Published in the Bulletin of Experimental Treatments for AIDS January 1999 issue, by the San Francisco AIDS Foundation.

January 1999 Table of Contents

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DRUG WATCH: Amprenavir -- A New Protease Inhibitor Nears Approval

Liz Highleyman

Amprenavir (brand name Agenerase) is a second-generation protease inhibitor that was discovered by Vertex Pharmaceuticals and has been clinically developed by Glaxo Wellcome. Earlier in its development, the drug was known variously as 141, 141W94, and VX-478. Amprenavir is awaiting regulatory approval in the U.S. and Europe, and is now available in the U.S. through an expanded access program.

Amprenavir is taken twice daily, either with food or on an empty stomach. The optimal dose for most people appears to be 2,400 mg daily, made up of eight 150 mg capsules twice daily; the dose is adjusted for those weighing less than 50 kilograms. There is also a liquid formulation for children.

The drug has shown promising results in human testing and appears to be a potent inhibitor of HIV replication. Early data also indicate that amprenavir can penetrate the blood/brain barrier and enter the central nervous system (brain and spinal cord), suggesting that it may be beneficial for people with HIV-related cognitive impairment (dementia).

Results from Recent Conferences

Amprenavir has been studied in Phase II and Phase III clinical trials that have included over 1,500 people, both adults and children. Researchers have looked at amprenavir in combination with several other drugs.

At the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in September 1998, and again at the 4th International Congress on Drug Therapy in HIV Infection in Glasgow in November 1998, Jeffrey Goodgame, MD, and colleagues presented data from Protocol 3001, an international, multicenter study of amprenavir/AZT/3TC. Two hundred and thirty-two antiretroviral-naive participants were randomized into the study, and 221 of these received treatment. An as-treated analysis showed that 88% of participants (65 of 74) taking the three-drug combination achieved an undetectable viral load (limit of detection 400 copies/mL) at 16 weeks, compared to 19% (17 of 90) of those taking AZT/3TC alone. Using a more conservative intent-to-treat analysis, 67% of participants (56 of 83) on the three-drug regimen achieved an undetectable viral load at 24 weeks using a more sensitive viral load test with a limit of detection of 50 copies/mL, compared to 10% (16 of 93) of those taking AZT/3TC alone. (For an explanation of as-treated and intent-to-treat, see BETA, October 1998.)

Also at the 1998 ICAAC, John Bilello, PhD, and colleagues presented data showing that there is synergy between amprenavir and the newly-approved nucleoside analog abacavir. Synergy is an effect greater than the expected additive effects of two or more drugs used together. The researchers analyzed various protease inhibitor/nucleoside analog pairs in the laboratory to determine their relative potency, and found that amprenavir appears to be more potent when used with abacavir than when used with other nucleoside analogs. The combination also appears promising in clinical trials. In a study presented by Pierre-Alexander BART, MD, and colleagues at the 12th World AIDS Conference in June 1998, eight of nine participants who received the amprenavir/abacavir combination had an undetectable viral load (limit of detection 50 copies/mL) after 48 weeks (see BETA, October 1998).

Side Effects and Drug Interactions

Amprenavir appears to be generally well-tolerated. The most commonly reported side effects are nausea, vomiting, diarrhea, intestinal gas, fatigue, headache, skin rash, and tingling around the mouth (circumoral paresthesia).

A growing concern regarding protease inhibitors is the increase in blood fat levels and the redistribution of body fat seen in many people taking these drugs. In Goodgame's study, participants receiving amprenavir did not have a significantly higher incidence of elevated cholesterol or triglyceride levels than those receiving AZT/3TC alone. No cases of central obesity ("protease paunch") or dorsocervical fat pad ("buffalo hump") have been seen so far; however, no such cases were reported in early studies of the approved protease inhibitors either.

Like the approved protease inhibitors, amprenavir is metabolized by the CYP3A isoenzyme, part of the liver's CP450 system. As such, it interacts with several other drugs, including rifampin and rifabutin (used to treat tuberculosis), certain heart medications and antihistamines, antibiotics of the erythromycin family (macrolides), and methadone. The drug's pharmacokinetic profile suggests that it may also interact with tricyclic antidepressants, which some people use to manage the symptoms of peripheral neuropathy.

Resistance and Cross-Resistance

Researchers have been trying to develop new protease inhibitors that have less cross-resistance with existing drugs in this class, so that the new drugs may be used by people for whom other protease inhibitor-based regimens have failed. Some early results suggest that amprenavir is less cross-resistant than the approved protease inhibitors, due to a unique resistance mutation profile, but other studies have not found this to be the case.

According to representatives from Vertex, it appears that resistance to amprenavir is conferred by mutations at positions 50 and 54 of the gag (core) gene.

Results of trial ACTG 373, presented at the Glasgow meeting by Robert Murphy, MD, and colleagues, showed that 70-90% of 55 people who took a four-drug indinavir-containing regimen (indinavir/nevirapine/d4T/3TC) after taking an amprenavir-containing regimen had viral loads of less than 500 copies/mL after 8-44 weeks, suggesting that amprenavir use does not rule out the subsequent use of other protease inhibitors due to cross-resistance.

Other results presented at the same meeting suggest that the use of amprenavir as part of a salvage regimen is less promising. Joseph Eron, MD, and colleagues presented preliminary data from a study of 99 participants who had switched to a regimen of amprenavir/abacavir/efavirenz after their previous protease inhibitor-containing regimen had failed. After 16 weeks, between 7% and 53% had achieved a viral load below the limit of detection of 400 copies/mL, depending on prior treatment and baseline viral load (see "Highlights from Recent Conferences").

Current Status: Expanded Access and Approval

In September 1998, Glaxo Wellcome began enrolling people into its amprenavir expanded access program. The program has three options. Participants may enroll in an open-label clinical trial to determine the drug's effect on body fat metabolism in people who are already experiencing body fat changes or high blood fat levels on their current protease inhibitor regimen, or in an open-label study to evaluate amprenavir in combination with other protease inhibitors. The drug is also available on expanded access to people whose current antiretroviral regimen is failing or who cannot tolerate their current drugs, and who need amprenavir to construct a viable regimen. For all options, participants must have received prior treatment with another protease inhibitor. To enroll patients in the expanded access program, physicians should call 800-248-9757; all enrollments must be done through a physician.

In October 1998, Glaxo Wellcome filed for approval of amprenavir by the U.S. Food and Drug Administration (FDA); a similar filing for European Union approval was made in November, 1998. The FDA has given the drug "fast track" status, and a decision on approval is expected by the middle of 1999.

Liz Highleyman is Acting Editor of BETA.

References

Page last updated 15 January 1999

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