Amprenavir, New Protease Inhibitor, Approved
The protease inhibitor amprenavir (Agenerase(tm)) was approved for marketing by the FDA on April 16. This approval was based on two 24-week controlled trials in adults, plus safety data in over 1,400 patients, under the FDA's accelerated-approval regulations. Amprenavir is also approved for children age 4 and above, based on pharmacokinetic studies in 84 children from ages 4 to 12.Amprenavir is taken twice a day, with or without food, but it should not be taken with a high-fat meal, as that would decrease the absorption of the drug.
The most common side effects are gastrointestinal (nausea, vomiting, and/or diarrhea), rashes, and oral paresthesia (a tingling sensation around the mouth). Patients should know that severe or life-threatening rash has occurred is 1% of recipients (4% of those who develop a rash), and that "amprenavir therapy should be discontinued for severe or life-threatening rashes and for moderate rashes accompanied by systemic symptoms" (quoted from the FDA's official labeling of the drug, which will be printed in the Physician's Desk Reference). Pregnant women should not use amprenavir unless it is medically necessary, because of concern about harm to the fetus in some animal tests (there are no human data). Also, several prescription drugs must not be taken with amprenavir, and several others require blood tests to monitor drug levels. Patients should receive written information about amprenavir, including these and other precautions, from their physician or pharmacist.
Amprenavir was developed by Vertex Pharmaceuticals Inc., using modern technology of rational drug design, and is being marketed by Glaxo Wellcome. It is the first new HIV protease inhibitor approved in more than two years.
Potential Advantages
Based on laboratory tests, Glaxo Wellcome has suggested that amprenavir may have certain advantages, but only clinical trials and clinical experience will tell if these possibilities are real for patients.
Studies of lipid biochemistry have suggested that amprenavir may be less likely than other protease inhibitors to be associated with certain problems of lipid metabolism (see AIDS Treatment News #315, March 19, 1999). No one knows today whether there will be a practical difference for patients, since these problems became prominent only after protease inhibitors had been used for some time. The labeling for amprenavir notes one case in which a "buffalo hump" did develop in a patient taking amprenavir plus other antiretrovirals in a clinical trial. However, there have been some such cases in persons who have never taken a protease inhibitor, or never taken antiretrovirals at all.
Amprenavir may have a different resistance profile from other protease inhibitors--which might or might not mean less problem with cross resistance. But it is not known at this time how much persons who have become resistant to other protease inhibitors could benefit from amprenavir--or conversely, whether those who start with amprenavir and become resistant to it can use the other protease inhibitors effectively. (One of the two efficacy trials on which amprenavir approval is based was in treatment-experienced patients; however, they were protease-inhibitor-naive, so the issue of cross resistance was not studied.)
In laboratory tests, amprenavir appears to be synergistic with abacavir (Ziagen(tm)), another Glaxo drug, meaning that they might work well together. But there is a practical problem with the combination, especially if the two drugs are started at about the same time--for if a serious drug reaction occurs and both drugs must be stopped, there may not be any way to determine which of them caused the problem.
Comment
Amprenavir is important because it provides an additional treatment option. The trial which compared it with indinavir found that, on the average, the two drugs were comparable, although the patients taking indinavir were somewhat more likely to have their viral load go below the 400-copy cutoff used in that study.
But no individual is average, as people vary greatly in which drugs will or will not work for them. Each new option means that some patients will be able to be treated effectively when otherwise they could not be. Unfortunately it is still hard to predict which drugs will likely work safely for a particular patient, so the process is often one of trial and error.
