of the patients were taking a medication that could significantly interfere with the metabolism or excretion Of the 40 enrolled patients, 34 patients (85%) completed the study and were evaluable. Failure to perform the number of sexual attempts required was the primary reason for the 6 patients who did not complete the study. Although the recommended dose for all patients was 100 mg, 11 patients (32%) underwent a dose reduction to 50 mg in response to the development of adverse events, mainly flushing. All patients had received the originally intended dose of 100 mg for the first 3 doses, and the 50-mg and 100-mg doses were shown to be equally effective. Dose reduction was allowed to patients providing they had a satisfactory clinical response to sildenafil. Administration of sildenafil was followed by successful intercourse (i.e., positive answer to the question Did the erection last long enough to have successful intercourse? ) at 1 hour in 97% (33/34) of patients. Overall, 74% (25/34) of patients reported successful intercourse at 12 hours after sildenafil intake. The percentage of patients with successful sexual intercourse at 12 hours was somewhat lower when patients had previously engaged in a sexual encounter at 1 hour after dosing (71% [24/34]) versus those who did not (79% [27/34]); this difference in response rates between parts 1 and 2 of the study was not statistically significant (Fig. 1). 4.Discussion Both onset of action and duration of action are receiving greater attention as new PDE5 inhibitors are being introduced as alternative treatments for ED. Currently, initial pharmacological treatment for

3 I. Moncada et al. / European Urology 46 (2004) No. of Evaluable Patients Attempt at 1 hour Negative response at 12h Positive response at 12h ED involves the use of an oral PDE5 inhibitor [8]. Sildenafil was the first PDE5 inhibitor to become widely available for clinical use [9], and vardenafil and tadalafil, two newer PDE5 inhibitors, were recently approved for this indication in many countries across Europe and the United States [3,10]. The present data demonstrate a high rate of response to sildenafil at 12 hours after dosing. Eardley et al. found that when visual sexual stimulation was initiated at 4 hours postdose, sildenafil 100 mg was associated with significantly prolonged erections compared with placebo [4]. Although it was known that the duration of action for sildenafil was at least as long as the t 1=2 of 4 hours, longer duration of action studies have not been reported. However, it is well known that t 1=2 does not necessarily directly correlate to duration of action. For example, proton pump inhibitors have a t 1=2 of around 1 hour, whereas their acid-suppressive effects are known to last over 24 hours [11]. The volume of distribution of sildenafil in the body is approximately 105 liters and therefore substantially exceeds the total volume of body water (42 liters), suggesting that drug distribution into tissues and possibly tissue binding may also contribute to sustained clinical effects [5]. Accumulating clinical data for sildenafil suggest that the window of opportunity for successful intercourse is broader than initially thought. Although anecdotal reports provided the primary evidence of a duration of action beyond 4 hours, 1 study in 16 patients with ED of no known organic cause reported response rates of 67%, 57% and 29% at 1, 8 and 12 hours after a 100-mg dose of sildenafil [12]. In addition, a recent publication showing the ability of sildenafil to improve 7 27 No Attempt at 1 hour Fig. 1. At 12 hours postdose, the percentage of patients expressing positive responses to the question Did the erection last long enough to have successful intercourse? was somewhat lower among patients who attempted a sexual encounter at 1 hour, but this finding was not statistically significant. the quantity and quality of nocturnal erections in normal volunteers taking a single dose at bedtime also is consistent with prolonged effects [13]. Owing to the lack of published head-to-head studies of agents within this class of compounds, any conclusions regarding clinical activity are reliant on acrossstudy comparisons that are confounded by differing patient selection criteria and other methodological considerations [10]. For example, in most cases, sildenafil nonresponders were excluded from studies of vardenafil and tadalafil and a large percentage of the patients enrolled in these studies were known to be sildenafil responders, making it impossible to compare and contrast response rates for the three agents. From a pharmacokinetic standpoint, sildenafil 100 mg and vardenafil 20 mg are similar in terms of the time to reach maximum concentrations (t max of 1.2 and 0.7 hours, respectively) and t 1=2 (3.8 and 3.9 hours, respectively) in fasting patients with ED [6,14,15]. Compared with these two agents, tadalafil 20mg would be expected to have a somewhat slower onset of action but a notably longer duration of action, with a t max of 2.0 hours and a t 1=2 of 17.5 hours in healthy volunteers [16]. Clinical data support the efficacy of tadalafil at both 24 and 36 hours after a single 20-mg dose [17]. At the present time, the clinical significance and relative advantages or disadvantages of such pharmacokinetic differences across PDE5 inhibitors is unclear. Broadening the therapeutic window may be a desirable feature for some patients, yet it is reasonable to speculate that a duration of action extending over a period of days could be accompanied by certain safety-related limitations, most notably a greater potential for adverse events and drug-drug interactions. Clearly, the introduction of new PDE5 inhibitors provides the opportunity for individualized treatment approaches, but further research efforts are needed to determine the therapeutic window that will provide patients with the greatest balance between safety and durability of effect. In summary, the therapeutic window of sildenafil was assumed to be between 30 minutes and 4 hours postdose based on randomized clinical trial data derived from the RigiScan device [4]. The present open-label study found that sildenafil was clinically active in the majority of patients up to 12 hours after administration. The tendency toward a lesser degree of effectiveness at 12 hours postdose when sexual activity was previously attempted at 1 hour may reflect a longer refractory period among older patients in general. Until these data are replicated in a larger, randomized, placebo-controlled study, our continued recommendation to patients will be to engage in sexual activity from

4 360 I. Moncada et al. / European Urology 46 (2004) hour to 4 hours after sildenafil dosing. Nonetheless, it is apparent that sexual intercourse can occur up to 12 hours postdose in a substantial proportion of patients taking sildenafil for ED. Acknowledgements This study was partially supported by an independent investigator initiated grant from Pfizer Inc. References [1] Althof SE. When an erection alone is not enough: biopsychosocial obstacles to lovemaking. Int J Impot Res 2002;14(Suppl 1):S [2] Althof SE, Turner LA, Levine SB, Bodner D, Kursh ED, Resnick MI. Through the eyes of women: the sexual and psychological responses of women to their partner s treatment with self-injection or external vacuum therapy. J Urol 1992;147: [3] Fink HA, Mac Donald R, Rutks IR, Nelson DB, Wilt TJ. Sildenafil for male erectile dysfunction: a systematic review and meta-analysis. Arch Intern Med 2002;162: [4] Eardley I, Ellis P, Boolell M, Wulff M. Onset and duration of action of sildenafil citrate for the treatment of erectile dysfunction. Br J Clin Pharmacol 2002;53:61S 5S. [5] Nichols DJ, Muirhead GJ, Harness JA. Pharmacokinetics of sildenafil citrate after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality. Br J Clin Pharmacol 2002;53:5S 12S. [6] Milligan PA, Marshall SF, Karlsson MO. A population pharmacokinetic analysis of sildenafil citrate in patients with erectile dysfunction. Br J Clin Pharmacol 2002;53:45S 52S. [7] Cappelleri JC, Siegel RL, Glasser DB, Osterloh IH, Rosen RC. Relationship between patient self-assessment of erectile dysfunction and the sexual health inventory for men. Clin Ther 2001;23: [8] Moncada I, Sáenz de Tejada I. Pharmacological treatment of erectile dysfunction. Curr Opin Urol 1999;9: [9] Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med 1998;338: [10] Gresser U, Gleiter CH. Erectile dysfunction: comparison of efficacy and side effects of the PDE-5 inhibitors sildenafil, vardenafil and tadalafil review of the literature. Eur J Med Res 2002;7: [11] Yacyshyn BR, Thomson ABR. The clinical importance of proton pump inhibitor pharmacokinetics. Digestion 2002;66: [12] Gepi-Attee S, Sultana SR, Hodgson G, Wulff MB, Gingell C. Duration of action of sildenafil citrate among men with erectile dysfunction of no known organic cause [abstract]. Int J Impot Res 2001;13(Suppl 1):S21. [13] Yaman Ö, Tokath Z, Inal T, Anafarta K. Effect of sildenafil on nocturnal erections of potent men. Int J Impot Res 2003;15: [14] Stark S, Sachse R, Liedl T, Hensen J, Rohde G, Wensing G, et al. Vardenafil increases penile rigidity and tumescence in men with erectile dysfunction after a single oral dose. Eur Urol 2001;40: [15] Klotz T, Sachse R, Heidrich A, Jockenhovel F, Rohde G, Wensing G, et al. Vardenafil increases penile rigidity and tumescence in erectile dysfunction patients: a RigiScan and pharmacokinetic study. World J Urol 2001;19:32 9. [16] Patterson B, Bedding A, Jewell H, Payne C, Mitchell M. The effect of intrinsic and extrinsic factors on the pharmacokinetic properties of tadalafil (IC351). Int J Impot Res 2001;13:S43 4. [17] Porst H, Padma-Nathan H, Giuliano F, Anglin G, Varanese L, Rosen R. Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: a randomized controlled trial. Urology 2003;62: Editorial Comment G. Brock, London, ON, Canada The recent approval of effective oral agents for ED, in addition to sildenafil, has placed clinicians into the interesting position of having to assist men in making the best choice. The ideal agent could be characterized as having a rapid onset, being free of side effects, efficacious across all etiologies and severities of ED, easily metabolized, effective for the appropriate duration desired and inexpensive. In truth today, that drug does not exist. In this report, Moncada and colleagues have carefully evaluated a cohort of known sildenafil responders to assess whether the period of effectiveness for sildenafil extends beyond the commonly believed 4 hour time-point. This information would be of value to current users of sildenafil, their physicians and to men receiving drug information in selecting which PDE5 inhibitor they wish to try initially. As described in this report, the major advantage of tadalafil is its long half-life and reported effectiveness out to 36 hours. It would be of value to know how the other PDE5 inhibitors compare in terms of duration of efficacy. In my opinion, several key findings are described in this study. Roughly 75% of men who completed the study responded to sildenafil at 12 hours. There was a slight reduction in efficacy if they had engaged in sexual activity at 1 hour. This period of effectiveness appears to be present independent of cause of erectile dysfunction. While an interesting report, readers of European Urology must be aware of several study limitations which limit the power of this study. They have included only sildenafil responders. We have no information on the rate of successful intercourse of an age matched placebo arm. We also were not given detailed information on the success rates of the 6/40 men excluded from analysis because of protocol violations. A more powerful subsequent study would be to simulate the inclusion and exclusion criteria used by tadalafil in its report

5 I. Moncada et al. / European Urology 46 (2004) describing a 36 hour window, where PDE5 naïve and experienced men with ED of varied etiologies were generally included. While I commend Dr Moncada and colleagues for this report, I agree with them that larger studies employing a wider patient population are required before changes to patient information are generally undertaken. Editorial Comment F. Montorsi, Milan, Italy In this study Moncada et al. show that sildenafil maintains a high degree of efficacy 12 hours after administration. I believe that this result will not surprise the majority of the urologists who have experience with sildenafil as many patients often report that they are seeing an effect on the morning following the administration of a dose What surprises me is that the company producing the drug has not thought to launch an appropriately designed (double blind, placebo controlled) trial aimed at assessing in a scientifically elegant manner this new possible way of using sildenafil. The most important point of the study is that the long lasting efficacy of sildenafil was seen in patients who initially responded to the drug when used in the conventional way, i.e. 60 minutes after dosing. My personal take home message would then be that I may suggest a patient to start using sildenafil 60 minutes after dosing and then, in those who respond nicely in this condition, to try use the drug in a more flexible way. This is a small study suggesting an interesting conclusion. Please be aware that we need more robust data to confirm this finding.