Abstract: Efavirenz (EFV) significantly decreases the AUC of amprenavir (APV). The addition of a second PI to prevent this reduction was evaluated.

19 PI-experienced HIV+ patients with plasma HIV RNA > 500 were enrolled into 3 treatment groups: (1) APV 1200 mg po BID, ritonavir (RTV) 200 mg po BID + EFV 600 mg po QD (n = 6); (2) APV 1200 mg po BID, RTV 500 mg po BID + EFV 600 mg po QD (n = 4); and (3) APV 1200 mg po BID, nelfinavir (NFV) 1250 mg po BID + EFV 600 mg po QD (n = 9). Sampling for APV concentrations was performed at steady-state on APV alone (groups I & 2) and with dual Pls and after the addition of EFV (all groups).

RTV increased the AUC of APV 2.5-fold and the C_{min} by over 400% (Table; mean±SD). No differences were noted between the low- and high-dose RTV regimens. Similarly, NFV increased APV AUC by 1.6-fold and Cmin by 200%. The addition of EFV to the dual-PI regimens did not alter APV PK.

Regimens were well tolerated although more diarrhea occurred in the NFV group.

The addition of RTV or NFV markedly increased APV levels, and these increased levels are unaffected by concomitant EFV. These data suggest that a once-daily regimen of RTV and APV will be effective.
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Pharmacokinetic (PK) Drug-Interaction between Amprenavir (APV) and Ritonavir (RTV) in HIV-Seronegative Subjects after Multiple, Oral Dosing.

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.

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.

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.

POSTER

*all AUCs are given for a 24-hour period to facilitate comparisons of bid & qd regimens

The authors said the APV 600/RTV 100 mg bid and APV 1200/RTV 200 mg qd regimens are being investigated further in ongoing and planned clinical trials for antiviral efficacy and safety.