February 10, 2004
These interactions are the very basis for the use of ritonavir (RTV, Norvir) boosting. Ritonavir blocks the metabolism of other protease inhibitors (PIs), enabling them to be used with fewer doses and fewer pills.
An additional potential consequence of boosting is the ability to boost, or increase the drug levels of PIs. These higher drug levels can translate into increased potency of the drugs, a critically important issue for the treatment of persons with drug-resistant HIV. For these persons, the use of ritonavir-boosted PIs has offered hope of achieving the grail of an undetectable viral load, and immune system health. Unfortunately, some patients have virus that is so resistant to PIs, that the conventional use of boosted PIs is insufficiently potent. This is often the case in my clinic, where I take care of a number of people with highly-resistant virus. Having as potent a combination as possible is essential for these persons, particularly, if we're thinking about using the new fusion inhibitor drug called enfuvirtide (T-20, Fuzeon).
This is where the concept of dual-boosted PIs comes in. We've had experience using two full-dose PIs in the past, with regimens that were composed of ritonavir and saquinavir (SQV, Invirase, Fortovase), but these regimens were difficult to take because of high pill burden and side effects. The availability of ritonavir coformulated with the PI lopinavir (LPV) as Kaletra, and the recent approval of the newer, very low pill count PIs -- atazanavir (ATV, Reyataz) and fosamprenavir (908, Lexiva) -- provides an opportunity to construct low pill count, and potentially very potent, dual-boosted PIs. This promise is particularly important for some drug-resistant patients who have a glint of drug sensitivity to amprenavir (APV, Agenerase).
The two studies discussed here address issues related to the administration of fosamprenavir with lopinavir/ritonavir. Normally, two pills of fosamprenavir are combined with ritonavir once- or twice-daily for boosting; lopinavir/ritonavir's dose is normally three pills twice-daily. If everything were simple, we'd expect that patients would simply take two pills of fosamprenavir with three pills of lopinavir/ritonavir, right? Unfortunately, it turns out that all three PIs appear to interact with one another. In a study presented by the AIDS Clinical Trials Group last fall at the ICAAC meeting, it was found that the drug levels of fosamprenavir and lopinavir were unexpectedly and dramatically reduced -- meaning that there wouldn't be enough of the drugs in the blood to be effective in stopping HIV. These studies explore ways to figure out just how to adjust the doses of these PIs.
The first study, by Corbett and colleagues from the University of North Carolina (Poster 611) examined the strategy of separating the dose of the two medications. Study subjects either took the medications at the same time or separated by four or 12 hours (the later with an extra 200 mg of ritonavir). The results of this study showed that the dose separation strategy corrected the drug levels of lopinavir, but, unfortunately, did not improve the levels of amprenavir in the dual-boosted regimen.
The second report, from Wire and colleagues from GlaxoSmithKline, the makers of fosamprenavir (Poster 612), looked at the use of different doses of fosamprenavir and lopinavir/ritonavir as a way to offset the metabolism issues. In this study, two new doses of the two medications were compared to the typical dose (and drug levels) of ritonavir-boosted fosamprenavir. The first regimen looked at 1,400-mg fosamprenavir (two pills) with 533/133 mg of lopinavir/ritonavir (four pills), all taken twice a day. The second evaluated 1,400-mg fosamprenavir (two pills) with 400/100 mg of lopinavir/ritonavir (three pills) with an additional 100 mg of ritonavir (one pill), all taken twice a day. Overall, the regimens were poorly tolerated, even in these healthy, HIV-negative persons. Elevations in cholesterol and triglyceride (lipid) levels were frequent.
After all of the blood sampling and analysis, the authors concluded that the increased doses of pills did increase the amprenavir levels, but the levels were still lower than had been seen in previous boosted studies; the lopinavir levels were maintained at their expected levels. They concluded that no specific recommendations about the dosing of fosamprenavir and lopinavir/ritonavir could be made.
So where does this leave us? The answer, I think depends on the patient. For those who have HIV with only limited drug resistance, there are a number of well-defined treatment options, with well-defined drug interactions (or lack thereof). For these persons, I would definitely not recommend the use of unproven dual-boosted PIs.
For persons with highly drug-resistant virus, the story, and the stakes are enormously different. In these circumstances, we sometimes cannot wait for the optimal scientific data sets to guide treatment -- doctors and patients are forced to make the best educated guesses, based on the best available studies. The later study, by Wire, provides a framework for thinking about how to use fosamprenavir with lopinavir/ritonavir, even if it is not an optimal regimen for patients. It is clear that the combination is not great with regards to side effects and its effect on lipid levels, but it might be essential, or even immune system saving, for the person whose virus only has some susceptibility to fosamprenavir and/or lopinavir, when combined with enfuvirtide. Because of the uncertain and uncharted waters of these regimens, I would request therapeutic drug monitoring tests to make sure the drugs that the patient was taking were achieving sufficient blood levels.
Abstract: Dose Separation Strategies to Overcome the Pharmacokinetic Interaction of a Triple Protease Inhibitor Regimen Containing Fosamprenavir, Lopinavir and Ritonavir (Poster 611)
Authored by: A. H. Corbett, L. Davidson, J. J. Park, K. Patterson, J. J. Eron, L. Ngo, M. L. Lim, M. Shelton, M. B. Wire, A. D. M. Kashuba
Affiliations: Chapel Hill, NC; Res. Triangle Park, NC
Abstract: The Pharmacokinetic Interaction Between GW433908 With Lopinavir/Ritonavir (APV10011 and APV10012) (Poster 612)
Authored by: M. B. Wire, O. J. Naderer, A. L. Masterman, Y. Lou, D. S. Stein
Affiliations: GlaxoSmithKline, Research Triangle Park, NC; GlaxoSmithKline, Montreal, Quebec, Canada
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