- Gary J
Muirhead, Maria B Wulff, et al (Early Clinical
Research Group, Pfizer Central Research, Sandwich
Kent, UK and Hoffmann-La Roche, Basel, Switzerland).
Pharmacokinetic interactions between sildenafil and saquinavir/ritonavir
Br. J.Clin.Pharmacol, vol.50(2), August 2000, p.99-107.
Aim of the study was to investigate the effect of antiretroviral protease inhibitors saquinavir (soft gelatin capsules) and ritonavir on the pharmacokinetics and tolerability of sildenafil and also to investigate the effect of sildenafil on steady-state pharmacokinetics of saquinavir and ritonavir.
Study was conducted in 28 healthy male volunteers. Both protease inhibitors significantly increased Cmax, AUC, Tmax and t.½ values for both sildenafil and UK-103, 320 (metabolite). Ritonavir showed a significantly greater effect than saquinavir with increases in sildenafil AUC and Cmax of 2 fold and 3.9 fold respectively. Steady-state pharmacokinetics of saquinavir and ritonavir were unaffected by sildenafil. There was no associated increased incidence of adverse events or clinically significant changes in BP, heart-rate or ECG parameters.
The results indicate that both saquinavir and ritonavir modify the pharmacokinetics of sildenafil, probably through inhibition of CYP3A4. More pronounced effect of ritonavir – due to additional potent inhibition of CYP2C9. A lower sildenafil starting dose (25mg) should be considered for patients receiving saquinavir and it is recommended not to exceed a maximum single dose of 25mg in a 48hr. period in patients receiving ritonavir.
Editors commentary-by D.J.Back
These data are consistent with a previous study which demonstrated that the AUC of sildenafil when given with the protease inhibitor indinavir was 4.4 fold greater than data from historical controls.
Not all drug interactions reported in the literature are clinically relevant. This one has direct relevance to HIV infected men. Prevalence of erectile dysfunction in this group has been reported as 33%, increasing with more advanced HIV disease. Many patients wish to avail themselves of sildenafil therapy. Protease inhibitors, especially ritonavir, are potent inhibitors of CYP3A4 and other cytochrome P450 enzymes. It is surprising that in this study, there were no adverse effects on BP, heart rate or ECG. In 2 other reported studies, adverse events were headache, facial flushing, dyspepsia and rhinitis – these 2 studies were conducted in HIV-infected patients.
Authors are agreed that a low starting-dose of sildenafil (- 25mg – in 1st study and 12.5 mg in 2nd study) is advisable in patients receiving concomitant protease inhibitors.
Erythromycin and cimetidine produce similar effects. There are grounds to be cautious when sildenafil is used with a whole range of drugs.
Frederic Westphal (Unit
of Geriatric Medicine, France)
Macrolide – induced clinically relevant drug interactions with cytochrome P-450a (cyp) 3A4: an update focused on clarithromycin, azithromycin and dirithromycin.
Br. Jr.Cl. Pharmacology, oct.2000, 50(4), 285-295
Summary: Erythromycin binds strongly, clarithromycin to a lesser extent and azithromycin the least to the cytochrome CYP 3A4, which is involved in oxidative phase of biotransformation of drugs. Hence, erythromycin produces maximum drug interactions and azithromycin and dirithromycin the least drug interactions.
Clinically relevant drug-interactions with benzodiazepines, neuroleptics, HMG CoA reductase inhibitors, anti-arrhythmic agents and warfarin are described.