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

2 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 Cmax and AUC0-12 of saquinavir and ritonavir with and without ketoconazole were not substantially altere