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Pharmacokinetic (PK) Drug-Interaction between Amprenavir (APV) and Ritonavir (RTV) in HIV-Seronegative Subjects after Multiple, Oral Dosing B. M. SADLER*1, P. J. PILIERO2, S. L. PRESTON2, L. YU1, and D. S. STEIN1.
1Glaxo Wellcome, Inc., Res. Triangle Park, NC; and 2Albany Med. Coll., NY Introduction: APV and RTV are both inhibitors of HIV-1 protease. RTV is a potent inhibitor of CYP3A4 and is used to increase the plasma concentrations of other PIs.
Objective: To determine the interaction of APV and RTV.
Methods: In the first Phase I, multiple-dose, open-label, randomized, two-sequence, cross-over study, 18 healthy, adult volunteers (10 M, 8 F) were randomized to receive either 300mg RTV q12h or 450mg APV q12h for 7 days. All subjects then received 300mg RTV + 450mg APV q12h for 7 days. Serial PK samples were obtained at steady-state (SS) for both drugs alone (Day 7) and in combination (Day 14). The second study is of similar design and uses RTV 100mg q12h.
Results: Of the 18 subjects in the first study, 7 had nausea/vomiting, 9 had diarrhea, and 3 had rashes. One of the subjects with a rash withdrew secondary to rapid progression with mucosal involvement. Five subjects had oral numbness while on APV+RTV, none was seen when APV or RTV was given alone. Elevated triglycerides and LFTs were observed during treatment with RTV alone, but not APV alone. The addition of RTV to APV resulted in elevations similar to those observed on RTV alone. Lower doses of RTV may be necessary to minimize these effects. The addition of APV to RTV resulted in no additional elevations in these parameters. RTV caused 9% (ratio=1.09), 238% (ratio=3.38), and 1325% (ratio=14.25) increases in the SS Cmax , Cavg , and Cmin of APV, respectively. APV did not affect RTV PK. Individual PK data were fit with a 2-compartment, first-order, open model with a lag time. Median fitted parameters simulated q12h and q24h regimens for APV. The effect duration was modeled as having a conservative 12h duration. The modeled exposures indicate that APV can be given once daily with Cmin at or above those for 1200 mg APV BID alone. PK, laboratory, and safety data on the effects of 100mg q12h doses of RTV will be presented.
Conclusions: RTV causes a clinically significant increase in APV exposure. Elevations in triglycerides and LFTs were observed on RTV and not on APV. Clinical safety and efficacy data are not available on the simulated regimens. Further modeling will be used to optimize the dose of RTV in APV regimens.
Key Words: amprenavir, interaction, ritonavir
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