Sildenafil pharmacokinetics

The manufacturers report that in population pharmacokinetic analysis, there was no effect on sildenafil pharmacokinetics in those taking ACE inhibitors, calcium-channel blockers and tMazide and related diuretics whereas the AUC of the less potent active metabolite of sildenafil is increased by 62% by loop and potassium-sparing diuretics and by 102% by non-selective beta blockers, although these changes were not considered clinically relevant. ... 

Retrospective analysis of clinical study data su ested that SSRIs and tricyclic antidepressants did not alter sildenafil pharmacokinetics. However, in one study fluvoxamine was found to modestly increase the levels and vascular effects of sildenafil. 

Even on a relatively small subset of reused data, it is possible to license old medicines for new therapeutic applications and greatly reduce the costs of clinical development—many of these reused medicines have already passed muster for pharmacokinetic safety, so smaller-scale clinical trials are possible, saving considerable money (e.g., Arakis—soon to become Sosei). Even Sildenafil may have new indications [39]. There are huge potential reserves of information to mine in each and every large pharmaceutical company ... 

Unless otherwise stated, general information applies to the entire class of phosphodiesterase inhibitors. Sildenafil is highlighted because it was the first to be marketed and is the most thoroughly studied. The newer agents tadalafil and vardenafil have different pharmacokinetic profiles (Table 83-3), drug-food interactions, and adverse effects. 

GFJ has been shown to increase the exposure of carbamazepine (175), cisapride (176-179), fluvoxamine (184), losartan (188), methadone (189), scopolamine (191), and sertraline (192). However, only the interaction of GFJ with carbamazepine and cisapride seems to be clinically relevant. No alteration in exposure was observed for clozapine (180,181), heophylline (195), halo-peridol (196), and omeprazole (190). Reports of increased pharmacokinetic parameters of clozapine, theophylline, and haloperidol suggest that an interaction is unlikely to be clinically relevant. Contradicting results were reported for itraconazole (185-187), digoxin (75,183), and sildenafil (193,194). An increased effect on concomitant use of diclofenac and GFJ was observed in rats (182). Overall, the clinical relevance for this drug class appears to be low. 

The available case reports in the FDA AERS support the published literature that there are pharmacokinetic interactions between St. John s wort and CYP3A4 and/or p-glycoprotein substrates, such as cyclosporine, levonorgestrel/estradiol and sildenafil, and pharmacodynamic interactions with the SSRIs or MAOI. Subsequent clinical studies including those conducted via a CDER clinical pharmacology research cooperative agreement (14—16) provided mechanistic basis of many of these interactions (refer to Chapter 4). 

Pharmacokinetics Sildenafil is rapidly absorbed after oral administration, and peak plasma levels are achieved within one hour. Bioavailability is about 40 percent of the oral dose. Sildenafil enters tissues, and has an apparent volume of distribution of 1.5 L/kg. Both sildenafil and its major N-desmethylated metabolite are > 95 percent bound to plasma proteins. Both CYP3A4 (major route) and CYP2C9 (minor route) are responsible for the metabolism of sildenafil. The major metabolite, N-desmethyl sildenafil, is approximately 50 percent as potent as sildenafil in inhibiting PDE5. The major route of elimination for sildenafil and its metabolites is via the bile. Clearance is decreased in older individuals free plasma concentrations are 40 percent higher in healthy volunteers > 65 years old. Severe renal impairment (< 30 mL/min) increases the AUC (see p. 7) by two-fold. Similarly, cirrhosis of the liver also significantly increases the AUC. 

Sexual dysfunction is a common adverse effect of SSRIs and various treatments have been proposed, of which sildenafil is the only strategy with consistent support from controlled trials. Sildenafil is metabolized by CYP3A4, which is inhibited by fluvoxamine. The effects of fluvoxamine (100 mg/day for 10 days) on the pharmacokinetics of sildenafil (50 mg orally) has been evaluated in 12 healthy men (mean age 25 years) using a doubleblind, placebo-controlled, crossover design (46). Fluvoxamine increased the AUC of sildenafil by about... 

PHOSPHODIESTERASE TYPE 5 INHIBITORS (e.g. sildenafil, tadalafil, vardenafil) GRAPEFRUIT JUICE Possibly t efficacy and t adverse effects, e.g. hypotension Small t in bioavailability, t variability in pharmacokinetics, i.e. interindividual variations in metabolism Safest to advise against intake of grapefruit juice for at least 48 hours prior to intending to take any of these preparations. When necessaiy, the starting dose of sildenafil should not exceed 25-50 mg and that of tadalafil 10 mg. Avoid co-administration with vardenafil... 

The effect of sildenafil on arterial pressure has been tested in 16 hypertensive men taking amlodipine 5-10 mg/day (23). Sildenafil did not affect amlodipine pharmacokinetics, but caused a further additive fall in blood pressure. Adverse events with the combination of sildenafil and amlodipine, headache, dyspepsia, and nausea, did not require drug withdrawal. 

D. J. Nichols, G. J. Muirhead, and J. A. Harness, Pharmacokinetics of sildenafil after single oral doses in healthy male subjects absolute bioavailability, food effects and dose proportionality. Br J Clin Pharmacol 53(Suppl 1) 5S-12S (2002). 

The three marketed phosphodiesterase inhibitors differ in their pharmacokinetic profiles, drug-food interactions, and adverse effects, and precautions are necessary in patients with cardiovascular disease (Table 81-5). Because sildenafil has been marketed longer and is better studied, it is emphasized in this section, with important differences among the three drugs highlighted as appropriate. 

Vardenafil and sildenafil are similar in their pharmacokinetic profiles. Both drugs share a similar 1 -hour onset of action, short duration of action, and oral absorption that is significantly delayed when the drug is taken within 2 hours of a fatty meal. In contrast, tadalafil has a delayed onset of action of 2 hours, a prolonged duration of action up to 36 hours, and food does not affect its rate of absorption. Thus tadalafil offers greater spontaneity for patients, as one dose can last through an entire weekend. " ... 

Muirhead GJ, Wulff MB, Fielding H, et al. Pharmacokinetic interactions between sildenafil and saquinavir/ritonavir. Br J Clin Pharmacol 2000 59 99-197. 

Tadalafil is different in structure from both sildenafil and vardenafil. It is rapidly absorbed and peaks in concentration (378 pg/L after a 20-mg dose) after 2 hours, displaying a long half-life of 17.5 hours. It also is metabolized by the liver (CYP3A4). Notably, its pharmacokinetics is not clinically influenced by alcohol or food intake or by factors such as diabetes or impaired hepatic or renal function (13). 

Muirhead GJ, Ranee DJ, Walker DK, Wastall P. Comparative human pharmacokinetics and metabolism of single-dose oral and intravenous sildenafil. Br J Clin Pharmacol 2002 53 (Suppl 1) 13SH20S. 

There is no established pharmacokinetic or pharmacodynamic interaction between the phosphodiesterase type-5 inhibitors and warfarin, and no warfarin dose adjustment would therefore be expected to be needed on concurrent use. However, in pulmonary hypertension, sildenafil appears to increase the risk of nosebleeds, and this may be greater in patients taking coumarins. Similarly, the two possible cases with acenocoumarol and warfarin, although not conclusive, do introduce a note of caution. 

Sildenafil does not appear to affect the pharmacokinetics of tacrolimus. The levels of sildenafil were higher in patients taking tacrolimus than in healthy subjects, but it is not clear whether this was due to tacrolimus alone. A marked blood pressure drop occurred when both drugs were given in one study. 

A man taking simvastatin developed symptoms of rhabdomyolysis after taking a single dose of sildenafil. The pharmacokinetics of atorvastatin and sildenafil do not appear to be altered by concurrent use, and tadalafll does not alter lovastatin pharmacokinetics. 

Wilner K, Laboy L, LeBel M. The effects of cimetidine and antacid on tiie pharmacokinetic profile of sildenafil citrate in healthy male volunteers. Br J Clin Pharmacol (2007) 53, 31S-... 

The manufacturer notes that in population pharmacokinetic analysis of patients with pulmonary hypertension, there appeared to be an increase in sildenafil exposure when it was taken with beta blockers (none named) in combination with CYP3A4 substrates (none named). " The clinical relevance of this is uncertain, and fiuther study is needed. 

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