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Once-daily dosing

Published in Efficacy
Tags: Doses, tadalafil

daily dosingThe latest innovation in the treatment of ED has arrived in the form of a simpler, once-daily dosing schedule for tadalafil, unlinking the temporal association of the medication and the sexual encounter. The unnatural process of taking a medication just prior to sex is a negative aspect of ED treatment for many patients. The 17.5 hour half-life of tadalafil lends itself to daily dosing because steady-state plasma concentrations are attained within five days of initiating daily dosing. Additionally, at steady-state concentration, the daily exposure is 1.6-fold greater than the same dose taken intermittently. Therefore, after 5 days of once-daily dosing, the plasma concentration of tadalafil (Cialis) achieved with a 2.5 mg and 5 mg dose is 4 mg and 8 mg, respectively. The FDA announced approval for once-daily dosing of tadalafil in January 2008 after a thorough review of the studies outlined below.

McMahon has compared once-daily with on-demand dosing of tadalafil in two independent, open-label studies in Australian men with ED. In 112 men with ED who were previously unresponsive to on-demand tadalafil, once-daily tadalafil at flexible doses of 10 mg and 20 mg for 12 weeks was provided. Baseline IIEF-EF, SEP, and GAQ data were obtained from the cohort prior to any treatment with tadalafil (Cialis Professional) and after the trial of on-demand tadalafil. Changes in the scores from both baselines were assessed after 12 weeks of daily dosing. Patients taking tadalafil 10 mg once-daily improved the IIEF-EF score 12.8 from the no-treatment baseline and 8.2 from the on-demand treatment baseline (p < 0.001). Compared with 42% of men with on-demand tadalafil, 69% of men with once-daily tadalafil (Cialis Super Active) reported improved erections at the endpoint. McMahon then compared once-daily tadalafil 10 mg with on-demand tadalafil 20 mg in an open-label, parallel-arm, crossover study of 145 Australian men with ED. While both dosing strategies were efficacious, the once-daily dosing of tadalafil improved the IIEF-EF score by 11.9, compared to an improvement of 8.3 with the on-demand dosing (p < 0.05). Additionally, compared with 30% at baseline, successful intercourse was reported in the SEP-Q3 in 69% and 84% of patients taking on-demand and once-daily tadalafil, respectively (p < 0.05). Overall, once-daily dosing was preferred by 72% of the patients.

The first multicentered, randomized, double-blind, placebo controlled study of once-daily tadalafil enrolled 268 men over 12 weeks and compared tadalafil 5 mg and 10 mg taken once-daily with placebo. The study took place in 20 centers across Europe and South America in men with ED of all severities and etiologies. IIEF-EF, SEP, and GAQ were assessed at baseline and at 12 weeks. The mean IIEF-EF change from baseline at the endpoint was 9.7 and 9.4 for tadalafil 5 mg and tadalafil 10 mg, respectively, compared with 0.9 for placebo (p < 0.001). Successful intercourse was achieved in 67.2% and 72.8%, compared with 36.7% with placebo (p < 0.001). The authors concluded once-daily tadalafil 5 mg or 10 mg significantly improved erectile function in men with ED.

Rajfer and associates performed a similar study of once-daily tadalafil in American men with lower doses over a longer study duration. Once-daily tadalafil 2.5 mg, 5 mg, or placebo was dosed over a 24 week period in a randomized, double-blind, placebo controlled, parallel-design study in 287 men evaluated in 15 US centers. Primary endpoints included the change from baseline to 24 weeks in mean IIEF-EF score and the percentage of “yes” responses in SEP-Q2 and SEP-Q3. The IIEF-EF and SEP data are summarized in Figure 3. The IIEF-EF score had a mean improvement over 24 weeks of 6.0 and 7.0 in the tadalafil 2.5 mg and 5 mg groups, respectively, compared with 1.2 in the placebo group (p < 0.001). Successful intercourse was improved over the 24-week period in 31.2% and 35.1% in the tadalafil groups compared with 9.5% with placebo (p <0.001).

Figure 3
IIEF-EF, SEP-Q2, and SEP-Q3 improvements from baseline to 24 weeks with once-daily tadalafil.

Figure 3

a-Erectile function domain score of the International Index of Erectile Function.
b-Question 2 from the Sexual Encounter Profile diary, “Were you able to insert your penis into your partner’s vagina?”
c-Question 3 from the Sexual Encounter Profile diary, “Did your erection last long enough for you to have successful intercourse?”
*-p < 0.001 versus placebo.

In open-label extensions of the two randomized, placebo controlled trials of once-daily tadalafil described above, Porst and colleagues have evaluated the long-term safety and efficacy of once-daily tadalafil 5 mg over 1 and 2 years. There were 208 of 234 possible patients (88.9%) who completed the 1-year extension and 139 of 238 possible patients (58.4%) who completed the 2-year extension. Efficacy was measured by changes in the IIEF-EF score, SEP, and the GAQ. The IIEF-EF score improved from baseline by 10.4 and 10.8 in the 1- and 2-year extensions, respectively. After 2 years, 95.7% of patients reported improved erections. Although an impressively positive response, the 2-year GAQ data had a significant dropout rate and likely contained selection bias toward patients who had a positive response.

Once-daily tadalafil has recently been studied in a population of men with ED secondary to diabetes mellitus. A randomized, double-blind, placebo controlled, multicentered study in North America, Europe, and Australia enrolled 298 diabetic men with ED and randomized them to tadalafil 2.5 mg, 5 mg, or placebo for 12 weeks. IIEF-EF, SEP, and GAQ were measured as primary outcomes. The mean age was 57, 42.6% of patients had severe ED, and comorbid conditions were prevalent and included 54% with hypertension and 43% with dyslipidemia. Eighty-nine percent of patients had diabetes mellitus type 2, average hemoglobin A1c was 7.7%, and glycemic control was good in 39%, fair in 48%, and poor in 13%. Mean changes in IIEF-EF scores were modest, including 4.8 and 4.5 for the canadian tadalafil 2.5 mg and 5 mg groups, respectively, compared with 1.3 for placebo (p < 0.005). Successful intercourse was improved by 25.9% and 25% in the tadalafil groups, versus 8.2% placebo (p < 0.005). In this first study of once-daily tadalafil (Cialis Soft Tabs) in diabetic men with ED, 2.5 mg and 5 mg once-daily both produced modest improvements in erectile function in this population.