title: Drug-drug interaction study of ketoconazole and ritonavir-boosted saquinavir.
abstract: Saquinavir, a potent human immunodeficiency virus protease inhibitor, is extensively metabolized by CYP3A4. Saquinavir is coadministered with ritonavir, a strong CYP3A4 inhibitor, to boost its exposure. Ketoconazole is a potent CYP3A inhibitor. The objectives of this study were to investigate the effect of ketoconazole on the pharmacokinetics of saquinavir/ritonavir and vice versa using the approved dosage regimens of saquinavir/ritonavir at 1,000/100 mg twice daily and ketoconazole at 200 mg once daily. This was an open-label, randomized two-arm, one-sequence, two-period crossover study in healthy subjects. In study arm 1, 20 subjects received saquinavir/ritonavir treatment alone for 14 days, followed in combination with ketoconazole treatment for 14 days. In arm 2, 12 subjects received ketoconazole treatment for 6 days, followed in combination with saquinavir/ritonavir treatment for 14 days. The pharmacokinetics were assessed on the last day of each treatment (days 14 and 28 in arm 1 and days 6 and 20 in arm 2). The exposures C(max) and the area under the concentration-time curve from 0 to 12 h (AUC(0-12)) of saquinavir and ritonavir with or without ketoconazole were not substantially altered after 2 weeks of concomitant dosing with ketoconazole. The C(max) and AUC(0-12) of ketoconazole, dosed at 200 mg once daily, were increased by 45% (90% confidence interval = 32 to 59%) and 168% (90% confidence interval = 146 to 193%), respectively, after 2 weeks of concomitant dosing with ritonavir-boosted saquinavir (1,000 mg of saquinavir/100 mg of ritonavir given twice daily). The greater exposure to ketoconazole when given in combination with saquinavir/ritonavir was not associated with unacceptable safety or tolerability. No dose adjustment for saquinavir/ritonavir (1,000/100 mg twice daily) is required when coadministered with 200 mg of ketoconazole once daily, and high doses of ketoconazole (>200 mg/day) are not recommended.
authors.affiliation: Hoffmann-La Roche, Ltd., Basel, Switzerland.
authors.forename: Benoite
authors.initials: B
authors.lastname: Kaeser
authors.forename: Hagen
authors.initials: H
authors.lastname: Zandt
authors.forename: Fabrice
authors.initials: F
authors.lastname: Bour
authors.forename: Elke
authors.initials: E
authors.lastname: Zwanziger
authors.forename: Christophe
authors.initials: C
authors.lastname: Schmitt
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D000935:Antifungal Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D007654:Ketoconazole / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D019438:Ritonavir / Q000009:adverse effects / Q000493:pharmacokinetics*; D019258:Saquinavir / Q000009:adverse effects / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D000935:Antifungal Agents; D017320:HIV Protease Inhibitors; D019258:Saquinavir; D019438:Ritonavir; D007654:Ketoconazole