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.Saquinavir, a potent human immunodeficiency virus (HIV) protease inhibitor, is extensively metabolized by cytochrome P450 (CYP3A4; see the product information for Invirase capsules and tablets [Hoffman-La Roche, Inc.]). For the antiretroviral combination treatment of HIV-infected patients, saquinavir is coadministered with ritonavir, another HIV protease inhibitor and strong CYP3A4 inhibitor (see the product information for the Norvir 100-mg capsule [Abbott Laboratories]), to boost the exposure of saquinavir. The new dosage form of saquinavir (Invirase), a 500-mg film-coated tablet, was approved in 2004 in the United States and 2005 in Europe and allows a lower pill burden using the dosing regimen of saquinavir/ritonavir at 1,000/100 mg twice daily, which was approved in 2003. Saquinavir exhibits a pronounced food effect, and patients are advised to take saquinavir with ritonavir always with a full meal (according to the product information for Invirase capsules and tablets [Hoffman-La Roche, Inc.]). The imidazole antifungal compound ketoconazole is effective in the treatment of oropharyngeal c...