December 18, 2001
Amprenavir is a potent protease inhibitor with unique resistance characteristics, but the current formulation involves extremely large 250mg gel caps, and the standard dose of 1,250mg twice a day. The materials used in the gel caps may in fact cause most of the gastrointestinal (GI) side effects.
Boosting amprenavir with ritonavir yields two advantages. One is a decreased pill burden -- from eight pills twice a day to five pills twice a day. The other, and perhaps the most important, is a ten-fold increase in the trough levels with little increase in AUC or side effects. This may allow amprenavir to be active against a variety of protease-inhibitor-resistant viruses, and may influence the resistance pathway.
ESS40006 is a four-arm study that randomized patients failing protease inhibitor therapy to two doses of boosted amprenavir (600mg/100mg or 900mg/100mg) and then assigned them to either an efavirenz arm if NNRTI naive, or tenofovir if NNRTI experienced. Pharmacokinetic studies (PK) were included. This was of interest because of the experience with lopinavir/ritonavir (Kaletra), where the use of efavirenz results in a significant drop in lopinavir levels, despite ritonavir boosting. In addition, drug interactions with tenofovir are still being worked out.
The study enrolled a truly experienced population who had been on some antiretrovirals for a median of almost five years, and the median time on protease inhibitors was 40 months (over three years!). The protocol required that the virus have phenotypic sensitivity to amprenavir. Of those with genotype available, 86 percent had protease and reverse transcriptase (RT) mutations, 3 percent had protease mutations alone, 48 percent had NNRTI resistance mutations and 3 percent had wild-type sequences.
The primary efficacy analysis was defined as intent-to-treat, observed (different from missing equals failure). At 24 weeks, roughly 70 percent of patients had viral loads below 200 copies and no major difference was found between the two amprenavir doses.
This is probably explained by the fact that the amprenavir levels (peak, AUC and Cmin) did not vary significantly between the two arms. This suggests -- as have other studies with amprenavir and its pro-drug, 908 -- that the ability to raise amprenavir levels with ritonavir is fairly maximal at 600mg and additional amprenavir (or 908) may not make much difference. Interestingly, the addition of Sustiva did not lower amprenavir levels in this study.
A fascinating observation was that the higher amprenavir dose caused considerably more nausea and vomiting. This could mean that the materials used to create the gel cap and allow the amprenavir to be absorbed (the excipients) cause much of the nausea. This may mean that 908 will prove to be much better tolerated -- trials are underway. Similar data were presented for ritonavir and saquinavir at the European meetings, where the fortavase preparation caused more nausea and vomiting than the invirase preparation.
The clinical implication of this study is threefold. First, if phenotype shows susceptibility to amprenavir, a boosted amprenavir regimen may be very active in multiple protease-inhibitor-experienced patients, if another new drug can be added. Second, it appears that the addition of tenofovir may support the salvage protease inhibitor as well as a non-nucleoside does in experienced patients, but we will need to see much more data. Third, this seems to confirm that for ritonavir-boosted amprenavir regimens, there may be no benefit in using more than 600mg. Lastly, it may be that the big, ugly gel cap formulations (fortavase, agenerase and perhaps tipranavir) are not only hard to swallow, but hard to tolerate and that, in boosted regimens, simpler formulations might be helpful.
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