AMPRENAVIR (Agenerase).

Amprenavir is supplied in 50 mg and 150 mg capsules. The 150 mg soft, gelatin capsule is large, cream-white, oblong and imprinted with "GX CC2" on one side. The drug is also available as a flavored solution.

"Agenerase is one of the most dramatic examples to date of drugs that are created by structuring their molecular shape to optimize their disease-fighting capability. This form of drug design, which relies heavily on three-dimensional computer imaging, allowed Vertex to come up with Agenerase in two years, rather than the six years it normally takes before a drug is ready to test in humans."

--The Wall Street Journal, April 16, 1999

"I can actually feel them explode when they hit my stomach."

--a constituent of The Center for AIDS on taking Agenerase (discussed at a Treatment Mixer)

Also known as: APV, AMP, 141W94

Background and description. Amprenavir received approval from the US Food and Drug Administration (FDA) in April 1999. The drug was discovered and initially developed by Vertex Pharmaceuticals and is now manufactured and distributed by Glaxo Wellcome. Amprenavir is a protease inhibitor recommended for use in combination with other antiretrovirals for the treatment of HIV infection.

Guidelines classification. The Panel on Clinical Practices for the Treatment of HIV Infection classifies amprenavir as an "alternative" protease inhibitor.

Dose. The recommended dose of amprenavir is 1200 mg (eight 150 mg capsules) twice a day.

Food restrictions. Amprenavir may be taken with or without food, although a high-fat meal decreases the drug's absorption and should be avoided. Patients taking amprenavir should not take supplemental vitamin E, since the drug's vitamin E content exceeds the recommended daily allowance; however, continued use of multivitamins is safe.

Storage. Capsules and solution should be stored at a room temperature of 68 [degrees] to 77 [degrees] F.

Side effects and toxicity. The side effects most frequently associated with amprenavir therapy are gastrointestinal intolerance (nausea, vomiting, diarrhea), rash, perioral paresthesia (numbness around the mouth) and hyperglycemia. Hemophiliacs may experience increased bleeding. Additionally, Stevens-Johnson syndrome, a life-threatening skin reaction, may occur in 1% of treated patients. Amprenavir therapy should be discontinued in patients with this syndrome and those with moderate rashes accompanied by systemic symptoms. Amprenavir should only be used during pregnancy if potential benefit outweighs risk. Data are incomplete and animal studies show adverse effects on the fetus. Metabolic (lipid and glucose) and morphologic (fat accumulation and fat atrophy) abnormalities have been associated with protease inhibitors in general.

Drug interactions. Amprenavir should not be given concurrently with bepridil (Vascor), cisapride (Propulsid), dihydroergotamine (DHE 45), ergotamine (Ergostat), midazolam (Versed), triazolam (Halcion), rifampin (Rifadin, Rimactane) and the lipid-lowering agents simvastatin (Zocor) and lovastatin (Mevacor). Lipid-lowering drugs such as atorvastatin (Lipitor), pravastatin (Pravachol) or fiuvastatin (Lescol) should be used with caution. When administered concomitantly with amprenavir, the dose of rifabutin (Mycobutin) should be reduced by half Sildenafil (Viagra) blood concentrations may be significantly raised in the presence of amprenavir and dose reductions to 25 mg within a 48-hour period are recommended. There is also a potential for metabolic interactions with oral contraceptives; alternative or additional methods are recommended.

The interactions between amprenavir and nevirapine (Viramune) or amprenavir and delavirdine (Rescriptor) are not yet known. The amount of amprenavir in the blood may be reduced by up to 36% in the presence of efavirenz (Sustiva). When combined with efavirenz, an adjusted 1200 mg dose 3 times a day is recommended. Alternatively a dose of 1200 mg of amprenavir with 200 mg ritonavir (Norvir) twice a day may be used. Because of potential problems with drug absorption, amprenavir should be taken at least 1 hour before or after an antacid or didanosine (Videx).

Resistance and cross-resistance. Resistance to amprenavir is associated with mutations at positions 50, 54, 82 and 84. The mutation at position 50 is associated with high-level resistance.

Clinical data. PROAB3001 is a double-blind, placebo-controlled study in which investigators randomized 232 treatment naive patients to a regimen of amprenavir/zidovudine (Retrovir)/lamivudine (Epivir) or to zidovudine/lamivudine. At week 24, using the conservative intent-to-treat method of analysis, almost half (47%) of the subjects in the amprenavir containing arm had withdrawn from study for toxicity or other reasons or for virologic failure. Data at week 24 show that 53% had viral loads less than 400 copies/mL versus 11% in the lamivudine/zidovudine arm.

PROA3006 is a randomized, open-label study in which investigators assigned 504 treatment experienced patients to a regimen of amprenavir/ NRTIs or indinavir/NRTIs. These patients were NNRTI experienced, but naive to protease inhibitors. After 24 weeks of therapy, 43% of' subjects in the amprenavir containing arm had achieved viral loads less than 400 copies/mL. Among patients in the indinavir containing arm, 53% achieved the same result.

Patient assistance. For those who qualify, Glaxo Wellcome offers a patient assistance program. For more information, call 800.722.9294.