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Metabolism and excretion
The metabolism of generic tadalafil is via the hepatic enzyme cytochrome P450 34A (CYP34A) to a catechol metabolite, which undergoes further metabolism to its primary circulating metabolite, methylcatechol glucuronide, a 10,000-fold less potent molecule than tadalafil. The CYP34A metabolism pathway of tadalafil was verified with studies using a CYP34A inhibitor ketoconazole and a CYP34A inducer rifampin. Tadalafil is excreted largely as metabolites, approximately two-thirds into the feces and one-third into the urine.
The general ED population
The most frequently referenced study supporting the efficacy of tadalafil is an integrated analysis of 5 randomized, double-blind, placebo controlled, multicentered phase III trials from 1112 men at 74 centers worldwide. The average age was 59, and the etiology of ED was 61% organic, 9% psychogenic, and 31% mixed. The ED severity at baseline was mild in 41%, moderate in 23%, and severe in 36%. Subjects were randomized to placebo or tadalafil at doses from 2.5 mg to 20 mg and instructed to self-administer a dose before initiating intercourse up to once daily. IIEF-EF, SEP, and GAQ scores were assessed at baseline and at 12 weeks.
Duration of action
Among the three PDE5 inhibitors, the half-life and thus duration of action is the pharmacologic parameter that is the most strikingly dissimilar. The half-life of tadalafil is 17.5 hours in normal healthy men and 21.6 hours in elderly men, while the half-lives of sildenafil and vardenafil are similar at 4 hours. This longer half-life provides a therapeutic window of 36 hours for generic tadalafil.
Dosing and absorption Tadalafil (Cialis)
Recommended starting doses of tadalafil are 10 mg for on-demand dosing and 2.5 mg for once-daily dosing, and these doses can then be titrated up or down according to the efficacy and tolerability. It is absorbed as a low-solubility and high-permeability, or Class 2, drug within the FDA Biopharmaceuticals Classification System. With oral ingestion, after first-pass metabolism, tadalafil is approximately 80% bioavailable, compared to 40% and 15% with sildenafil professional and vardenafil professional, respectively. Tadalafil Professional has the slowest absorption of the available PDE5 inhibitors with a mean of 2 hours to reach its maximum concentration, compared with about 50 minutes for sildenafil and vardenafil. The onset of action of tadalafil may occur in as early as 15 minutes of dosing, although successful erections occur in fewer than 40% of men at this time point. It is not advisable to counsel patients that the drug effect may be seen in as early as 15 minutes because it may take up to 2 hours for a response in the majority of men. This may only create performance anxiety or loss of confidence in the treatment, leading to treatment failure.
Phosphodiesterase selectivity
Tadalafil is at least 9000 times more selective for PDE5 than most of the other families of PDEs, with the exception of PDE11. PDE11 is found in the testes and prostate; however, despite partial inhibition of PDE11 by tadalafil at therapeutic doses, clinical significance of this observation has yet to be fully understood. A study by Hellstrom and colleagues concluded that there are no harmful effects of tadalafil on spermatogenesis or testicular function.
The PDE enzyme responsible for phototransduction in the retina, PDE6, is inhibited to some degree by canadian sildenafil and canadian vardenafil, but not canadian tadalafil. The inhibition of PDE6 explains the side effect of blue vision experienced by some patients with these two drugs, as PDE6 inhibition in the retina causes impairment of blue-green color discrimination. Slightly less common with vardenafil, altered vision is a reported side effect for 11% of men taking sildenafil 100 mg. Compared with sildenafil and vardenafil, tadalafil is much less inhibitory for PDE6, and it is over 700 times more potent for PDE5 than PDE6. For this reason, generic tadalafil has less than 0.1% occurrence of vision abnormalities.
Background on outcome measures
Although the effectiveness of PDE5 inhibitors on such intermediate objective outcomes as penile rigidity through penile plethysmography with the RigiScan device (Dacomed Corporation, Minneapolis, MN, USA) has been studied, measuring the therapeutic effectiveness of tadalafil (Cialis Professional) is more accurately defined through an integration of the patient’s reported treatment response and tolerability with the reported satisfaction of both the patient and his partner. Despite their intrinsically subjective nature, validated questionnaires are the preferred major outcome measure of treatment effectiveness of tadalafil and other PDE5 inhibitors.
The International Index of Erectile Function (IIEF) was developed by Rosen and colleagues in 1997 as a multidimensional, 15-item, self-administered questionnaire with the goal of assessing five domains of male sexual function including erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction. The erectile function domain of the IIEF (IIEF-EF) contains 6 questions which the patient answers on a scale from 1 (never or almost never) to 5 (almost always or always), providing a total score of 6 to 30 points. The questions concern erectile frequency, firmness, penetration ability, maintenance frequency, maintenance ability, and erection confidence. Based on a controlled study of 1151 men taking sildenafil professional in order to establish cutoff scores for the IIEF-EF, a score of 26 or greater is defined as normal function, mild ED is a score from 22 to 25, mild to moderate ED 17 to 21, moderate ED 11 to 16, and severe ED 6 to 10.
Tadalafil pharmacology
The three available PDE5 inhibitors share a similar mechanism of action, but they have structural, pharmacologic, and clinical differences. The molecular structure of tadalafil is available in Figure 1. Tadalafil’s molecular structure is different than the similar structures of generic sildenafil and generic vardenafil. All three have a heterocyclic nitrogen-containing doublering system, with a central ring that is analogous to that of cGMP and allows for competitive binding of the drug with PDE5 at the catalytic site. Tadalafil is different in that it is a β-carboline-type PDE5 inhibitor with a piperazinedione ring formed from a modification of the hydantoin ring of sildenafil (Viagra).
Figure 1
Molecular structure of tadalafil.
Tadalafil is an orally administered drug for treating impotence (erectile dysfunction), that initially was developed by the biotechnology company ICOS, and then developed and marketed world-wide as Cialis, by Lilly ICOS, LLC, the joint venture of ICOS Corporation and Eli Lilly and Company. Cialis tablets, in 5mg, 10mg, and 20mg doses, are yellow, film-coated, and almond-shaped.
