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Titolo:
Pharmacokinetic interactions between sildenafil and saquinavir/ritonavir
Autore:
Muirhead, GJ; Wulff, MB; Fielding, A; Kleinermans, D; Buss, N;
Indirizzi:
Pfizer Ltd, Cent Res, Early Clin Res Grp, Sandwich CT13 9NJ, Kent, EnglandPfizer Ltd Sandwich Kent England CT13 9NJ andwich CT13 9NJ, Kent, England F Hoffmann La Roche & Co Ltd, CH-4002 Basel, Switzerland F Hoffmann La Roche & Co Ltd Basel Switzerland CH-4002 asel, Switzerland
Titolo Testata:
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
fascicolo: 2, volume: 50, anno: 2000,
pagine: 99 - 107
SICI:
0306-5251(200008)50:2<99:PIBSAS>2.0.ZU;2-2
Fonte:
ISI
Lingua:
ENG
Soggetto:
HIV PROTEASE INHIBITORS; ERECTILE DYSFUNCTION; CLINICAL-PHARMACOLOGY; DRUG-INTERACTIONS; ORAL SILDENAFIL; INFECTION; RITONAVIR; INDINAVIR; EFFICACY; COMBINATION;
Keywords:
antiretroviral protease inhibitors; cytochrome P4502C9; cytochrome P450 3A4; pharmacokinetic interactions; ritonavir; saquinavir; sildenafil citrate;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
29
Recensione:
Indirizzi per estratti:
Indirizzo: Muirhead, GJ Pfizer Ltd, Cent Res, Early Clin Res Grp, Sandwich CT13 9NJ, Kent, England Pfizer Ltd Sandwich Kent England CT13 9NJ 9NJ, Kent, England
Citazione:
G.J. Muirhead et al., "Pharmacokinetic interactions between sildenafil and saquinavir/ritonavir", BR J CL PH, 50(2), 2000, pp. 99-107

Abstract

Aims To investigate the effect of the antiretroviral protease inhibitors saquinavir (soft gelatin capsule) and ritonavir on the pharmacokinetic properties and tolerability of sildenafil and to investigate the effect of sildenafil on the steady-state pharmacokinetics of saquinavir and ritonavir. Methods Two independent, 8 day, open, randomized, placebo-controlled, parallel-group studies (containing a double-blind crossover phase) were conducted at Pfizer Clinical research units (Canterbury, UK. and Brussels, Belgium). Twenty-eight healthy male volunteers entered each study. In each study, volunteers were randomized (n = 14 per group) to receive sildenafil on day 1 followed by a 7-day treatment period (days 2-8) with saquinavir or placebo (Study I) or ritonavir or placebo (Study II). Sildenafil or placebo (Study I and Study II) was administered alternately on day 7 or day 8, dependingon initial randomization. The effect of saquinavir and ritonavir on the pharmacokinetics of sildenafil and its primary circulating metabolite (UK-103, 320) and the effect of single-dose sildenafil on the steady-state pharmacokinetics of saquinavir (1200 mg three times daily) and ritonavir (500 mg twice daily) were determined. The safety and tolerability of sildenafil coadministered with saquinavir or ritonavir were also assessed. Results Both protease inhibitors significantly increased C-max, AUC, t(max) and t(1/2) values for both sildenafil and UK-103, 320. Ritonavir showed asignificantly greater affect than saquinavir with increases in sildenafil AUC and C-max, of 11-fold (95% CI: 9.0, 12.0) and 3.9-fold (95% CI: 3.2, 4.9), respectively. This compared with increases of 3.1-fold (95% CI: 2.5, 4.0) and 2.4-fold (95% CI: 1.8, 3.3) for coadministration with saquinavir. Incontrast, the steady-state pharmacokinetics of saquinavir and ritonavir were unaffected by sildenafil. The increases in systemic exposure to sildenafil and UK-103, 320 were not associated with an increased incidence of adverse events or clinically significant changes in blood pressure, heart rate or ECG parameters. Conclusions These results indicate that both saquinavir and ritonavir modify the pharmacokinetics of sildenafil presumably through inhibition of CYP3A4. The more pronounced effect of ritonavir may be attributed to its additional potent inhibition of CYP2C9. No change in safety or tolerability was observed when sildenafil was coadministered with either protease inhibitor. However, given the extent of the interactions, a lower sildenafil starting dose (25 mg) should be considered for patients receiving saquinavir and it is recommended not to exceed a maximum single dose of 25 mg in a 48 h period for patients receiving ritonavir.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 25/01/20 alle ore 18:54:24