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The effect of a single 100-mg dose of tadalafil on QT interval, which
represents ventricular depolarization and repolarization, was evaluated at
the time of peak tadalafil concentration in a randomized, double-blind,
placebo- and active (intravenous ibutilide)-controlled crossover study in
90 healthy males 18 to 53 yr of age. The mean change in QTc (Fridericia
QT correction) for tadalafil, relative to placebo, was 3.5 ms (two-sided
90%, confidence interval = 1.9, 5.1). The mean change in QTc (individual
QT correction) for tadalafil, relative to placebo, was 2.8 ms (two-sided
90%, confidence interval = 1.2, 4.4). A 100-mg dose of tadalafil (five times
the recommended dose) was chosen because this dose yields exposures
covering those observed on coadministration of tadalafil with potent
CYP3A4 inhibitors. In this study, the mean increase in heart rate associated
with a 100-mg dose of tadalafil compared with placebo was 3.1 beats
per min. These changes are not likely to be clinically relevant.

ED is a frequent complication of radical prostatectomy. Despite improvements
in surgical techniques used in prostatectomy, trauma to neurovascular
bundles leaves many patients with ED. In fact, more than 50% of patients
who undergo prostatectomy procedures will have ED. In one study, the
effects of tadalafil were examined in men who had developed ED after
bilateral nerve-sparing radical retropubic prostatectomy (BNRRP). After a
4-wk no-treatment baseline period, patients received 20 mg of tadalafil or
placebo as needed for the next 12 wk. Patients who received tadalafil had
significantly improved EF, with a five-point increase in scores for the
EF domain of the IIEF (compared with a one-point increase for placebo
[p < 0.001]). (An increase of just five points in the IIEF EF domain is consistent
with an improvement, such as moving from severe to moderate ED
or from moderate to mild ED). By the end of the 12-wk treatment period, the
group of all randomized patients receiving 20 mg of tadalafil after BNRRP
had significantly better rates of successful intercourse attempts (41%) than
those receiving placebo (19%) (p < 0.001) (Fig. 7). All randomized patients responded positively to the GAQ (62% with
20 mg of tadalafil vs 23% with placebo; p < 0.001). Additionally, encouraging
results for patients with this type of ED were observed in a subgroup
of men who exhibited at least some erection or tumescence at baseline and
experienced an even better response to tadalafil than subjects in a separate
study. Another study showed that after nerve-sparing surgery, the highest
dose of a PDE5 inhibitor, such as tadalafil, is usually the most efficacious
dose, and that best results are seen 12 mo after surgery.

In one study, significantly greater penile rigidity (as measured by
RigiScan® [Timm Medical Technologies, Eden Prairie, MN] and compared
with placebo) was observed at an average of 45 min after subjects took a
single 10-mg dose of tadalafil. Achievement of erection was observed as
early as 16 min after subjects took a single 20-mg dose.
Although tadalafil has a relatively fast onset of action, comparable with
that of other PDE5 inhibitors, its long half-life and consequent prolonged
duration of action sets it apart from other drugs in this class. Several studies
have been conducted to determine whether tadalafil’s rapid appearance in
the blood and long half-life translate into a quick onset of action and prolonged
period of responsiveness in terms of erectile function.
One multicenter, randomized, double-blind, placebo-controlled study
to determine the duration of action of tadalafil was divided into two 4-wk
intervals of treatment. Men with mild to severe ED were provided with two
20-mg doses of tadalafil for at-home use and, in one 24-h treatment interval,
were asked to attempt sexual intercourse. In a separate 36-h treatment interval, men were also asked to attempt intercourse. In response to
Question (Q) 3 of the Sexual Encounter Profile (SEP) (i.e., “Did your
erection last long enough to have successful intercourse?”), more than
60% of men taking tadalafil reported having successful intercourse at
24 h and 64% at 36 h after dosing (p < 0.001). Tadalafil was effective for
36 h, with 59% of sexual intercourse attempts at 36 h being successful in
patients randomly assigned to receive the 20-mg dose, compared with
28% for placebo.
The integrated analysis of trials in which patients took tadalafil without
restriction on food or alcohol intake also showed that 79–80% of attempts
at sexual intercourse made between 4 and 36 h after tadalafil dosing were
successful. A subsequent analysis of 11 clinical trials involving more
than 2000 men with ED confirmed the long period of responsiveness with
tadalafil, with the mean-per-patient rate of successful intercourse attempts
ranging from 65.5% (at 30 min–1 h) to 73.4% (at 24–36 h) after a single
20-mg dose of tadalafil.
The long period of responsiveness to tadalafil allows couples to take full
advantage of the long duration of effectiveness associated with ED medication. In another study assessing the period of responsiveness after
taking tadalafil, 82% of men with ED attempted sexual intercourse at least
once in the 4 to 36 h after dosing. As many as 59% of men in this study
attempted intercourse between 12 and 36 h. Clearly, tadalafil represents
a new step forward in the pharmacotherapy of ED by removing
restrictions associated with other PDE5 inhibitors on the timing of sexual
activity. The pharmacokinetic profile of tadalafil has the potential to allow
couples increased flexibility, reducing the need to plan and schedule sexual
activity under time constraints. This is a key consideration for couples
seeking real-life sexual effectiveness.

Pharmacokinetic studies conducted in healthy subjects show that
tadalafil is rapidly absorbed, with mean peak plasma levels observed
between 30 min and 6 h (median time of 2 h) after single oral-dose
administration. Tadalafil exhibits linear pharmacokinetics
over the dosage range of 2.5 to 20 mg, and steady-state plasma concentrations
are attained within 5 d of once-daily dosing, with exposure approx
1.6-fold greater than after a single dose. At therapeutic concentrations,
94% of tadalafil in plasma is protein bound, but, as indicated by its
large apparent volume of distribution, tadalafil is widely distributed in
tissues. In vitro studies indicate that tadalafil is metabolized via
cytochrome P450 3A4 (CYP3A4), but tadalafil itself is neither an inhibitor
nor an inducer of CYP3A4. This has been confirmed by clinical
pharmacology studies of tadalafil given in combination with other substrates
(lovastatin, midazolam) for CYP3A4, or with an inhibitor
(ketoconazole) or inducer (rifampin) of CYP3A4. No dosing adjustment of tadalafil is warranted when taken in combination with CYP3A4
inducers. Studies have shown that drugs inhibiting CYP3A4 can
increase tadalafil exposure. Based on study results, in patients taking
concomitant potent CYP3A4 inhibitors, the dose of tadalafil should not
exceed 10 mg, and the dose should not be taken more frequently than
once every 72 h.
Notably, tadalafil has an elimination half-life of 17.5 h, considerably
longer than the half-lives of the other drugs in this class (i.e., sildenafil
[3–5 h] and vardenafil [4–5 h]). With respect to metabolism, no
active metabolites of tadalafil have been identified. Tadalafil is excreted
predominantly as inactive metabolites mainly in the feces (61% of the
dose) and, to a lesser extent, in the urine (36% of the dose).
Clinical pharmacology studies have examined the effects of tadalafil on
pharmacokinetics in special populations (i.e., elderly patients and those
with diabetes, renal impairment, or hepatic insufficiency). For healthy,
elderly male subjects (65 yr or older), a lower oral clearance of tadalafil
was observed, resulting in 25% higher exposure (area under the doseresponse
curve [AUC]) with no effect on Cmax relative to that observed in
healthy subjects 19 to 45 yr of age. No dose adjustment is warranted based
on age alone; however, greater sensitivity to medications in some older
individuals should be considered.
In the case of patients with mild or moderate hepatic impairment, the
maximum dose should not exceed 10 mg, and use in patients with severe
hepatic impairment is not recommended. No dose adjustment is required
in patients with diabetes or with mild renal insufficiency. For patients with
moderate renal insufficiency, tadalafil should be limited to 5 mg not more
than once daily, with the maximum dose limited to 10 mg not more than
once every 48 h. In patients with severe renal insufficiency or end-stage
renal disease, tadalafil should be limited to 5 mg not more than once daily. Likewise, common extrinsic factors appear to exert no influence on
tadalafil’s pharmacokinetics. For instance, the presence of high-fat food
affects neither the rate nor the extent of tadalafil absorption; thus, tadalafil
may be taken with or without food.
Although previous studies showed no pharmacodynamic interactions
between tadalafil and alcohol, recent studies show that both alcohol
and PDE5 inhibitors, including tadalafil, are mild systemic vasodilators.
When mild vasodilators are taken in combination, blood pressure-lowering
effects of each individual compound may be increased. Substantial
consumption of alcohol (e.g., 5 units or greater) in combination with
tadalafil can increase the potential for orthostatic signs and symptoms,
including increase in heart rate, decrease in standing blood pressure, dizziness,
and headache.

Tadalafil is a selective inhibitor of the enzyme phosphodiesterase type
5 (PDE5), one of a family of 11 PDEs that degrade cyclic guanosine monophosphate
(cGMP) and/or cyclic adenosine monophosphate (cAMP).
Compared with other agents in the class of PDE5 inhibitors, tadalafil has
a unique chemical structure.
Tadalafil is also considered to be highly selective for PDE5 and is more
selective for PDE5 than for any other PDEs . For example, tadalafil
is more than 10,000-fold more potent for PDE5 than for PDE1, PDE2,
PDE4, and PDE7 enzymes, which are found in the heart, brain, blood
vessels, liver, leukocytes, skeletal muscles, and other organs. In addition,
tadalafil is 9000-fold more potent for PDE5 than for PDE8, PDE9, and
PDE10 and 14-fold more potent for PDE5 than for PDE11A1, an enzyme
found in human skeletal muscle. The physiological role and clinical relevance
of PDE11 inhibition in humans, however, have not been determined.
PDE5 is found in high concentrations in the corpus cavernosum of
the penis and, to a lesser extent, in vascular smooth muscle cells. Because
PDEs are found in a variety of tissues and are implicated in a broad range
of cellular functions, the selectivity for PDE5 over other PDEs may
have clinical relevance for adverse events. For example, tadalafil is a
weak inhibitor of PDE6, which is found in high concentrations only in
the photoreceptors of the retina. This lower affinity of tadalafil for PDE6
may explain the low incidence of visual adverse effects reported in clinical
trials in patients receiving the drug. Inhibition of PDE6 is thought to
underlie the visual disturbances sometimes reported by patients taking
PDE5 inhibitors, such as sildenafil.
The mechanism by which tadalafil inhibits PDE5 and improves erections
in men with ED requires an understanding of the physiology of the erectile
response to sexual stimulation. During sexual stimulation, nitric oxide
(NO) released from nonadrenergic, noncholinergic (NANC) neurons and
endothelial cells stimulates guanylate cyclase to produce cGMP, which in
turn decreases intracellular calcium levels. This ultimately results in the
relaxation of the vascular smooth muscle and increased blood flow into the
corpus cavernosa, followed by penile erection.
Tadalafil augments this naturally occurring NO-cGMP pathway by
inhibiting PDE5-induced cGMP degradation, thereby increasing levels
of cGMP and ultimately enhancing erectile function. This has been
demonstrated in vitro using tissue taken from men with ED undergoing
surgery for penile implantation. Consistent with increased cGMP
levels, tadalafil, like other PDE5 inhibitors, also enhances sodium nitroprusside
(SNP)-induced relaxation of corpus cavernosum and penile
arterial tissues, as well as relaxation induced by NO stimulation and by
acetylcholine. In vivo, this process results in penile erection in the
presence of sexual stimulation. Because sexual stimulation is required to
initiate the local release of NO, the inhibition of PDE5 has no effect in
the absence of sexual stimulation.