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Antimicrob. Agents Chemother. doi:10.1128/AAC.00769-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Drug-Drug Interaction Study of Ketoconazole and Ritonavir-boosted Saquinavir

Hoffmann-La Roche Ltd, Basel Switzerland; Hoffman-La Roche Inc, Nutley New Jersey, USA; Institut de Pharmacologie Clinique, Roche, Strasbourg, France

^* To whom correspondence should be addressed. Email: Xiaoping.zhang{at}roche.com.

	Abstract

Saquinavir, a potent HIV protease inhibitor, is extensively metabolized by CYP3A4. Saquinavir is co-administered 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 1000/100 mg twice daily and ketoconazole 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. 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 AUC_0-12 of saquinavir and ritonavir with and without ketoconazole were not substantially altered after two weeks of concomitant dosing with ketoconazole. The C_max and AUC_0-12 of ketoconazole, dosed 200 mg once daily, were increased by 45% (90% confidence interval: 32% to 59%) and 168% (90% confidence interval: 146% to 193%), respectively, after two weeks of concomitant dosing with ritonavir-boosted saquinavir (1000 mg saquinavir/100 mg ritonavir 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 (1000/100 mg twice daily) is required when co-administered with 200 mg ketoconazole once daily and high doses of ketoconazole (> 200 mg/day) are not recommended.