Pharmacokinetics of Concurrent Administration of Fosamprenavir and Atazanavir Without Ritonavir in Human Immunodeficiency Virus-Negative Subjects

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Study objective: To quantify the pharmacokinetics of amprenavir and atazanavir (administered as the prodrug fosamprenavir) alone and in combination in human immunodeficiency virus (HIV)-negative subjects.

Design: Randomized, open-label, three-way crossover study.

Setting: Research facility.

Participants: Eleven men and 10 women who were seronegative for HIV.

Intervention: Subjects were randomized to 14-day treatment periods of fosamprenavir 1400 mg once/day, atazanavir 400 mg once/day, or fosamprenavir 1400 mg plus atazanavir 400 mg once/day; after a washout period of at least 21 days between each treatment, they received the other two treatments.

Measurements and main results: Subjects underwent 24-hour pharmacokinetic sampling at baseline and on day 14 of each treatment period. Primary outcome measures were area under the plasma concentration-time curve (AUC) and maximum concentration (C(max)) for amprenavir and atazanavir. Atazanavir significantly enhanced the exposure of amprenavir. When fosamprenavir was given alone, the geometric mean of amprenavir's AUC was 20.2 microg x hour/ml (95% confidence interval [CI] 19.1-21.2 microg x hr/ml). When given in combination with atazanavir, amprenavir had an AUC of 39.8 microg x hour/ml (95% CI 38.7-40.9 microg x hr/ml). Similarly, the C(max) for amprenavir increased from 4193 ng/ml (95% CI 3927-4459 ng/ml) to 6621 ng/ml (95% CI 6427-6814 ng/ml) when given in combination with atazanavir. In contrast, AUC and C(max) for atazanavir significantly decreased when atazanavir was coadministered with fosamprenavir; AUC decreased from 17.6 microg x hour/ml (95% CI 16.6-18.7 microg x hr/ml) to 11.8 microg x hour/ml (95% CI 11.3-12.3 microg x hr/ml), and C(max) decreased from 2507 ng/ml (95% CI 2379-2635 ng/ml) to 1832 ng/ml (95% CI 1752-1911 ng/ml). Adverse events were assessed at each study visit and 1 month after the subjects completed the three treatments. Both drugs were well tolerated. One serious adverse event (grade 3 acute pancreatitis) occurred and resolved without further incident.

Conclusion: Atazanavir 400 mg/day plus fosamprenavir 1400 mg/day significantly decreased concentrations of atazanavir compared with standard dosing regimens of each drug alone. This dosing scheme is not a recommended combination of dual, fully active protease inhibitors.



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