The effects of steady-state erythromycin and azithromycin on the pharmacokinetics of sildenafil in healthy volunteers.
OBJECTIVE
Sildenafil, an effective oral treatment for erectile dysfunction, is predominantly metabolized by the cytochrome P450 isozyme 3A4, which is inhibited by a number of the macrolide antibiotics. Therefore, two placebo-controlled, parallel-group studies were conducted to evaluate the effects of multiple doses of erythromycin and azithromycin on the pharmacokinetics, safety and tolerability of a single oral 100-mg dose of sildenafil.


METHODS
In the erythromycin interaction study, 26 male volunteers (18--45 years of age) received open-label sildenafil 100 mg on day 1. Half received blinded erythromycin (500 mg) twice daily on days 2--6, and the other half received placebo. On day 6, all subjects received a second 100-mg dose of sildenafil. In the azithromycin interaction study, 24 male volunteers (19--33 years of age) received open-label 100 mg sildenafil on day 1. Half then received blinded azithromycin (500 mg) once daily on days 2--4, and the other half received placebo. On day 4, all subjects received another 100-mg dose of sildenafil. In both studies, blood samples were collected on the first and last study day for the analysis of plasma concentrations of sildenafil and its primary metabolite, UK-103,320.


RESULTS
Repeated dosing with erythromycin caused statistically significant increases in the AUC and Cmax of sildenafil (2.8-fold and 2.6-fold, respectively) but had no effect on Tmax, kel or t1/2. A statistically significant 1.4-fold increase in the AUC of UK-103,320 was also observed, as well as a significant decrease in kel, resulting in an increase of about 1 h in t1/2. In contrast, repeated dosing with azithromycin caused no significant change in any pharmacokinetic parameter of either sildenafil or UK-103,320. Erythromycin, azithromycin and sildenafil were well tolerated; adverse events were mild and transient. No subject withdrew from either trial for any reason related to study drug.


CONCLUSIONS
These results indicate that erythromycin modifies the pharmacokinetics of sildenafil by inhibiting its CYP3A4-mediated first-pass metabolism. Given these data, a lower starting dose of sildenafil (25 mg) may be considered for patients receiving erythromycin or other potent CYP3A4 inhibitors. Azithromycin did not affect the pharmacokinetics of sildenafil; therefore, no adjustment in dosage is necessary for patients receiving these drugs concomitantly.
Muirhead
Gary J
GJ
Clinical Sciences, Pfizer Central Research, Sandwich, Kent and Charterhouse Clinical Research Unit, The Royal Masonic Hospital, London, UK. gary_muirhead@sandwich.pfizer.com
Faulkner
Stephen
S
Harness
Jane A
JA
Taubel
Jörg
J
D000328:Adult; D000704:Analysis of Variance; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019540:Area Under Curve; D017963:Azithromycin / Q000008:administration & dosage / Q000494:pharmacology*; D001682:Biological Availability; D004338:Drug Combinations; D004917:Erythromycin / Q000008:administration & dosage / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011687:Purines; D011744:Pyrimidinones / Q000493:pharmacokinetics; D000068677:Sildenafil Citrate; D013450:Sulfones
D000900:Anti-Bacterial Agents; D004338:Drug Combinations; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D011744:Pyrimidinones; D013450:Sulfones; C109995:UK 103320; D004917:Erythromycin; D017963:Azithromycin; D000068677:Sildenafil Citrate