Vardenafil

Vardenafil is a potent and selective inhibitor of the cGMP specific phosphodiesterase type 5 (PDE5), the most prominent PDE in the human corpus cavernosum. Vardenafil potently enhances the effect of endogenous nitric oxide in the corpus cavernosum by inhibiting PDE5.

Vardenafil is an oral therapy for the improvement of erectile function in men with erectile dysfunction. In the natural setting, i.e. with sexual stimulation it restores impaired erectile function by increasing blood flow to the penis.

Penile erection is a haemodynamic process. During sexual stimulation, nitric oxide is released. It activates the enzyme guanylate cyclase, resulting in an increased level of cyclic guanosine monophosphate (cGMP) in the corpus cavernosum. This in turn results in smooth muscle relaxation, allowing increased inflow of blood into the penis. The level of cGMP is regulated by the rate of synthesis via guanylate cyclase and by the rate of degradation via cGMP hydrolysing phosphodiesterases (PDEs). When nitric oxide is released in response to sexual stimulation, inhibition of PDE5 by vardenafil results in increased corpus cavernosum levels of cGMP. Sexual stimulation is therefore required for vardenafil to produce its beneficial therapeutic effects.

In vitro studies have shown that vardenafil is more potent on PDE5 than on other known phosphodiesterases (>15-fold relative to PDE6, >130-fold relative to PDE1, >300-fold relative to PDE11, and >1000-fold relative to PDE2, PDE3, PDE4, PDE7, PDE8, PDE9 and PDE10).

Bioequivalence studies have shown that vardenafil 10 mg orodispersible tablet is not bioequivalent to vardenafil 10 mg film-coated tablets. Therefore the orodispersible formulation should not be used as an equivalent to vardenafil 10 mg film-coated tablets.

Absorption

In vardenafil film-coated tablets, vardenafil is rapidly absorbed with maximum observed plasma concentrations reached in some men as early as 15 minutes after oral administration. However, 90% of the time, maximum plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. The mean absolute oral bioavailability is 15%. After oral dosing of vardenafil AUC and C_max increase almost dose proportionally over the recommended dose range (5-20 mg).

When vardenafil film-coated tablets are taken with a high fat meal (containing 57% fat), the rate of absorption is reduced, with an increase in the median t_max of 1 hour and a mean reduction in C_max of 20%.

Vardenafil AUC is not affected. After a meal containing 30% fat, the rate and extent of absorption of vardenafil (t_max, C_max and AUC) are unchanged compared to administration under fasting conditions.

Vardenafil is rapidly absorbed after administration of 10 mg orodispersible tablets without water. The median time to reach C_max varied between 45 to 90 minutes and was similar or slightly delayed (by 8 to 45 min) compared to the film-coated tablets. Mean vardenafil AUC was increased by 21 to 29% (middle aged and elderly ED patients) or 44% (young healthy subjects) with 10 mg orodispersible tablets compared to film-coated tablets as a result of local oral absorption of a small amount of drug in the oral cavity. There was no consistent difference in mean C_max between orodispersible tablets and film-coated tablets.

In subjects taking vardenafil 10 mg orodispersible tablets with a high fat meal no effect on vardenafil AUC and t_max was observed, while vardenafil C_max was reduced by 35% in the fed condition. Based on these results vardenafil 10 mg orodispersible tablets can be taken with or without food.

If vardenafil 10 mg orodispersible tablets are taken with water, the AUC is reduced by 29%, C_max remains unchanged and median t_max is shortened by 60 minutes compared to intake without water. Vardenafil 10 mg orodispersible tablets must be taken without liquid.

Distribution

The mean steady state volume of distribution for vardenafil is 208 l, indicating distribution into the tissues.

Vardenafil and its major circulating metabolite (M1) are highly bound to plasma proteins (approximately 95% for vardenafil or M1). For vardenafil as well as M1, protein binding is independent of total drug concentrations.

Based on measurements of vardenafil in semen of healthy subjects 90 minutes after dosing, not more than 0.00012% of the administered dose may appear in the semen of patients.

Biotransformation

Vardenafil in film-coated tablets is metabolised predominantly by hepatic metabolism via cytochrome P450 (CYP) isoform 3A4 with some contribution from CYP3A5 and CYP2C isoforms.

In humans the one major circulating metabolite (M1) results from desethylation of vardenafil and is subj ect to further metabolism with a plasma elimination half-life of approximately 4 hours. Parts of M1 are in the form of the glucuronide in systemic circulation. Metabolite M1 shows a phosphodiesterase selectivity profile similar to vardenafil and an in vitro potency for phosphodiesterase type 5 of approximately 28% compared to vardenafil, resulting in an efficacy contribution of about 7%.

The mean terminal half-life of vardenafil in patients receiving 10 mg orodispersible tablets ranged between 4-6 hours. The elimination half-life of the metabolite M1 is between 3 to 5 hours, similar to parent drug.

Elimination

The total body clearance of vardenafil is 56 l/h with a resultant terminal half-life of approximately 4-5 hours. After oral administration, vardenafil is excreted as metabolites predominantly in the faeces (approximately 91-95% of the administered dose) and to a lesser extent in the urine (approximately 2-6% of the administered dose).

Pharmacokinetics in special patient groups

Elderly

Hepatic clearance of vardenafil in healthy elderly volunteers (65 years and over) was reduced as compared to healthy younger volunteers (18-45 years). On average elderly males taking vardenafil film-coated tablets had a 52% higher AUC, and a 34% higher C_max than younger males.

Vardenafil AUC and C_max in elderly patients (65 years or over) taking vardenafil orodispersible tablets were increased by 31 to 39% and 16 to 21%, respectively, in comparison to patients aged 45 years and below. Vardenafil was not found to accumulate in the plasma in patients aged 45 years and below or 65 years or over following once-daily dosing of vardenafil 10 mg orodispersible tablets over ten days.

Renal impairment

In volunteers with mild to moderate renal impairment (creatinine clearance 30-80 ml/min), the pharmacokinetics of vardenafil were similar to that of a normal renal function control group. In volunteers with severe renal impairment (creatinine clearance <30 ml/min) the mean AUC was increased by 21% and the mean C_max decreased by 23%, compared to volunteers with no renal impairment. No statistically significant correlation was observed between creatinine clearance and vardenafil exposure (AUC and C_max). Vardenafil pharmacokinetics has not been studied in patients requiring dialysis.

Hepatic impairment

In patients with mild to moderate hepatic impairment (Child-Pugh A and B), the clearance of vardenafil was reduced in proportion to the degree of hepatic impairment. In patients with mild hepatic impairment (Child-Pugh A), the mean AUC and C_max increased 17% and 22% respectively, compared to healthy control subjects. In patients with moderate impairment (Child-Pugh B), the mean AUC and C_max increased by 160% and 133% respectively, compared to healthy control subjects. The pharmacokinetics of vardenafil in patients with severely impaired hepatic function (Child-Pugh C) has not been studied.

Additional information

In vitro data suggest that effects of vardenafil on P-glycoprotein substrates more sensitive than digoxin cannot be excluded. Dabigatran etexilate is an example for highly sensitive intestinal P-glycoprotein substrates.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.