Cialis - Tadalafil
Classification:
Genitourinary Agents
- Impotence Agents
- Phosphodiesterase inhibitors
Description: Tadalafil (Cialis®) is an oral drug for the treatment of male erectile dysfunction. It is a selective phosphodiesterase (PDE) type 5 inhibitor similar to sildenafil (Viagra®) and vardenafil (Levitra™). This class of drugs does not inhibit prostaglandins as do some agents for treating impotence (e.g., alprostadil). The duration of action of tadalafil (up to 36 hours) appears to be longer than that of sildenafil and vardenafil. Because PDE inhibitors promote erection only in the presence of sexual stimulation, the longer duration of action of tadalafil allows for more spontaneity in sexual activity. Unlike sildenafil, visual disturbances have not been reported with tadalafil, which is more selective for PDE5 than for PDE6 present in the retina. Tadalafil was in phase II trials for the treatment of female sexual dysfunction, however, further investigation has been discontinued. In July 2001, Lilly ICOS filed the NDA for tadalafil for the treatment of male erectile dysfunction; an approvable letter was issued in April 2002. Final FDA approval was granted November 21, 2003. Cialis® is also available in Europe, New Zealand, and Australia.
Mechanism of Action: Tadalafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cGMP. Cyclic guanosine monophosphate causes smooth muscle relaxation in the corpus cavernosum thereby allowing inflow of blood; the exact mechanism by which cGMP stimulates relaxation of smooth muscles has not been determined. Phosphodiesterase type 5 is responsible for degradation of cGMP in the corpus cavernosum. Tadalafil enhances the effect of NO by inhibiting PDE5 thereby raising concentrations of cGMP in the corpus cavernosum. Tadalafil has no direct relaxant effect on isolated human corpus cavernosum and, at recommended doses, has no effect in the absence of sexual stimulation. In vitro studies show that tadalafil is selective for PDE5 and is >10,000-fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7, which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle, and other organs. Tadalafil is >10,000 fold more potent for PDE5 than for PDE3 found in the heart and blood vessels. Also, tadalafil has 700-fold greater selectivity for PDE5 versus PDE6, an enzyme found in the retina and involved in phototransduction. Compare this selectivity to the selectivity of sildenafil which has only a 10-fold selectivity for PDE5 versus PDE6. This lower selectivity of sildenafil for PDE5 vs PDE6 is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma concentrations of sildenafil. Further, 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. Inhibition of human recombinant PDE11A1 activity occurs at tadalafil concentrations within the therapeutic range. The physiological role and clinical effects of PDE11 inhibition in humans have not been elucidated.
Phosphodiesterase type 5 (PDE5) is also abundant in lung tissue and esophageal smooth muscle. Inhibition of PDE5 in lung tissue results in pulmonary vasodilation which can be effective in treating pulmonary hypertension. Inhibition of esophageal smooth muscle PDE5 can cause a marked reduction in esophageal motility as well as in lower esophageal sphincter (LES) tone. These effects may be beneficial in certain motor disorders involving the esophagus such as diffuse spasm, nutcracker esophagus, and hypertensive LES. However, the reduction in LES tone can worsen the symptoms of gastroesophageal reflux disease (GERD). Dyspepsia is one of the most common adverse reactions associated with PDE inhibitor therapy.
Pharmacokinetics: Tadalafil is administered orally. The pharmacokinetics of tadalafil were evaluated in healthy young volunteers. After a single oral dose, the maximum observed plasma concentration (Cmax) occurs between 30 minutes and 6 hours (Tmax median time of 2 hours). The usual onset of action is within 30 to 45 minutes and the usual duration is up to 36 hours. Food has no effect on the pharmacokinetics of tadalafil, however, absolute bioavailability data are not available. Once absorbed, tadalafil is distributed into the tissues. Protein binding is 94% at therapeutic concentrations. Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.
The primary route of elimination for tadalfil is via the hepatic cytochrome P450 isoenzyme CYP3A4, which metabolizes the drug to a catechol metabolite. The catechol metabolite undergoes extensive methylation to form the methylcatechol metabolite and then glucuronidation to the form the methylcatechol glucuronide conjugate. The major circulating metabolite is the methylcatechol glucuronide, which is 13,000 times less potent for PDE5 than tadalafil. Methylcatechol concentrations are less than 10% of glucuronide concentrations. Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose). The mean elimination half-life is 17.5 hours in healthy subjects.
- Special Populations: In a healthy volunteer study of elderly males (>= 65 years) and younger males (19-45 years), the AUC of tadalafil was 25% higher in the elderly males with no effect on Cmax. No dosage adjustment is warranted based on age alone. However, greater sensitivity to medications in some older individuals should be considered. Tadalafil has not been studied in persons less than 18 years of age.
In clinical pharmacology studies involving persons with mild (CrCl 51-80 ml/min) or moderate renal impairment (CrCl 31-50 ml/min), tadalafil AUC was doubled after single doses of 5 to 10 mg compared to persons with normal renal function. In those with end-stage renal disease on hemodialysis, there was a two-fold increase in Cmax and 2.7- to 4.1-fold increase in AUC following single-dose administration of 10 or 20 mg tadalafil. Exposure to total methylcatechol (unconjugated plus glucuronide) was 2- to 4-fold higher in patients with renal impairment, compared to those with normal renal function. Hemodialysis (performed between 24 and 30 hours post-dose) had neglegible effects on tadalafil or metabolite clearance.
In patients with mild to moderate hepatic impairment (Child-Pugh class A or B), the AUC following a 10 mg tadalafil dose was comparable to that of healthy subjects. There are no data available for doses higher than 10 mg of tadalafil in patients with hepatic impairment. Tadalafil has not been studied in patients with severe hepatic impairment (Child-Pugh class C).
In male patients with diabetes mellitus after a 10 mg tadalafil dose, AUC was reduced approximately 19% and Cmax was 5% lower than that observed in healthy subjects. No dosage adjustment is necessary in diabetic patients as long as organ function is normal.
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