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Pharmacology: Pharmacodynamics: Mechanism of action: Sexual stimulation initiates the release of nitric oxide (NO) from the nerve terminals and endothelial cells, which stimulates synthesis of cyclic GMP in smooth muscles causing the relaxation of the penile arteries and corpus cavernosum and leads to penile erection. Tadalafil inhibits phosphodiesterase type 5 (PDE5) and enhances erectile function by increasing amount of cGMP. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 by tadalafil has no effect in the absence of sexual stimulation. The effect of PDE5 inhibition on cGMP concentration in the corpus cavernosum and pulmonary arteries is also observed in the smooth muscle of the prostate, the bladder and their vascular supply. The mechanism of BPH has not been established. PDE5 is found in the smooth muscle of the corpus cavernosum, prostate, and bladder as well as in vascular and visceral smooth muscle, skeletal muscle, urethra, platelets, kidney, lung, cerebellum, heart, liver, testis, seminal vesicle, and pancreas.
Pharmacokinetics: Absorption: After single oral-dose administration, the maximum observed plasma concentration (Cmax) of tadalafil is achieved between 30 minutes and 6 hours (median time of 2 hours). Absolute bioavailability of tadalafil following oral dosing has not been determined. The rate and extent of absorption of tadalafil are not influenced by food; thus, tadalafil tablets may be taken with or without food.
Distribution: The mean apparent volume of distribution following oral administration is approximately 63 L, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins. Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.
Metabolism: Tadalafil is predominantly metabolized by CYP3A4 to a catechol metabolite. The catechol metabolite undergoes extensive methylation and glucuronidation to form the methylcatechol and methylcatechol glucuronide conjugate, respectively. The major circulating metabolite is the methylcatechol glucuronide. Methylcatechol concentrations are less than 10% of glucuronide concentrations. In vitro data suggests that metabolites are not expected to be pharmacologically active at observed metabolite concentrations.
Excretion: The mean oral clearance for tadalafil is 2.5 L/hr and the mean terminal half-life is 17.5 hours in healthy subjects. 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).
Special Populations: Geriatric: Healthy male elderly subjects (65 years or over) had 25% higher exposure (AUC) with no effect on Cmax relative to that observed in healthy subjects 19 to 45 years of age. No dose adjustment required based on age alone. However, greater sensitivity to medications in some older individuals should be considered.
Torfil 2.5: Patients with Diabetes Mellitus: In male patients with diabetes mellitus after a 10 mg tadalafil dose, exposure (AUC) was reduced approximately 19% and Cmax was 5% lower than that observed in healthy subjects. No dose adjustment required.
Patients with BPH: In patients with BPH following single and multiple-doses of 20 mg tadalafil, no statistically significant differences in exposure (AUC and Cmax) were observed between elderly (70 to 85 years) and younger (≤60 years of age) subjects. No dose adjustment required.
Torfil 10/Torfil 20: Renal impairment: Exposure to tadalafil is much higher in patients with renal impairment as compared to healthy subjects.
Hepatic Impairment: No dosage adjustment required for patients with mild to moderate hepatic impairment. No data available for patients with severe hepatic impairment.
Patients with diabetes: Exposure of tadalafil is lower in diabetic patients compared in healthy subjects.
