Efficacy and Tolerability of Tadalafil, a
`Novel Phosphodiesterase 5 Inhibitor, in
`Treatment of Erectile Dysfunction
`Harin Padma-Nathan, MD
`
`Advances in molecular biology and protein chemistry,
`along with increasing understanding of the mechan-
`isms of penile erection, have spurred development of
`pharmacologic approaches to the treatment of erectile
`dysfunction (ED). The next generation of oral agents
`includes tadalafil, a potent, highly selective phosphodi-
`esterase 5 inhibitor. In vitro studies have shown that
`tadalafil enhances relaxation of trabecular smooth mus-
`cle, and clinical trials have supported its efficacy and
`tolerability in a broad population of men with ED. The
`effect of tadalafil in enhancing the erectile response to
`sexual stimulation is relatively rapid in onset and lasts
`for >24 hours. The ability of patients with ED treated
`with tadalafil to achieve improved erectile function is
`demonstrated by significantly increased subjective mea-
`sures of penetration ability, successful intercourse, and
`
`The era of oral treatment for erectile dysfunction
`
`(ED) began in 1976 with the identification in lung
`tissue of a phosphodiesterase (PDE) specific to cyclic
`guanosine monophosphate (cGMP), as reviewed by
`Corbin and Francis.1 The advent of oral treatment,
`however, awaited advances in molecular biology and
`protein chemistry, as well as insight into the neuro-
`vascular mechanisms of the erectile response.
`A key 1989 study by Sa´enz de Tejada et al2 found
`that neural and endothelium-dependent mechanisms that
`would normally cause relaxation in corporal smooth
`muscle were impaired in tissue collected from men with
`diabetes and ED. This evidence led the investigators to
`conclude that decreased synthesis or release of an endo-
`thelium-dependent relaxing factor was responsible.2 This
`factor has since been identified as nitric oxide.
`Nitric oxide is now known to be the principal
`mediator of smooth muscle relaxation in the corpus
`cavernosum.3 Released from nerve endings and endo-
`thelial cells on sexual stimulation, nitric oxide triggers
`an intracellular cascade that leads to erection. Nitric
`oxide activates the cytosolic enzyme guanylate (also
`termed guanylyl) cyclase in smooth muscle cells, in-
`creasing the generation of cGMP. A specific protein
`kinase (protein kinase G) is, in turn, activated with
`
`From the Male Clinic, Beverly Hills, California, USA; and Keck School
`of Medicine, University of Southern California, Los Angeles, Califor-
`nia, USA.
`Harin Padma-Nathan, MD, has received grant/research support
`from Bayer/GSK, Lilly ICOS, and Pfizer, and is a consultant
`for
`Bayer/GSK and Pfizer.
`Address for reprints: Harin Padma-Nathan, MD, 9100 Wilshire
`Boulevard, East Tower, Suite 360, Beverly Hills, California 90212.
`E-mail: hpn@insyght.com.
`
`sexual satisfaction. Partners have expressed similar or
`higher levels of satisfaction with the results of treatment.
`Men with ED of psychogenic, organic, or mixed etiology
`and in a range from mild to severe have experienced
`significant
`improvment with tadalafil
`treatment. Re-
`sponse to treatment in men with diabetes has been
`robust and not affected by disease severity. Tadalafil
`has been well tolerated. Adverse events have generally
`been mild or moderate and have abated with continued
`treatment. Headache and dyspepsia have been most
`frequently reported. Changes in color vision have been
`trials.
`rare (<0.1%) with tadalafil across all clinical
`Tadalafil appears to be a safe and effective treatment
`for men with ED. 䊚2003 by Excerpta Medica, Inc.
`Am J Cardiol 2003;92(suppl):19M–25M
`
`ensuing phosphorylation events. The end result is a
`decrease in cytosolic calcium levels and relaxation of
`smooth muscle.4,5
`Elucidation of the nitric oxide– cGMP pathway
`identified PDE5, which inactivates cGMP. It was rea-
`soned that inhibiting PDE5 would prolong the effects
`of nerve stimulation, and considerable therapeutic in-
`terest was directed to drugs with inhibitory capacity.
`Although early PDE5 inhibitors were developed for
`cardiac conditions and allergic asthma, it became ap-
`parent that these drugs might be effective treatments
`for ED.6 The selective PDE5 inhibitor sildenafil was
`introduced in 1996, and the next generation of PDE5
`inhibitors includes tadalafil (Cialis; Lilly ICOS LLC
`Bothell, WA, and Indianapolis, IN), which is under
`investigation for the treatment of ED.
`Orally administered, tadalafil is a potent, highly
`selective, reversible inhibitor of PDE5. Pharmacoki-
`netic studies in healthy volunteers have shown that
`tadalafil
`is rapidly absorbed, with the maximum
`plasma concentration occurring at 2.0 hours, and that
`it has an elimination half-life of 17.5 hours.7 Clinical
`response to tadalafil, which may be evident as early as
`16 minutes after an oral dose, persists for ⱖ24
`hours.8,9 The absorption of tadalafil is unaffected by
`age, the presence of diabetes or mild-to-moderate he-
`patic insufficiency, or food intake.10 In clinical trials
`to date, tadalafil has shown evidence of both broad
`efficacy and tolerability.11,12
`
`TADALAFIL SPECIFICITY AND EFFECT
`ON TRABECULAR SMOOTH MUSCLE
`The selectivity profile of tadalafil was evaluated
`against 14 human recombinant PDEs, including PDE6
`
`©2003 by Excerpta Medica, Inc.
`All rights reserved.
`
`0002-9149/03/$ – see front matter
`doi:10.1016/S0002-9149(03)00828-2
`
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`FIGURE 1. Tadalafil inhibition of human phosphodiesterase 5 (PDE5) and 6 (PDE6) isoenzymes. Compared with PDE5, a 780-fold
`greater concentration of tadalafil is needed to inhibit PDE6. Error bars indicate standard deviation. (Adapted from Eur Urol.5)
`
`obtained from human retinas.5 Tadalafil was found to
`be highly selective for PDE5, with an approximately
`700-fold greater affinity for PDE5 than for the related
`retinal enzyme PDE6.13 Compared with inhibition of
`PDE5, a 780-fold greater concentration of tadalafil
`was needed to inhibit PDE6 (Figure 1) in a study by
`Angulo et al.5 A ⬎10,000-fold concentration of
`tadalafil is needed to inhibit the activity of all the other
`recombinant PDE isoforms tested (PDE1 to PDE4 and
`PDE7 to PDE10) compared with PDE5.13 Tadalafil
`has exhibited a 14-fold greater affinity for PDE5 com-
`pared with PDE11, a newly identified isoenzyme that
`is widely distributed throughout the body and whose
`clinical significance is unknown.
`To evaluate the effect of tadalafil on smooth mus-
`cle relaxation in human penile resistance arteries and
`trabecular smooth muscle, Angulo et al5 collected
`corpora cavernosa tissues from patients with ED dur-
`ing penile prosthesis
`implantation surgery. The
`tadalafil formulation significantly increased the neu-
`rogenic relaxant effects of acetylcholine and sodium
`nitroprusside on human trabecular smooth muscle.
`This finding suggests that tadalafil potentiates the re-
`laxant effect of nitric oxide, whichever the route of
`production: acetylcholine induces release of nitric ox-
`ide, leading to endothelium-dependent vasodilation,
`whereas sodium nitroprusside acts directly on vascular
`smooth muscle to stimulate guanylate cyclase.14
`Taken together, these in vitro findings indicate that
`tadalafil is highly selective for PDE5 and improves
`penile erection in patients with ED by augmenting the
`nitric oxide– cGMP pathway.
`
`EFFICACY OF TADALAFIL
`The following trials of tadalafil summarize clinical
`experience to date in various populations of men with
`ED. Eligibility criteria for all trials included ED of ⱖ3
`months’ duration and a stable relationship with a
`female partner. All trials were randomized, double
`blind, and placebo controlled. All but 1 study (of time
`
`to onset of response) was multicenter. Except for a
`pilot study—which assessed erectile response to
`tadalafil with a RigiScan (Timm Medical Technolo-
`gies, Eden Prairie, MN), a penile plethysmography
`device— efficacy outcome measures have been eval-
`uated using a validated, self-administered recall in-
`strument and at-home diary (Table 1).8
`The International Index of Erectile Function (IIEF)
`is a validated, 15-item, self-administered question-
`naire that comprises 5 relevant domains of sexual
`function: (1) erectile function, (2) orgasmic function,
`(3) sexual desire, (4) intercourse satisfaction, and (5)
`overall sexual satisfaction.15 Extensively tested and
`validated (and used worldwide), the IIEF is a sensitive
`and specific instrument for detecting treatment-related
`changes (Table 1).15
`Sexual Encounter Profile (SEP) diaries consist of a
`series of yes/no questions (6 for the patient, 4 for his
`partner) specific to each sexual encounter (Table 1).
`Two global assessment questions (GAQs), adminis-
`tered after the treatment period, assess whether treat-
`ment improved patients’ erections (GAQ-1) and their
`ability to engage in sexual activity (GAQ-2) (Table 1).
`For all trials that took place at home, baseline IIEF
`and SEP data were obtained at a pretreatment clinic
`visit.
`Duration of response: The duration of response to
`tadalafil was assessed in a crossover study of 61 men
`aged 18 to 65 years, each of whom received both
`tadalafil 10 mg and placebo.8 The study comprised 2
`sequential treatment periods, separated by 7 to 14
`days. Each treatment period included 2 test sessions
`with RigiScan evaluation: a 60-minute session with
`visual sexual stimulation immediately after adminis-
`tration of a single study dose, and a 30-minute session
`24 hours after administration of the dose.8 Response
`was defined as ⱖ55% penile rigidity for ⱖ3 consec-
`utive minutes. Extreme responders (those achieving
`high rigidity over prolonged periods during the
`screening) were excluded from the study; these were
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`TABLE 1 Subjective Assessments for Efficacy Outcome Measures
`Global Assessment Questions
`Q1. Has the treatment you have been taking over the past study interval improved your erections? [yes/no]
`Q2. [If yes] Has the treatment improved your ability to engage in sexual activity? [yes/no]
`
`Sexual Encounter Profile
`Q. Did you attempt to have a sexual encounter? [yes/no] If yes:
`Q1. Were you able to achieve at least some erection? [yes/no]
`Q2. Were you able to insert your penis into your partner’s vagina? [yes/no]
`Q3. Did your erection last long enough for you to complete intercourse with ejaculation? Or, Did your erection last long enough to have
`successful sexual intercourse? [yes/no]
`Q4. Were you satisfied with the hardness of your erection? [yes/no]
`Q5. Were you satisfied overall with this sexual experience? [yes/no]
`
`International Index of Erectile Function Domains
`Erectile Function Domain
`Q1. Over the past 4 weeks, how often were you able to get an erection during sexual activity? (scored 1–5)
`Q2. Over the past 4 weeks, when you had erections with sexual stimulation, how often were your erections hard enough for
`penetration? (scored 1–5)
`Q3. Over the past 4 weeks, when you attempted sexual intercourse, how often were you able to penetrate (enter) your partner? (scored
`0–5)
`Q4. Over the past 4 weeks, during sexual intercourse, how often were you able to maintain your erection after you had penetrated
`(entered) your partner? (scored 0–5)
`Q5. Over the past 4 weeks, during sexual intercourse, how difficult was it to maintain your erection to completion of intercourse? (scored
`1–5)
`Q15. Over the past 4 weeks, how do you rate your confidence that you can get and keep an erection? (scored 1–5)
`Overall Satisfaction Domain (scored 0–10)
`Q13. Over the past 4 weeks, how satisfied have you been with your overall sex life?
`Q14. Over the past 4 weeks, how satisfied have you been with your sexual relationship with your partner?
`Intercourse Satisfaction Domain (scored 1–15)
`Q6. Over the past 4 weeks, how many times have you attempted sexual intercourse?
`Q7. Over the past 4 weeks, when you attempted sexual intercourse, how often was it satisfactory for you?
`Q8. Over the past 4 weeks, how much have you enjoyed sexual intercourse?
`
`men with rigidity at the base of the penis for ⱖ3
`minutes. Also excluded were men who were unable to
`achieve ⱖ20% rigidity for ⱖ3 minutes during an
`initial 30-minute RigiScan session.8
`Compared with placebo, tadalafil 10 mg signifi-
`cantly increased the proportion of patients able to
`achieve an erection at 24 hours after dose (Figure 2)
`and the cumulative mean time of ⱖ55% penile rigidity
`at 24 hours after dose (both, p ⫽ 0.001). The differ-
`ence in response between tadalafil 10 mg and placebo
`was statistically significant 45 minutes after the dose
`was administered (p ⬍0.05). Approximately 1 hour
`after tadalafil 10-mg dosing, the plasma tadalafil con-
`centration was 113 ␮g/L, which decreased to 69 ␮g/L
`24 hours later. At both plasma concentrations, tadalafil
`was superior to placebo in producing an erectile
`response.8
`Time to onset of response: A 3-arm study evaluated
`time to response in 223 patients randomly assigned to
`1 of 3 groups: (1) tadalafil 10 mg, (2) tadalafil 20 mg,
`or (3) placebo. Exclusion criteria included a history
`of alcohol abuse, glycosylated hemoglobin values
`⬎13%, hypertension, or hypotension. Patients (ⱖ21
`years old) received a total of 4 doses of study medi-
`cation and were instructed to take 1 dose every 8 to 10
`days when ready to engage in sexual activity.8
`After each dose, the earliest time to an erection
`enabling vaginal penetration and successful
`inter-
`course was measured with a stopwatch. Although pa-
`tients were not specifically instructed to make addi-
`tional sexual attempts during the first 24 hours after
`
`dose, such attempts were also recorded in SEP diaries
`if they occurred.8
`Response was defined as ⱖ1 erection sufficient for
`successful intercourse within 30 minutes after dose
`over the course of the study. The earliest time that
`tadalafil was statistically superior to placebo in reach-
`ing this end point was 16 minutes after a 20-mg dose
`(p ⫽ 0.012). At 30 minutes, 52% of men taking
`tadalafil 20 mg and 38% of men taking tadalafil 10 mg
`were considered responders. Among the responders,
`tadalafil 20 mg resulted in an erection within 30 min-
`utes 80% of the time, within 25 minutes 61% of the
`time, and within 20 minutes 47% of the time.
`Daily tadalafil in a dose-ranging study: Among the
`earliest clinical trials of tadalafil was a European study
`of the safety and effectiveness of daily doses up to 100
`mg in men with mild-to-moderate ED.16 Doses of the
`study drug (10, 25, 50, or 100 mg) or placebo were
`randomly assigned to 294 men (mean age, 52.4 years),
`who took the test dose daily for 3 weeks. All doses
`significantly increased, over placebo, the ability to
`penetrate the partner (IIEF– question [Q]3) and to
`maintain an erection after penetration (IIEF-Q4).
`Scores for every IIEF domain in each active-treatment
`group were significantly increased (improved) over
`placebo (p ⱕ0.001). Figure 3 shows results on the
`IIEF erectile function domain.16
`Based on SEP diary scores, the proportions of
`both successful intercourse attempts and satisfying
`intercourse attempts were significantly increased over
`placebo for both patient and partner (p ⱕ0.001).16
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`FIGURE 2. Proportions of patients able to achieve an erection 24 hours after administration of tadalafil 10 mg or placebo. Response
`is defined as having an erection with >55% rigidity for >3 minutes. *p ⴝ 0.001 vs placebo. (Adapted from J Urol.8 Reprinted from
`Eur Urol Suppl 1, Porst H. Restoring a normal sexual response: the ultimate goal of erectile dysfunction therapy, 19–24. Copyright
`(2002), with permission from the European Association of Urology.)
`
`FIGURE 3. Effects of tadalafil treatment (10, 25, 50, 100 mg) compared with placebo on the International Index of Erectile Function
`(IIEF) erectile function domain score (the sum of IIEF questions 1 through 5, plus 15). *p <0.001 vs placebo, based on comparison of
`the least-square means. Dashed lines indicate mean baseline scores. (Adapted from Eur Urol.16)
`
`These results compare well with previously pub-
`lished proportions of successful and satisfying inter-
`course attempts that range up to 93% with PDE5
`inhibitor treatment. Patients receiving tadalafil re-
`ported, in a range from 81% to 90%, that the study
`drug improved erections (GAQ-1). In contrast, 38%
`of the placebo group reported improved erections
`(p ⱕ0.001).16
`As-needed tadalafil for a broad range of ED: From
`April 1999 to April 2001, 5 randomized, double-blind,
`placebo-controlled, parallel-group trials were con-
`ducted at 74 centers in eligible patients (n ⫽ 1,112)
`with mild-to-severe ED.12 These patients were ran-
`domly allocated to receive oral placebo (n ⫽ 308) or
`tadalafil at doses of 2.5 mg (n ⫽ 74), 5 mg (n⫽ 151),
`10 mg (n ⫽ 321), or 20 mg (n ⫽ 258) at a maximum
`frequency of once daily for ⱖ12 weeks. Patients were
`instructed to take tadalafil as needed anytime before
`intercourse, without restrictions on food intake or the
`timing of sexual activity. A broad range of patients
`
`was eligible for randomization, with the exception of
`those taking nitrates, having unstable cardiovascular
`disease, or exhibiting other conditions unsuitable for
`sexual activity.12 Patients could participate regardless
`of prior treatment with sildenafil citrate or the thera-
`peutic outcome of such therapy.
`The IIEF, SEP diaries, and a GAQ were used to
`evaluate erectile function. Both the IIEF and SEP
`diaries were collected at baseline and at each 4-week
`visit. At the final visit, patients were asked, “Has the
`treatment you have been taking improved your erec-
`tions?” (GAQ-1 with yes/no response).12
`The 5 treatment arms (placebo and tadalafil 2.5, 5, 10,
`and 20 mg) were well matched in baseline characteris-
`tics. Patients ranged in age from 22 to 82 (mean, 59)
`years, and most (approximately 90% in all treatment
`arms) had ED durations of ⬎1 year.12 In 59% of patients,
`ED was moderate or severe according to scores on the
`erectile function domain of the IIEF,17 and the predom-
`inant etiology based on clinical judgment was organic
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`FIGURE 4. Proportions of tadalafil-treated (2.5, 5, 10, 20 mg) patients (vs placebo controls) with normal erectile function17 at end
`point. Normal erectile function is defined as International Index of Erectile Function (IIEF) erectile function domain score >26. *p
`<0.05 for tadalafil 2.5 mg vs placebo; †p <0.001 for tadalafil 5, 10, and 20 mg vs placebo. (Reprinted with permission from
`J Urol.12)
`
`(60.5%). A total of 235 men (21%) had diabetes mellitus,
`329 (30%) had hypertension, 86 (8%) had coronary
`artery disease, and 57 (5%) had depression.12
`Treatment with tadalafil significantly enhanced
`erectile function (compared with placebo) across all 3
`co-primary efficacy outcome variables. Patients ran-
`domized to as-needed tadalafil at all doses had signif-
`icantly greater (p ⬍0.001) improvements from base-
`line in the erectile function domain of the IIEF, with
`end point scores of 21.1 and 23.9 in the tadalafil
`10-mg and 20-mg groups, respectively, compared
`with 15.1 in placebo controls.12
`The IIEF erectile function domain score observed
`in the tadalafil 20-mg treatment arm approached the
`threshold value associated with “no ED.”17 As shown
`in Figure 4, erectile function returned to normal in
`59% of patients randomized to tadalafil 20 mg and
`40% of patients randomized to tadalafil 10 mg, com-
`pared with 11% of controls (p ⬍0.001).12 Within each
`baseline ED severity category, tadalafil 5 to 20 mg
`significantly augmented mean IIEF erectile function
`domain scores compared with placebo, and responses
`to tadalafil 20 mg were consistently greater than re-
`sponses to tadalafil 10 mg (Figure 5).12
`Tadalafil taken as needed at each dose also signif-
`icantly increased (from baseline) the likelihood of
`vaginal penetration (SEP-Q2) and intercourse comple-
`tion (SEP-Q3) compared with placebo. At study end
`point, 61% and 75% of sexual encounters resulted in
`successful
`intercourse among men treated with
`tadalafil 10 and 20 mg, respectively, compared with
`32% in controls (p ⬍0.001 for each comparison; Fig-
`ure 6).12
`improvements,
`In addition to these significant
`tadalafil treatment also enhanced erectile function ac-
`cording to the GAQs. Of men randomized to tadalafil,
`81% taking tadalafil 20 mg and 67% taking tadalafil
`
`10 mg reported that treatment improved their erec-
`tions, as against 35% with placebo (p ⬍0.001).12
`Compared with placebo controls, men who re-
`ceived as-needed tadalafil exhibited significant im-
`provements from baseline to end point in both IIEF
`erectile function domain scores and percentages of
`attempts leading to successful intercourse regardless
`of baseline age (ⱖ65 or ⬍65 years), diabetes status, or
`ED severity.12
`Efficacy in a population with diabetes: A phase 3
`trial of tadalafil focused on men with diabetes mellitus
`(type 1 or 2) with or without retinopathy and with
`mild-to-severe ED. Men whose diabetes was uncon-
`trolled, however, were excluded. After a 4-week
`run-in period, 216 patients (mean age, 55.7 years)
`were randomly assigned to 1 of 3 treatment arms
`(tadalafil 10 mg, tadalafil 20 mg, or placebo) to be
`taken for 12 weeks.18
`Scores on the IIEF erectile function domain increased
`(improved) significantly from baseline in both active-
`treatment groups compared with placebo controls
`(p ⬍0.001). For this domain, the proportion of patients
`whose scores increased ⬎5 points over baseline (consid-
`ered a clinically significant response) was greater in the
`tadalafil 20-mg treatment group than in the tadalafil
`10-mg group.18 Improvement in erectile function with
`tadalafil 10 or 20 mg was unrelated to diabetes type,
`current diabetes therapy, initial level of glycemic control,
`or presence of microvascular complications. Compared
`with placebo, both 10- and 20-mg tadalafil doses signif-
`icantly improved (p ⬍0.001) penetration ability and the
`ability to maintain erection during intercourse, as as-
`sessed by IIEF-Q3 and IIEF-Q4, respectively. Scores on
`both the IIEF intercourse satisfaction domain and overall
`satisfaction domain were significantly higher in patients
`treated with tadalafil 10 mg or tadalafil 20 mg compared
`with placebo.18 Both 10- and 20-mg doses of tadalafil
`were also superior to placebo in improving the propor-
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`FIGURE 5. Effects of tadalafil treatment (2.5, 5, 10, 20 mg) compared with placebo on the International Index of Erectile Function
`(IIEF) erectile function domain score at end point according to baseline severity.17 (Baseline severity was defined by IIEF erectile func-
`tion domain scores: severe [1–10], moderate [11–16], and mild [17–30].) (*p <0.05; †p <0.001). (Reprinted with permission from
`J Urol.12)
`
`FIGURE 6. Effects of tadalafil treatment (2.5, 5, 10, 20 mg) compared with placebo on positive responses to Sexual Encounter Profile
`question 3 (SEP-Q3): “Did your erection last long enough to have successful intercourse?” (yes/no) at end point. *p <0.05; †p
`<0.001. (Reprinted with permission from J Urol.12)
`
`tion of successful intercourse attempts. The proportion of
`patients achieving a ⬎25% increase in positive responses
`was greater for the 20-mg treatment group.18
`In response to the GAQs at treatment end point,
`tadalafil-treated patients were significantly more likely
`than placebo controls to indicate that treatment im-
`proved their erection (GAQ-1) and improved their
`ability to engage in sexual activity (GAQ-2; both
`p ⬍0.001).18
`
`TOLERABILITY/ADVERSE EVENTS
`PROFILE
`The most extensive data on adverse events associ-
`ated with the class of PDE5 inhibitors have been
`limited largely to sildenafil. Adverse events primarily
`reflect expression of PDE5 in the vasculature and
`gastrointestinal tract, in addition to corpus caverno-
`sum smooth muscle. Among ⬎3,700 men with 1,631
`patient-years of exposure to sildenafil, the main ad-
`verse events of sildenafil included headache (16%),
`
`flushing (10%), and dyspepsia (7%).19 Adverse events
`have been predominantly mild or moderate.
`Sildenafil is approximately 10-fold more selective for
`PDE5 than for PDE6.20 Visual disturbances reported for
`sildenafil probably reflect some inhibition of PDE6 in the
`retina. Clinically, a description of transient blue hue or
`brightness can be a result of inhibition. The overall
`incidence of abnormal vision was 3% in flexible-dose
`studies up to 100 mg.20 The effect is dose related, how-
`ever; up to 11% of men receiving the 100-mg sildenafil
`dose may be affected.19,20
`Tadalafil has been well tolerated in all trials reported
`to date. With the exception of visual effects, which have
`been rare (color vision changes in ⬍0.1% of patients
`across all tadalafil clinical trials13), adverse events with
`tadalafil mirror those with sildenafil. Adverse events are
`dose related, reported as mild or moderate, and generally
`abate with treatment. In a trial of daily tadalafil doses up
`to 100 mg, the most common adverse events were head-
`ache, back pain, myalgia, and dyspepsia.16 No significant
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`changes were observed in laboratory values, electrocar-
`diograms, or vital signs.16
`
`CONCLUSION
`In vitro studies of tadalafil have shown it to be a
`highly selective inhibitor of PDE5, with ⬎10,000-fold
`selectivity for PDE5 over PDE1 to PDE4 and approx-
`imately 700-fold selectivity for PDE5 over the closely
`configured PDE6. Whether taken daily or as needed,
`tadalafil doses of 5 to 100 mg have been effective in
`improving erectile function in men with a mild-to-
`severe range of ED. With tadalafil 20 mg, the time to
`onset of erection sufficient for completion of success-
`ful intercourse was as early as 16 minutes after dosing.
`The clinical effectiveness of tadalafil extends to ⱖ24
`hours after dosing, and this broad window should
`allow many patients to have sexual activity without
`planning intercourse around the time of tadalafil
`administration.
`Each tadalafil dose ⬎2.5 mg has produced im-
`provements in primary and secondary study end points
`based on subjective measures of erectile function.
`Responses to IIEF erectile function domain questions
`improved significantly, especially those related to the
`ability to penetrate (IIEF-Q3) and maintain erection
`during intercourse (IIEF-Q4). These scores mirrored
`significantly enhanced responses to similar SEP diary
`questions in ED patients. Posttreatment proportions of
`positive partner responses recorded in SEP diaries
`have been close to those of ED patients. Indeed,
`proportions of ED patients’ partners with positive
`responses on overall satisfaction with the sexual ex-
`perience have even exceeded those of patients.
`Clinical experience with tadalafil has shown it to
`be safe and well tolerated at all doses tested. Adverse
`events have been generally mild or moderate, attenu-
`ating with treatment. The high selectivity of tadalafil
`for PDE5 appears to have minimized the potential for
`vision anomalies. In summary, tadalafil shows prom-
`ise of being a safe and effective treatment for ED, to
`the benefit of both the patient and his partner.
`
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`
`A SYMPOSIUM: ERECTILE DYSFUNCTION AND CARDIOVASCULAR RISK FACTORS 25M
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`INTELGENX 1028