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Determining the Earliest Time within 30 Minutes to Erectogenic Effect after Tadalafil 10 and 20 mg: A Multicenter, Randomized, Double‐Blind, Placebo‐Controlled, At‐Home Study
Blackwell Science, LtdOxford, UKJSMJournal of Sexual Medicine1743-6095Journal of Sexual Medicine 1743 6095200412193200Original ArticleEarliest Time to Erectogenic Effect After TadalafilRosen et al.
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Determining the Earliest Time within 30 Minutes to Erectogenic Effect after Tadalafil 10 and 20 mg: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, At-Home Study Raymond C. Rosen, PhD,* Harin Padma-Nathan, MD,† Ridwan Shabsigh, MD,‡ Khalil Saikali, PhD, Exec MB,§ Vish Watkins, MD,¶ and William Pullman, MD, PhD** *Robert Wood Johnson Medical School, Piscataway, NJ; †The Male Clinic, Beverly Hills, CA; ‡Columbia-Presbyterian Medical Center, New York, NY; §ICOS Corporation, Bothell, WA; ¶Lilly Research Laboratories, Indianapolis, IN; **Lilly Research Laboratories, Indianapolis, IN, USA Conflict of Interest. Dr. Saikali is an employee of ICOS. Drs. Watkins and Pullman are employees of Lilly. ABSTRACT
Introduction. Tadalafil is a phosphodiesterase 5 (PDE5) inhibitor used for the treatment of erectile dysfunction (ED). The minimal time to onset of erectogenic effect in the at-home setting has not been evaluated. Aim. The goal was to determine the earliest time to erectogenic effect leading to successful intercourse within 30 minutes after taking tadalafil 10 and 20 mg. Methods. The multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase-2 study enrolled men at least 21 years old with a minimum 3-month history of ED. Four single doses each of placebo, tadalafil 10 mg, or 20 mg were taken at home once every 8–10 days. Using a stopwatch, couples recorded in Sexual Encounter Profile diaries the earliest time within 30 minutes after dosing to the first erection adequate for vaginal penetration, and whether the erection led to successful intercourse. Main Outcome Measures. The primary analysis compared the percentage of erections resulting in successful intercourse between tadalafil groups and placebo at one-minute intervals using a stepdown procedure. A secondary analysis compared the overall distribution of time to erectogenic effect between treatment groups using the Cox Regression Method. Results. Compared to placebo, a significant erectogenic response to tadalafil 20 mg was found from 30 minutes down to 16 minutes after dosing (P = 0.012). Response to tadalafil 10 mg approached significance (P = 0.054) at 30 minutes. As analysed by the Cox Regression Method, a significant erectogenic response was found from 30 minutes down to 15 minutes after dosing for tadalafil 20 mg (P = 0.020), and from 30 minutes down to 26 minutes for tadalafil 10 mg (P = 0.042). Fiftytwo percent of men taking tadalafil 20 mg had at least one successful intercourse attempt within 30 minutes compared to 35.1% of men taking placebo (P = 0.038). Conclusions. This stopwatch-based study demonstrated a pharmacodynamic effect within 30 minutes after dosing for tadalafil 10 and 20 mg. Key Words. Tadalafil; PDE5 Inhibitor; Erectogenic Effect; Pharmacodynamic Effect
Introduction
P
DE5 inhibitors have revolutionized the treatment of erectile dysfunction (ED). The currently available drugs—sildenafil, vardenafil, and
tadalafil—are all relatively safe and highly effective [1–8]. Differences have been noted, however, among the pharmacokinetic properties of each drug, such as Cmax (maximum plasma concentration), tmax (time to Cmax), and half-life, which may J Sex Med 2004; 1: 193–200
194 result in differences in the pharmacodynamic properties of each drug, such as minimal time to onset of action and duration of action. Clinical studies have shown the duration of action of tadalafil to be up to 36 hours in most men [3,9,10]. However, the minimal time to erectogenic effect for tadalafil has been less well characterized. In a study using penile plethysmography (using RigiScan) with visual sexual stimulation (VSS) [11], a 10-mg dose of tadalafil produced an erectogenic effect by 45 minutes after dosing. However, this study was done in the clinic setting, the clinical endpoint was rigidity, not successful intercourse, which is a more conservative endpoint, and the 20-mg dose was not investigated.
Aims
The present study used a stopwatch design to determine whether tadalafil 10 mg and 20 mg could produce a significant erectogenic effect within 30 minutes post dose. Erectogenic effect was defined as an erection adequate for vaginal penetration and leading to successful intercourse. The study was designed to meet “real world” criteria in that patients were included with a wide range of severity and etiology, most were treatment naïve and not selected as previous drug responders, and the clinical endpoint (successful intercourse) was conservative. Finally, patients were permitted a maximum of four uses of the drug. Recognizing the wide range of individual variation, the study was not designed to determine the optimal time post dose that most patients would recognize an erectogenic effect. Rather, the overall goal of this pharmacodynamic study was to determine the minimal time at which a significant drug effect relative to placebo could be detected within the first 30 minutes after dosing. Methods
Study Population Heterosexual men who were at least 21 years of age, and reported a history of ED ≥ 3 months duration were eligible to participate in the study. ED was defined as the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance [12]. Subjects who were included in the study had to be in a monogamous relationship with a female partner and were not to use any other erectile dysfunction therapy during the study, although previous use of other J Sex Med 2004; 1: 193–200
Rosen et al. erectile dysfunction therapy did not prohibit inclusion. Men were excluded from the study for the following reasons: ED caused by untreated endocrine disorders, history of penile implant or significant penile deformities; history of radical prostatectomy; clinically significant hepatic, renal, cardiovascular, or central nervous system disease or injury, including stroke or spinal cord injury; treatment with nitrates, cancer chemotherapy, or antiandrogens; current infection with any sexually transmitted disease; and history of drug, alcohol, or substance abuse within the past 6 months. In addition, any persons who had previously completed or withdrawn from any other study investigating tadalafil were not eligible to participate in this study. Signed informed consent was required from both the study subject and the female partner. The study was conducted in conformity with the ethical principles of the Declaration of Helsinki (adopted by the 18th World Medical Assembly, Helsinki, Finland, 1964, and revised at the World Medical Assembly, Tokyo, Japan, 1975; Venice, Italy, 1983; and Hong Kong, 1989), the applicable guidelines for Good Clinical Practice, or the applicable U.S. laws and regulations, whichever provided the greater protection of the individual.
Study Design This was a multicenter (10 U.S. sites), randomized, double-blind, placebo-controlled, parallelgroup, phase-2 study (study code LVCK). Visit 1 was a screening visit. After obtaining informed consent, patients underwent a physical examination, clinical laboratory tests, a 12-lead electrocardiogram (ECG), and had a medical history taken. A central laboratory performed all clinical laboratory assessments, and ECGs were interpreted by a single cardiologist. Eligible patients who met the inclusion and exclusion criteria after screening entered a treatment-free run-in period of 28 days. During the run-in period, patients were asked to record the outcome of all sexual attempts in a Sexual Encounter Profile (SEP) diary to determine baseline values. At visit 2, the International Index of Erectile Function (IIEF) was administered. The Erectile Function (EF) Domain of the IIEF (adapted from Cappelleri [13]) was used to determine ED severity: mild (22–25), moderate (11–21), severe (£10). Patients were stratified by EF Domain scores and randomly assigned into treatment groups in a 1 : 1 : 1 fashion to receive placebo, or tadalafil 10 mg, or tadalafil 20 mg.
Earliest Time to Erectogenic Effect After Tadalafil The treatment phase consisted of four doses, with a single dose taken at home without regard to food, approximately once every 8–10 days. Patients were instructed to take a dose when they and their partner developed a desire to engage in sexual activity, and immediately start the stopwatch. Couples were to continue with sexual stimulation, and then, at the earliest time to the first erection adequate for vaginal penetration within 30 minutes, stop the stopwatch and record the time. They were instructed to continue with sexual activity and record whether the erection lasted long enough for successful intercourse in their SEP diaries (SEP Question 3: “Did your erection last long enough for you to have successful intercourse?”). Visit 3 was 1–4 days after the final treatment was taken, or approximately 4–5 weeks after visit 2. At visit 3, SEP diaries were collected, vital signs were measured, urinalysis, blood chemistries, and hematology were done, adverse events were recorded and, at the discretion of the investigator, a physical exam was performed. Subjects were then discharged from the study. Main Outcome Measures
The primary efficacy variable was the earliest time to erectogenic effect determined by stopwatch within 30 minutes of dosing, defined as the elapsed time from dosing until attainment of the first erection adequate for penetration, but only for those erections that lasted long enough for successful intercourse (SEP3). Consequently, for an erection to be counted as successful in the analysis, it had to (1) occur within 30 minutes after dosing; (2) be assessed by the patient as hard enough for vaginal penetration; and (3) last long enough to result in successful sexual intercourse. The overall time to erectogenic effect was obtained by comparing the percentage of first erections adequate for successful intercourse after dosing to that for placebo.
Safety The analysis of safety included all enrolled patients. Safety was assessed by evaluating all reported treatment-emergent adverse events, vital signs and clinical laboratory tests. Treatmentemergent adverse events were defined as any adverse events that first occurred or worsened in severity after randomization, and were mapped using COSTART (Coding Symbols for Thesaurus of Adverse Reaction Terms). Prompted by nonleading questions, subjects reported adverse events
195 on a volunteer basis throughout the study. A physical exam was performed at the final visit at the discretion of the investigator.
Statistical Analysis Primary and secondary efficacy analyses were done in an intent-to-treat (ITT) basis. The primary analysis was a comparison of the percentage of first erections resulting in successful intercourse within 30 minutes of taking study drug. The data were analysed by a method for handling repeated measurements of binary data (the Generalized Estimating Equation approach) [14]. The statistical model included treatment, site, severity of ED, and week as main effects. Starting from 30 minutes after dosing, treatments were to be compared based on the proportion of attempts that were successful. If there was a statistically significant treatment effect for the 20-mg dose group of tadalafil (P < 0.05) at 30 minutes, then a step-down procedure was to be applied. Comparisons were to be made at 1-minute decrements and were to stop as soon as tadalafil was found not to be statistically different from placebo. Comparisons of earlier time points were not performed as soon as P > 0.05. The earliest time to erectogenic effect was consequently defined as the shortest time after dosing that tadalafil was shown to be significantly different from placebo. If there was a statistically significant treatment effect for the 20-mg dose of tadalafil within 30 minutes, the time to erectogenic effect for the 10-mg dose of tadalafil was to be determined similarly. A secondary analysis, stipulated in the protocol, was to compare the overall distribution of time to erectogenic effect between treatments using the Cox Regression Method. Whereas the primary analysis compared the proportion of responses between tadalafil and placebo groups up to a given point in time, the Cox Regression Method was a survival analysis technique that took into consideration the actual time it took the patient to achieve a response up to a given time point when the treatment responses were compared between groups. Patients who did not have a successful attempt up to a given point in time were treated as censored observations at that point in time. In the Cox Regression analysis, therapy was included as a covariate. Additionally, because patients were instructed to make one attempt approximately once a week, “week” was used as a stratification variable according to the model of Prentice et al. [15] to adjust for multiple, within-patient observations. In this analysis the distribution of time to J Sex Med 2004; 1: 193–200
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successful intercourse across treatments was compared for dose 1 (week 1), dose 2 (week 2), dose 3 (week 3), and dose 4 (week 4), which were then combined to obtain an overall test. In the Cox Regression, a sequential testing was employed which was identical to that employed in the primary analysis. Standard patient baseline characteristics were summarized for each treatment group, including age, duration of ED, prior use of other ED therapeutic modalities, smoking category, use of antihypertensive medications, and alcohol intake. For continuous patient characteristics, means were compared using ANOVA. The incidence of the categorical variables was compared using the appropriate chi-square test (e.g., Pearson chi-square, Fisher’s exact). Results
Patient Demographics Ten centers enrolled 223 patients: 74 patients were randomized to the placebo group, 74 to the tadalafil 10 mg group and 75 to the tadalafil 20 mg group. The treatment groups were similar in key baseline characteristics, including age, ethnicity, comorbid conditions, ED severity, and ED duration (Table 1). Whereas prior exposure to tadalafil was an exclusion criterion, prior use of sildenafil citrate was not. However, less than 10% of men
Table 1
had previous experience with sildenafil (Table 1). Therefore, the population was generally PDE5 inhibitor-naïve.
Minimal Time to Erectogenic Effect At 1-minute decrements, starting from 30 minutes after dosing, treatment with tadalafil 20 mg was found to be statistically different from placebo at 30 minutes down to 16 minutes (Table 2), indicating that the earliest time to erectogenic effect for tadalafil 20 mg was 16 minutes after dosing. The cumulative number of successful intercourse attempts at £16 minutes after dosing was 47 (15.7%) out of 300 doses taken in the tadalafil 20mg group compared with 22 (7.7%) successful intercourse attempts out of 284 doses taken in the placebo group (P = 0.012). By 30 minutes after dosing, the cumulative number of successful intercourse attempts was 102 (34.0%) in the tadalafil 20 mg group and 50 (17.6%) in the placebo group (odds ratio 2.7, P = 0.002). The cumulative number of successful intercourse attempts in the tadalafil 10-mg group at 30 minutes was 73 (25.0%) out of 292 doses taken compared to 50 (17.6%) in the placebo group (odds ratio = 1.9, P = 0.054) (Table 2). As analysed by the Cox Regression Method, a statistically significant response to tadalafil 20 mg compared with placebo was found from 30 minutes down to 15 minutes after dosing
Baseline demographics and clinical characteristics Tadalafil treatment group
Characteristic
Placebo (N = 74)
10 mg (N = 74)
20 mg (N = 75)
Age (years) mean ± SD Weight (kg) mean ± SD Ethnicity, N (%) African descent Western Asian Caucasian East/SE Asian Hispanic Erectile dysfunction history, N (%) ≥3 months and < 6 months ≥6 months and < 1 year ≥1 year IIEF erectile function domain score, N (%) Mild (22–25) Moderate (11–21) Severe (6–10) Comorbid conditions Hypertension Diabetes mellitus Depression Hyperlipidemia Prior use of sildenafil citrate
58.8 ± 10.8 91.2 ± 17.1
57.6 ± 10.9 93.6 ± 16.7
59.1 ± 12.0 92.1 ± 17.7
5 0 64 3 2
(86.5) (4.1) (2.7)
4 (5.4) 0 68 (91.9) 0 2 (2.7)
7 1 63 0 4
1 (1.4) 4 (5.4) 69 (93.2)
3 (4.1) 5 (6.8) 66 (89.2)
0 8 (10.7) 67 (89.3)
9 (12.2) 39 (52.7) 26 (35.1)
10 (13.5) 39 (52.7) 25 (33.8)
11 (14.7) 39 (52.0) 25 (33.3)
35 17 5 7 7
24 20 5 3 7
25 23 11 4 5
J Sex Med 2004; 1: 193–200
(6.8)
(47.3) (23.0) (6.8) (9.5) (9.5)
(32.4) (27.0) (6.8) (4.1) (9.5)
(9.3) (1.3) (84.0) (5.3)
(33.3) (30.7) (14.7) (5.3) (6.7)
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Table 2 The percent of successful intercourse attempts within 30 minutes after dosing: step-down analysis determining time to erectogenic effect for tadalafil 10 mg and 20 mg Percent (%) of successful intercourse attempts (SEP3) Time (minute) after dosing
Placebo (N1 = 284)†
Tadalafil 10 mg (N1 = 292)
Tadalafil 20 mg (N1 = 300)
P-value‡ placebo vs. 10 mg
P-value placebo vs. 20 mg
30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14
17.6 17.6 16.5 15.5 14.4 14.1 13.0 12.3 12.3 12.0 11.3 10.6 9.9 9.5 7.7 7.4 6.0
25.0 24.3 22.9 21.6 20.5 17.1 16.4 16.1 14.4 13.0 12.0 10.6 10.3 9.6 9.2 7.9 7.5
34.0 33.0 31.0 30.0 26.7 25.7 25.3 25.0 24.0 21.3 20.3 19.0 17.3 16.0 15.7 13.7 12.3
0.054 * * * * * * * * * * * * * * * *
0.002 0.004 0.002 0.001 0.004 0.006 0.004 0.002 0.004 0.010 0.013 0.017 0.021 0.026 0.012 0.052 *
* Analysis stopped at first time-point where P = 0.05. † N1 is the total number of doses. ‡ P-values are computed using the generalized estimating equation (GEE approach) to the analysis of repeated successful erection.
Cumulative Response Rate Within 30 Minutes by Dose We also conducted a post hoc, descriptive analysis to determine the cumulative proportion of men taking tadalafil 20 mg who were able to achieve at least one erection leading to successful intercourse within 30 minutes after dosing for each of the four doses taken during the study treatment period (Figure 1). After dose 1, 37.3% of men taking tadalafil 20 mg were able to have an erection sufficient for successful intercourse within 30 minutes after dosing compared to 17.6% of men taking placebo. By dose 4, 52.0% of men taking tadalafil 20 mg were able to have at least one erection leading to successful intercourse within 30 minutes after dosing compared to 35.1% of men taking placebo (P = 0.038). When ED severity was considered, by dose 4, 62.0% of men with mild to moderate ED taking tadalafil 20 mg were able to have at least one erection leading to successful intercourse within 30 minutes post dose compared to 43.8% taking placebo, and 32.0% of men with
severe ED taking tadalafil 20 mg had at least one erection leading to successful intercourse compared to 19.2% of men taking placebo. When age was considered, by dose 4, 63.3% of men 55 years and younger taking tadalafil 20 mg were able to have at least one erection leading to successful intercourse within 30 minutes post dose compared to 42.3% of men taking placebo, and 44.4% of men over age 55 taking tadalafil 20 mg had at least one erection leading to successful intercourse
SEP3: Cumulative proportion of men (%)
(P = 0.02). A statistically significant response to tadalafil 10 mg compared with placebo was found from 30 minutes down to 26 minutes after dosing (P = 0.042). Thus, the results obtained for time to erectogenic effect were similar as determined by either the primary objective analysis or the Cox Regression Method.
Placebo Tadalafil 10 mg 60
Tadalafil 20 mg
52.0
52.0
46.7
50 37.3
40 30 23.0 17.6
20
37.8
37.8
37.8 35.1
28.4
25.7
10 0 0
1
2
3
4
Dose number
Figure 1 Cumulative response to tadalafil within 30 minutes by dose. The cumulative proportion of men achieving at least one successful intercourse (SEP3) attempt within 30 minutes post dose for each of the four doses taken.
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within 30 minutes compared to 31.3% of men taking placebo.
Safety Ninety-six percent (214) of men enrolled completed the study (Table 3). Six of the nine men who discontinued treatment were in the placebo group, two were in the 10-mg group, and one was in the 20-mg group. Four men discontinued the study due to adverse events: two in the placebo group (one due to back pain caused by a herniated disc and one due to chest pain caused by a partially reversible perfusion defect), one in the tadalafil 10 mg group (due to back pain), and one in the tadalafil 20 mg group (due to diarrhea). Two patients were lost to follow-up, and in the placebo group, one patient discontinued due to personal conflict and another two patients due to sponsor decision. The most common treatment-emergent adverse events were headache, myalgia, dyspepsia, nausea, vasodilatation, and back pain (Table 3). Discussion
The results of this study are consistent with previous reports suggesting that the time to erectogenic effect with PDE5 inhibitors may be significantly less than would be expected based on specific pharmacokinetic parameters such as tmax. Previous studies have shown onset of erectogenic effect to be less than 30 minutes for both sildenafil [15] and vardenafil [16] even though the median tmax for both drugs is 60 minutes (range 30– 120 minutes) [17,18]. A pharmacodynamic effect distinguishable from placebo was noted within
Table 3
Patient disposition and adverse events
Event classification
Placebo N = 74 N (%)
Tadalafil 10 mg N = 74 N (%)
Tadalafil 20 mg N = 75 N (%)
Patients’ discontinuations Adverse event Protocol violation Perceived lack of efficacy Other* Headache Myalgia Dyspepsia Nausea Vasodilation Back pain
6 2 0 0 4 0 0 0 0 0 1
2 1 0 0 1 3 3 1 1 1 2
1 1 0 0 0 6 1 2 2 2 0
(8.1) (2.7)
(5.4)
(1.4)
(2.7) (1.4)
(1.4) (4.1) (4.1) (1.4) (1.4) (1.4) (2.7)
(1.3) (1.3)
(8.0) (1.3) (2.7) (2.7) (2.7)
* In the placebo group, one patient was lost to follow-up, one patient discontinued due to personal conflict, and another two patients due to sponsor decision; in the 10 mg group, one patient was lost to follow-up.
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14 minutes after dosing with sildenafil 100 mg [15] and a pharmacodynamic effect was noted within 16 minutes after dosing with vardenafil 20 mg [16]. The median tmax of tadalafil is 2 hours (range 30 minutes to 6 hours) [10]. Although a slower onset of erectogenic effect might be expected for tadalafil, we were able to demonstrate a significant erectogenic effect compared to placebo at 16 minutes following drug administration for the 20-mg dose and at 30 minutes following drug administration for the 10-mg dose. All three studies investigating the minimal time to erectogenic effect for PDE5 inhibitors demonstrate that a significant pharmacodynamic effect is achieved prior to reaching the maximum observed plasma concentration (Cmax), that is, prior to tmax. In addition, all three studies demonstrate that an erectogenic effect is not predicated on the need to reach Cmax, consistent with the knowledge that the time to efficacious plasma level is usually shorter than the time to maximum plasma level. In the absence of a single clinical trial that directly compares the onset of action for the three drugs, it is difficult to make comparisons. The studies differ in their inclusion and exclusion criteria, the patient population enrolled, the dose used, the dosing instructions, and the number of attempts given to achieve successful intercourse. However, all three studies indicate that the PDE5 inhibitors exhibit a distinguishable erectogenic effect sooner than would be expected based on specific pharmacokinetic parameters such as tmax. One of the limitations of stopwatch studies in general is the potential lack of clinical application. The minimal time to erectogenic effect may not be applicable to all men with ED because most men with ED will not experience a pharmacodynamic effect at the minimal time. In all three studies, approximately one-third of patients responded to PDE5 inhibitor therapy within 16 minutes. However, men were given either four attempts (vardenafil study [16] and this study) or eight attempts (sildenafil study [15]) to be successful at least once in order to be considered a responder. In the current study, at 16 minutes after dosing, 32% of men taking tadalafil 20 mg and 15.7% of attempts were successful at 16 minutes. Thus, at this early time point after dosing, a small percentage of men have a successful intercourse attempt, and a small percentage of intercourse attempts made by these men are successful, given that over 50% of men will be successful at later time points (i.e., 30 minutes). Therefore, the clinical significance may not be as strong as the statistical sig-
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Earliest Time to Erectogenic Effect After Tadalafil nificance, because only a minority of patients responds so early. Another limitation of our study is that we collected response data only from the first 30 minutes after dosing. Therefore, the full range of response times descriptive of men with ED was not observed. Determining the full distribution of onset times, as well as the median time to erectogenic effect, would perhaps better enable physicians to advise patients regarding the relationship between the onset of pharmacodynamic effect and the timing of sexual intercourse, and for patients to be aware that some individuals have the potential for a rapid response to onset of stimulation. There is considerable variation among men with ED with regard to etiology, severity, and comorbid conditions that may affect the time needed to respond to PDE5 therapy and the degree to which they respond. Also, some men may not respond at all to PDE5 inhibitors [19]. Therefore, responsiveness can vary, and the time and duration of erectogenic effect can vary widely depending on the individual. The results for tadalafil clearly indicate that an erectogenic effect can be detected within 30 minutes after dosing, well before the tmax of 2 hours. We should stress that while onset of pharmacodynamic effect can be less than 30 minutes in some men, most men will require more time for tadalafil to be optimally effective. Patients with more severe ED, or older patients, in particular, should not be encouraged to attempt sexual activity quickly after dosing, and they should be instructed to optimize the conditions of sexual stimulation. In addition, based on the faster time to onset observed for the 20-mg vs. the 10-mg dose, patients with severe ED may benefit from titrating to tadalafil 20 mg. Because both tadalafil 10 mg and 20 mg have been shown to improve erectile response for up to 36 hours after dosing [3,9,10], the time it takes for onset of erectogenic effect may be a secondary consideration for some men.
Conclusion
Tadalafil 10 and 20 mg are capable of producing a pharmacodynamic effect distinguishable from placebo within 30 minutes after dosing. The minimal time to onset of erectogenic effect was, in a minority of men, 16 minutes for tadalafil 20 mg. Onset was assessed by a stopwatch measure, with approximately one-third to one-half of patients respond-
ing within 30 minutes. Both tadalafil 10 mg and 20 mg were well tolerated. Acknowledgments
The authors thank the participating clinical investigators: Stanley A. Brosman, MD, Santa Monica, CA; Michael J. Kaempf, MD, Portland, OR; Joel M. Kaufman, MD, Aurora, CO; James G. McMurray, MD, Huntsville, AL; Christopher P. Steidle, MD, Fort Wayne, IN; Jay M. Young, MD, Laguna Woods, CA; Norman R. Zinner, MD, Torrance, CA. In addition, we thank Diane R. Stothard, PhD (Eli Lilly and Company, Indianapolis, IN) for editorial assistance; William H. Cordell, MD (Eli Lilly and Company, Indianapolis, IN) and J. Steve Whitaker, MD (ICOS Corporation, Bothell, WA) for critical review of the manuscript; Jonathan Denne, PhD, and Tim Costigan, PhD (Eli Lilly and Company, Indianapolis, IN) and Greg Anglin, PhD (Eli Lilly Canada) for assistance with statistical analysis; and Amy Hoover (Eli Lilly and Company, Indianapolis, IN) for clinical study support and review of the manuscript. Corresponding Author: Raymond C. Rosen, PhD, Robert Wood Johnson Medical School, Piscataway, NJ, USA. Tel: (732) 235-4485; Fax: (732) 235-5818; E-mail: [email protected]
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Determining the Earliest Time within 30 Minutes to Erectogenic Effect after Tadalafil 10 and 20 mg: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, At-Home Study Raymond C. Rosen, PhD,* Harin Padma-Nathan, MD,† Ridwan Shabsigh, MD,‡ Khalil Saikali, PhD, Exec MB,§ Vish Watkins, MD,¶ and William Pullman, MD, PhD** *Robert Wood Johnson Medical School, Piscataway, NJ; †The Male Clinic, Beverly Hills, CA; ‡Columbia-Presbyterian Medical Center, New York, NY; §ICOS Corporation, Bothell, WA; ¶Lilly Research Laboratories, Indianapolis, IN; **Lilly Research Laboratories, Indianapolis, IN, USA Conflict of Interest. Dr. Saikali is an employee of ICOS. Drs. Watkins and Pullman are employees of Lilly. ABSTRACT
Introduction. Tadalafil is a phosphodiesterase 5 (PDE5) inhibitor used for the treatment of erectile dysfunction (ED). The minimal time to onset of erectogenic effect in the at-home setting has not been evaluated. Aim. The goal was to determine the earliest time to erectogenic effect leading to successful intercourse within 30 minutes after taking tadalafil 10 and 20 mg. Methods. The multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase-2 study enrolled men at least 21 years old with a minimum 3-month history of ED. Four single doses each of placebo, tadalafil 10 mg, or 20 mg were taken at home once every 8–10 days. Using a stopwatch, couples recorded in Sexual Encounter Profile diaries the earliest time within 30 minutes after dosing to the first erection adequate for vaginal penetration, and whether the erection led to successful intercourse. Main Outcome Measures. The primary analysis compared the percentage of erections resulting in successful intercourse between tadalafil groups and placebo at one-minute intervals using a stepdown procedure. A secondary analysis compared the overall distribution of time to erectogenic effect between treatment groups using the Cox Regression Method. Results. Compared to placebo, a significant erectogenic response to tadalafil 20 mg was found from 30 minutes down to 16 minutes after dosing (P = 0.012). Response to tadalafil 10 mg approached significance (P = 0.054) at 30 minutes. As analysed by the Cox Regression Method, a significant erectogenic response was found from 30 minutes down to 15 minutes after dosing for tadalafil 20 mg (P = 0.020), and from 30 minutes down to 26 minutes for tadalafil 10 mg (P = 0.042). Fiftytwo percent of men taking tadalafil 20 mg had at least one successful intercourse attempt within 30 minutes compared to 35.1% of men taking placebo (P = 0.038). Conclusions. This stopwatch-based study demonstrated a pharmacodynamic effect within 30 minutes after dosing for tadalafil 10 and 20 mg. Key Words. Tadalafil; PDE5 Inhibitor; Erectogenic Effect; Pharmacodynamic Effect
Introduction
P
DE5 inhibitors have revolutionized the treatment of erectile dysfunction (ED). The currently available drugs—sildenafil, vardenafil, and
tadalafil—are all relatively safe and highly effective [1–8]. Differences have been noted, however, among the pharmacokinetic properties of each drug, such as Cmax (maximum plasma concentration), tmax (time to Cmax), and half-life, which may J Sex Med 2004; 1: 193–200
194 result in differences in the pharmacodynamic properties of each drug, such as minimal time to onset of action and duration of action. Clinical studies have shown the duration of action of tadalafil to be up to 36 hours in most men [3,9,10]. However, the minimal time to erectogenic effect for tadalafil has been less well characterized. In a study using penile plethysmography (using RigiScan) with visual sexual stimulation (VSS) [11], a 10-mg dose of tadalafil produced an erectogenic effect by 45 minutes after dosing. However, this study was done in the clinic setting, the clinical endpoint was rigidity, not successful intercourse, which is a more conservative endpoint, and the 20-mg dose was not investigated.
Aims
The present study used a stopwatch design to determine whether tadalafil 10 mg and 20 mg could produce a significant erectogenic effect within 30 minutes post dose. Erectogenic effect was defined as an erection adequate for vaginal penetration and leading to successful intercourse. The study was designed to meet “real world” criteria in that patients were included with a wide range of severity and etiology, most were treatment naïve and not selected as previous drug responders, and the clinical endpoint (successful intercourse) was conservative. Finally, patients were permitted a maximum of four uses of the drug. Recognizing the wide range of individual variation, the study was not designed to determine the optimal time post dose that most patients would recognize an erectogenic effect. Rather, the overall goal of this pharmacodynamic study was to determine the minimal time at which a significant drug effect relative to placebo could be detected within the first 30 minutes after dosing. Methods
Study Population Heterosexual men who were at least 21 years of age, and reported a history of ED ≥ 3 months duration were eligible to participate in the study. ED was defined as the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance [12]. Subjects who were included in the study had to be in a monogamous relationship with a female partner and were not to use any other erectile dysfunction therapy during the study, although previous use of other J Sex Med 2004; 1: 193–200
Rosen et al. erectile dysfunction therapy did not prohibit inclusion. Men were excluded from the study for the following reasons: ED caused by untreated endocrine disorders, history of penile implant or significant penile deformities; history of radical prostatectomy; clinically significant hepatic, renal, cardiovascular, or central nervous system disease or injury, including stroke or spinal cord injury; treatment with nitrates, cancer chemotherapy, or antiandrogens; current infection with any sexually transmitted disease; and history of drug, alcohol, or substance abuse within the past 6 months. In addition, any persons who had previously completed or withdrawn from any other study investigating tadalafil were not eligible to participate in this study. Signed informed consent was required from both the study subject and the female partner. The study was conducted in conformity with the ethical principles of the Declaration of Helsinki (adopted by the 18th World Medical Assembly, Helsinki, Finland, 1964, and revised at the World Medical Assembly, Tokyo, Japan, 1975; Venice, Italy, 1983; and Hong Kong, 1989), the applicable guidelines for Good Clinical Practice, or the applicable U.S. laws and regulations, whichever provided the greater protection of the individual.
Study Design This was a multicenter (10 U.S. sites), randomized, double-blind, placebo-controlled, parallelgroup, phase-2 study (study code LVCK). Visit 1 was a screening visit. After obtaining informed consent, patients underwent a physical examination, clinical laboratory tests, a 12-lead electrocardiogram (ECG), and had a medical history taken. A central laboratory performed all clinical laboratory assessments, and ECGs were interpreted by a single cardiologist. Eligible patients who met the inclusion and exclusion criteria after screening entered a treatment-free run-in period of 28 days. During the run-in period, patients were asked to record the outcome of all sexual attempts in a Sexual Encounter Profile (SEP) diary to determine baseline values. At visit 2, the International Index of Erectile Function (IIEF) was administered. The Erectile Function (EF) Domain of the IIEF (adapted from Cappelleri [13]) was used to determine ED severity: mild (22–25), moderate (11–21), severe (£10). Patients were stratified by EF Domain scores and randomly assigned into treatment groups in a 1 : 1 : 1 fashion to receive placebo, or tadalafil 10 mg, or tadalafil 20 mg.
Earliest Time to Erectogenic Effect After Tadalafil The treatment phase consisted of four doses, with a single dose taken at home without regard to food, approximately once every 8–10 days. Patients were instructed to take a dose when they and their partner developed a desire to engage in sexual activity, and immediately start the stopwatch. Couples were to continue with sexual stimulation, and then, at the earliest time to the first erection adequate for vaginal penetration within 30 minutes, stop the stopwatch and record the time. They were instructed to continue with sexual activity and record whether the erection lasted long enough for successful intercourse in their SEP diaries (SEP Question 3: “Did your erection last long enough for you to have successful intercourse?”). Visit 3 was 1–4 days after the final treatment was taken, or approximately 4–5 weeks after visit 2. At visit 3, SEP diaries were collected, vital signs were measured, urinalysis, blood chemistries, and hematology were done, adverse events were recorded and, at the discretion of the investigator, a physical exam was performed. Subjects were then discharged from the study. Main Outcome Measures
The primary efficacy variable was the earliest time to erectogenic effect determined by stopwatch within 30 minutes of dosing, defined as the elapsed time from dosing until attainment of the first erection adequate for penetration, but only for those erections that lasted long enough for successful intercourse (SEP3). Consequently, for an erection to be counted as successful in the analysis, it had to (1) occur within 30 minutes after dosing; (2) be assessed by the patient as hard enough for vaginal penetration; and (3) last long enough to result in successful sexual intercourse. The overall time to erectogenic effect was obtained by comparing the percentage of first erections adequate for successful intercourse after dosing to that for placebo.
Safety The analysis of safety included all enrolled patients. Safety was assessed by evaluating all reported treatment-emergent adverse events, vital signs and clinical laboratory tests. Treatmentemergent adverse events were defined as any adverse events that first occurred or worsened in severity after randomization, and were mapped using COSTART (Coding Symbols for Thesaurus of Adverse Reaction Terms). Prompted by nonleading questions, subjects reported adverse events
195 on a volunteer basis throughout the study. A physical exam was performed at the final visit at the discretion of the investigator.
Statistical Analysis Primary and secondary efficacy analyses were done in an intent-to-treat (ITT) basis. The primary analysis was a comparison of the percentage of first erections resulting in successful intercourse within 30 minutes of taking study drug. The data were analysed by a method for handling repeated measurements of binary data (the Generalized Estimating Equation approach) [14]. The statistical model included treatment, site, severity of ED, and week as main effects. Starting from 30 minutes after dosing, treatments were to be compared based on the proportion of attempts that were successful. If there was a statistically significant treatment effect for the 20-mg dose group of tadalafil (P < 0.05) at 30 minutes, then a step-down procedure was to be applied. Comparisons were to be made at 1-minute decrements and were to stop as soon as tadalafil was found not to be statistically different from placebo. Comparisons of earlier time points were not performed as soon as P > 0.05. The earliest time to erectogenic effect was consequently defined as the shortest time after dosing that tadalafil was shown to be significantly different from placebo. If there was a statistically significant treatment effect for the 20-mg dose of tadalafil within 30 minutes, the time to erectogenic effect for the 10-mg dose of tadalafil was to be determined similarly. A secondary analysis, stipulated in the protocol, was to compare the overall distribution of time to erectogenic effect between treatments using the Cox Regression Method. Whereas the primary analysis compared the proportion of responses between tadalafil and placebo groups up to a given point in time, the Cox Regression Method was a survival analysis technique that took into consideration the actual time it took the patient to achieve a response up to a given time point when the treatment responses were compared between groups. Patients who did not have a successful attempt up to a given point in time were treated as censored observations at that point in time. In the Cox Regression analysis, therapy was included as a covariate. Additionally, because patients were instructed to make one attempt approximately once a week, “week” was used as a stratification variable according to the model of Prentice et al. [15] to adjust for multiple, within-patient observations. In this analysis the distribution of time to J Sex Med 2004; 1: 193–200
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successful intercourse across treatments was compared for dose 1 (week 1), dose 2 (week 2), dose 3 (week 3), and dose 4 (week 4), which were then combined to obtain an overall test. In the Cox Regression, a sequential testing was employed which was identical to that employed in the primary analysis. Standard patient baseline characteristics were summarized for each treatment group, including age, duration of ED, prior use of other ED therapeutic modalities, smoking category, use of antihypertensive medications, and alcohol intake. For continuous patient characteristics, means were compared using ANOVA. The incidence of the categorical variables was compared using the appropriate chi-square test (e.g., Pearson chi-square, Fisher’s exact). Results
Patient Demographics Ten centers enrolled 223 patients: 74 patients were randomized to the placebo group, 74 to the tadalafil 10 mg group and 75 to the tadalafil 20 mg group. The treatment groups were similar in key baseline characteristics, including age, ethnicity, comorbid conditions, ED severity, and ED duration (Table 1). Whereas prior exposure to tadalafil was an exclusion criterion, prior use of sildenafil citrate was not. However, less than 10% of men
Table 1
had previous experience with sildenafil (Table 1). Therefore, the population was generally PDE5 inhibitor-naïve.
Minimal Time to Erectogenic Effect At 1-minute decrements, starting from 30 minutes after dosing, treatment with tadalafil 20 mg was found to be statistically different from placebo at 30 minutes down to 16 minutes (Table 2), indicating that the earliest time to erectogenic effect for tadalafil 20 mg was 16 minutes after dosing. The cumulative number of successful intercourse attempts at £16 minutes after dosing was 47 (15.7%) out of 300 doses taken in the tadalafil 20mg group compared with 22 (7.7%) successful intercourse attempts out of 284 doses taken in the placebo group (P = 0.012). By 30 minutes after dosing, the cumulative number of successful intercourse attempts was 102 (34.0%) in the tadalafil 20 mg group and 50 (17.6%) in the placebo group (odds ratio 2.7, P = 0.002). The cumulative number of successful intercourse attempts in the tadalafil 10-mg group at 30 minutes was 73 (25.0%) out of 292 doses taken compared to 50 (17.6%) in the placebo group (odds ratio = 1.9, P = 0.054) (Table 2). As analysed by the Cox Regression Method, a statistically significant response to tadalafil 20 mg compared with placebo was found from 30 minutes down to 15 minutes after dosing
Baseline demographics and clinical characteristics Tadalafil treatment group
Characteristic
Placebo (N = 74)
10 mg (N = 74)
20 mg (N = 75)
Age (years) mean ± SD Weight (kg) mean ± SD Ethnicity, N (%) African descent Western Asian Caucasian East/SE Asian Hispanic Erectile dysfunction history, N (%) ≥3 months and < 6 months ≥6 months and < 1 year ≥1 year IIEF erectile function domain score, N (%) Mild (22–25) Moderate (11–21) Severe (6–10) Comorbid conditions Hypertension Diabetes mellitus Depression Hyperlipidemia Prior use of sildenafil citrate
58.8 ± 10.8 91.2 ± 17.1
57.6 ± 10.9 93.6 ± 16.7
59.1 ± 12.0 92.1 ± 17.7
5 0 64 3 2
(86.5) (4.1) (2.7)
4 (5.4) 0 68 (91.9) 0 2 (2.7)
7 1 63 0 4
1 (1.4) 4 (5.4) 69 (93.2)
3 (4.1) 5 (6.8) 66 (89.2)
0 8 (10.7) 67 (89.3)
9 (12.2) 39 (52.7) 26 (35.1)
10 (13.5) 39 (52.7) 25 (33.8)
11 (14.7) 39 (52.0) 25 (33.3)
35 17 5 7 7
24 20 5 3 7
25 23 11 4 5
J Sex Med 2004; 1: 193–200
(6.8)
(47.3) (23.0) (6.8) (9.5) (9.5)
(32.4) (27.0) (6.8) (4.1) (9.5)
(9.3) (1.3) (84.0) (5.3)
(33.3) (30.7) (14.7) (5.3) (6.7)
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Earliest Time to Erectogenic Effect After Tadalafil
Table 2 The percent of successful intercourse attempts within 30 minutes after dosing: step-down analysis determining time to erectogenic effect for tadalafil 10 mg and 20 mg Percent (%) of successful intercourse attempts (SEP3) Time (minute) after dosing
Placebo (N1 = 284)†
Tadalafil 10 mg (N1 = 292)
Tadalafil 20 mg (N1 = 300)
P-value‡ placebo vs. 10 mg
P-value placebo vs. 20 mg
30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14
17.6 17.6 16.5 15.5 14.4 14.1 13.0 12.3 12.3 12.0 11.3 10.6 9.9 9.5 7.7 7.4 6.0
25.0 24.3 22.9 21.6 20.5 17.1 16.4 16.1 14.4 13.0 12.0 10.6 10.3 9.6 9.2 7.9 7.5
34.0 33.0 31.0 30.0 26.7 25.7 25.3 25.0 24.0 21.3 20.3 19.0 17.3 16.0 15.7 13.7 12.3
0.054 * * * * * * * * * * * * * * * *
0.002 0.004 0.002 0.001 0.004 0.006 0.004 0.002 0.004 0.010 0.013 0.017 0.021 0.026 0.012 0.052 *
* Analysis stopped at first time-point where P = 0.05. † N1 is the total number of doses. ‡ P-values are computed using the generalized estimating equation (GEE approach) to the analysis of repeated successful erection.
Cumulative Response Rate Within 30 Minutes by Dose We also conducted a post hoc, descriptive analysis to determine the cumulative proportion of men taking tadalafil 20 mg who were able to achieve at least one erection leading to successful intercourse within 30 minutes after dosing for each of the four doses taken during the study treatment period (Figure 1). After dose 1, 37.3% of men taking tadalafil 20 mg were able to have an erection sufficient for successful intercourse within 30 minutes after dosing compared to 17.6% of men taking placebo. By dose 4, 52.0% of men taking tadalafil 20 mg were able to have at least one erection leading to successful intercourse within 30 minutes after dosing compared to 35.1% of men taking placebo (P = 0.038). When ED severity was considered, by dose 4, 62.0% of men with mild to moderate ED taking tadalafil 20 mg were able to have at least one erection leading to successful intercourse within 30 minutes post dose compared to 43.8% taking placebo, and 32.0% of men with
severe ED taking tadalafil 20 mg had at least one erection leading to successful intercourse compared to 19.2% of men taking placebo. When age was considered, by dose 4, 63.3% of men 55 years and younger taking tadalafil 20 mg were able to have at least one erection leading to successful intercourse within 30 minutes post dose compared to 42.3% of men taking placebo, and 44.4% of men over age 55 taking tadalafil 20 mg had at least one erection leading to successful intercourse
SEP3: Cumulative proportion of men (%)
(P = 0.02). A statistically significant response to tadalafil 10 mg compared with placebo was found from 30 minutes down to 26 minutes after dosing (P = 0.042). Thus, the results obtained for time to erectogenic effect were similar as determined by either the primary objective analysis or the Cox Regression Method.
Placebo Tadalafil 10 mg 60
Tadalafil 20 mg
52.0
52.0
46.7
50 37.3
40 30 23.0 17.6
20
37.8
37.8
37.8 35.1
28.4
25.7
10 0 0
1
2
3
4
Dose number
Figure 1 Cumulative response to tadalafil within 30 minutes by dose. The cumulative proportion of men achieving at least one successful intercourse (SEP3) attempt within 30 minutes post dose for each of the four doses taken.
J Sex Med 2004; 1: 193–200
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within 30 minutes compared to 31.3% of men taking placebo.
Safety Ninety-six percent (214) of men enrolled completed the study (Table 3). Six of the nine men who discontinued treatment were in the placebo group, two were in the 10-mg group, and one was in the 20-mg group. Four men discontinued the study due to adverse events: two in the placebo group (one due to back pain caused by a herniated disc and one due to chest pain caused by a partially reversible perfusion defect), one in the tadalafil 10 mg group (due to back pain), and one in the tadalafil 20 mg group (due to diarrhea). Two patients were lost to follow-up, and in the placebo group, one patient discontinued due to personal conflict and another two patients due to sponsor decision. The most common treatment-emergent adverse events were headache, myalgia, dyspepsia, nausea, vasodilatation, and back pain (Table 3). Discussion
The results of this study are consistent with previous reports suggesting that the time to erectogenic effect with PDE5 inhibitors may be significantly less than would be expected based on specific pharmacokinetic parameters such as tmax. Previous studies have shown onset of erectogenic effect to be less than 30 minutes for both sildenafil [15] and vardenafil [16] even though the median tmax for both drugs is 60 minutes (range 30– 120 minutes) [17,18]. A pharmacodynamic effect distinguishable from placebo was noted within
Table 3
Patient disposition and adverse events
Event classification
Placebo N = 74 N (%)
Tadalafil 10 mg N = 74 N (%)
Tadalafil 20 mg N = 75 N (%)
Patients’ discontinuations Adverse event Protocol violation Perceived lack of efficacy Other* Headache Myalgia Dyspepsia Nausea Vasodilation Back pain
6 2 0 0 4 0 0 0 0 0 1
2 1 0 0 1 3 3 1 1 1 2
1 1 0 0 0 6 1 2 2 2 0
(8.1) (2.7)
(5.4)
(1.4)
(2.7) (1.4)
(1.4) (4.1) (4.1) (1.4) (1.4) (1.4) (2.7)
(1.3) (1.3)
(8.0) (1.3) (2.7) (2.7) (2.7)
* In the placebo group, one patient was lost to follow-up, one patient discontinued due to personal conflict, and another two patients due to sponsor decision; in the 10 mg group, one patient was lost to follow-up.
J Sex Med 2004; 1: 193–200
14 minutes after dosing with sildenafil 100 mg [15] and a pharmacodynamic effect was noted within 16 minutes after dosing with vardenafil 20 mg [16]. The median tmax of tadalafil is 2 hours (range 30 minutes to 6 hours) [10]. Although a slower onset of erectogenic effect might be expected for tadalafil, we were able to demonstrate a significant erectogenic effect compared to placebo at 16 minutes following drug administration for the 20-mg dose and at 30 minutes following drug administration for the 10-mg dose. All three studies investigating the minimal time to erectogenic effect for PDE5 inhibitors demonstrate that a significant pharmacodynamic effect is achieved prior to reaching the maximum observed plasma concentration (Cmax), that is, prior to tmax. In addition, all three studies demonstrate that an erectogenic effect is not predicated on the need to reach Cmax, consistent with the knowledge that the time to efficacious plasma level is usually shorter than the time to maximum plasma level. In the absence of a single clinical trial that directly compares the onset of action for the three drugs, it is difficult to make comparisons. The studies differ in their inclusion and exclusion criteria, the patient population enrolled, the dose used, the dosing instructions, and the number of attempts given to achieve successful intercourse. However, all three studies indicate that the PDE5 inhibitors exhibit a distinguishable erectogenic effect sooner than would be expected based on specific pharmacokinetic parameters such as tmax. One of the limitations of stopwatch studies in general is the potential lack of clinical application. The minimal time to erectogenic effect may not be applicable to all men with ED because most men with ED will not experience a pharmacodynamic effect at the minimal time. In all three studies, approximately one-third of patients responded to PDE5 inhibitor therapy within 16 minutes. However, men were given either four attempts (vardenafil study [16] and this study) or eight attempts (sildenafil study [15]) to be successful at least once in order to be considered a responder. In the current study, at 16 minutes after dosing, 32% of men taking tadalafil 20 mg and 15.7% of attempts were successful at 16 minutes. Thus, at this early time point after dosing, a small percentage of men have a successful intercourse attempt, and a small percentage of intercourse attempts made by these men are successful, given that over 50% of men will be successful at later time points (i.e., 30 minutes). Therefore, the clinical significance may not be as strong as the statistical sig-
199
Earliest Time to Erectogenic Effect After Tadalafil nificance, because only a minority of patients responds so early. Another limitation of our study is that we collected response data only from the first 30 minutes after dosing. Therefore, the full range of response times descriptive of men with ED was not observed. Determining the full distribution of onset times, as well as the median time to erectogenic effect, would perhaps better enable physicians to advise patients regarding the relationship between the onset of pharmacodynamic effect and the timing of sexual intercourse, and for patients to be aware that some individuals have the potential for a rapid response to onset of stimulation. There is considerable variation among men with ED with regard to etiology, severity, and comorbid conditions that may affect the time needed to respond to PDE5 therapy and the degree to which they respond. Also, some men may not respond at all to PDE5 inhibitors [19]. Therefore, responsiveness can vary, and the time and duration of erectogenic effect can vary widely depending on the individual. The results for tadalafil clearly indicate that an erectogenic effect can be detected within 30 minutes after dosing, well before the tmax of 2 hours. We should stress that while onset of pharmacodynamic effect can be less than 30 minutes in some men, most men will require more time for tadalafil to be optimally effective. Patients with more severe ED, or older patients, in particular, should not be encouraged to attempt sexual activity quickly after dosing, and they should be instructed to optimize the conditions of sexual stimulation. In addition, based on the faster time to onset observed for the 20-mg vs. the 10-mg dose, patients with severe ED may benefit from titrating to tadalafil 20 mg. Because both tadalafil 10 mg and 20 mg have been shown to improve erectile response for up to 36 hours after dosing [3,9,10], the time it takes for onset of erectogenic effect may be a secondary consideration for some men.
Conclusion
Tadalafil 10 and 20 mg are capable of producing a pharmacodynamic effect distinguishable from placebo within 30 minutes after dosing. The minimal time to onset of erectogenic effect was, in a minority of men, 16 minutes for tadalafil 20 mg. Onset was assessed by a stopwatch measure, with approximately one-third to one-half of patients respond-
ing within 30 minutes. Both tadalafil 10 mg and 20 mg were well tolerated. Acknowledgments
The authors thank the participating clinical investigators: Stanley A. Brosman, MD, Santa Monica, CA; Michael J. Kaempf, MD, Portland, OR; Joel M. Kaufman, MD, Aurora, CO; James G. McMurray, MD, Huntsville, AL; Christopher P. Steidle, MD, Fort Wayne, IN; Jay M. Young, MD, Laguna Woods, CA; Norman R. Zinner, MD, Torrance, CA. In addition, we thank Diane R. Stothard, PhD (Eli Lilly and Company, Indianapolis, IN) for editorial assistance; William H. Cordell, MD (Eli Lilly and Company, Indianapolis, IN) and J. Steve Whitaker, MD (ICOS Corporation, Bothell, WA) for critical review of the manuscript; Jonathan Denne, PhD, and Tim Costigan, PhD (Eli Lilly and Company, Indianapolis, IN) and Greg Anglin, PhD (Eli Lilly Canada) for assistance with statistical analysis; and Amy Hoover (Eli Lilly and Company, Indianapolis, IN) for clinical study support and review of the manuscript. Corresponding Author: Raymond C. Rosen, PhD, Robert Wood Johnson Medical School, Piscataway, NJ, USA. Tel: (732) 235-4485; Fax: (732) 235-5818; E-mail: [email protected]
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