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Antimicrobial Agents and Chemotherapy, February 2009, p. 609-614, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.00769-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Drug-Drug Interaction Study of Ketoconazole and Ritonavir-Boosted Saquinavir{triangledown}

Benoite Kaeser,1 Hagen Zandt,1 Fabrice Bour,3 Elke Zwanziger,1 Christophe Schmitt,1 and Xiaoping Zhang2*

Hoffmann-La Roche, Ltd., Basel, Switzerland,1 Hoffman-La Roche, Inc., Nutley, New Jersey,2 Institut de Pharmacologie Clinique, Roche, Strasbourg, France3

Received 12 June 2008/ Returned for modification 28 September 2008/ Accepted 8 November 2008

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 Cmax and the area under the concentration-time curve from 0 to 12 h (AUC0-12) of saquinavir and ritonavir with or without ketoconazole were not substantially altered after 2 weeks of concomitant dosing with ketoconazole. The Cmax and AUC0-12 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.

* Corresponding author. Mailing address: Department of Clinical Pharmacology, Hoffmann-La Roche, Inc., 340 Kingsland St., Nutley, NJ 07110. Phone: (973) 235-6584. Fax: (973) 235-5635. E-mail: xiaoping.zhang{at}roche.com

{triangledown} Published ahead of print on 17 November 2008.

Antimicrobial Agents and Chemotherapy, February 2009, p. 609-614, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.00769-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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