Amprenavir

Amprenavir is an antiretroviral drug used to treat HIV/AIDS. It is branded under the tradename Agenerase.

Glaxo began marketing Agenerase in April 1999. However, in October 2007, sales of the 50mg capsules and the liquid version of Agenerase were halted in favor of a new preparation called Lexiva.



Uses
Amprenavir is used to treat HIV infection in patients over four years of age. It is typically prescribed in combination with other anti-HIV medications in what is commonly known as a "drug cocktail".

Amprenavir is not a cure for HIV infection or AIDS; thus, symptoms and complications of HIV infection and AIDS may still develop in patients taking amprenavir. Moreover, the drug does not prevent transmission of HIV to others through sexual contact or blood transfusion.

How Amprenavir is Taken
Amprenavir is available in 50 mg capsules as well as a 15 mg/ml oral solution.

If taken alone, the typical dose is 1200 mg taken twice a day. More commonly, however, amprenavir is given in combination with another antiretroviral. In combination with ritonavir (Norvir), the dose is only 1200 mg once a day.

Amprenavir is given at a dose of 20 mg/kg twice daily (up to a maximum daily dose of 2400 mg) in patients weighing less than 110 pounds (50 kg), or who are between 13 and 16 years of age. Dosing is also reduced in patients with liver damage.

How Amprenavir Works
Amprenavir belongs to a class of drugs known as protease inhibitors. Protease inhibitors, as their name suggests, act by inhibiting enzymes called proteases. Proteases are enzymes essential for successful viral replication inside human cells.

Amprenavir inhibits the HIV-1 protease which, in turn, slows the progress of HIV infection by interfering with a critical step in the replicating cycle of the virus (see video below).

Resistance to amprenavir develops due to HIV mutation. These mutations cause changes in the structure of the protease which, in turn, prevents amprenavir from effectively binding to and inhibiting the protease.

How the Body Affects Amprenavir
Amprenavir is taken orally and levels peak approximately 1-2 hours after dosing.

The liver metabolizes amprenavir through an enzyme called CYP3A4. Consequently, moderate or severe liver damage increases circulating levels of amprenavir. Naturally, amprenavir is given at a reduced dose in patients with liver damage.

Most of the products of the aforementioned liver metabolism are excreted in the feces. The time needed for the circulating levels of amprenavir to be reduced by half (what is known as the "half-life") is approximately 7-10 hours.

Although amprenavir can be taken with food, high-fat meals reduce the absorption of amprenavir.

Side Effects
Common side effects of amprenavir use include the following:


 * Skin rash
 * Nausea
 * Vomiting
 * Diarrhea
 * Tingling sensation in the limbs and/or around the mouth
 * Fatigue
 * Changes in mood

In most cases, these reactions are manageable without stopping treatment. However, some serious complications have been reported. Severe or life-threatening rashes, including cases of Stevens-Johnson syndrome, have occurred in approximately 1% of patients taking amprenavir. In rare cases, patients can develop diabetes and/or develop fat redistribution.

Risks and Precautions
To reduce the risk of the virus developing resistance, amprenavir is often prescribed with other anti-HIV drugs.

Amprenavir is known to exacerbate symptoms of certain other diseases. It can increase blood sugar levels (hyperglycemia) and cause diabetes in rare cases. Consequently, dosing of diabetic medications are sometimes adjusted while taking amprenavir.

Amprenavir can also exacerbate bleeding in hemophilia. The Agenerase preparation of amprenavir contains more than the recommended daily allowance of vitamin E. Therefore, this preparation can interfere with blood-thinning medications, or exacerbate the symptoms of vitamin K deficiency. Because of this vitamin E content, supplementation with vitamin E during treatment with Agenerase is generally not indicated.

Amprenavir is a sulfonamide. Allergic reactions that occur during treatment with other sulfonamide drugs may also occur with amprenavir.

The effects of amprenavir on the developing fetus are not known. Amprenavir is only used in pregnancy if the benefits outweigh the risks. However, the oral solution of amprenavir is not used during pregnancy because it contains propylene glycol, a chemical that is harmful to the fetus. Breast-feeding is avoided during treatment because amprenavir, and the HIV infection itself, could be passed to the infant.

Because of the interaction with oral contraceptives, other forms of contraception (condoms, diaphragm) are used during treatment with amprenavir.

Drug Interactions
As discussed earlier, the CYP3A4 enzyme metabolizes amprenavir; however, CYP3A4 is also responsible for the metabolism of many other drugs. This shared metabolism has the potential to cause drug interactions. The potential for drug interactions is increased even further because amprenavir also inhibits the activity of the CYP3A4 enzyme. Consequently, numerous drug interactions with amprenavir have been reported.

Because of the risk of serious side effects, amprenavir is generally not given with the following drugs:


 * Astemizole (Hismanal)
 * Bepridil (Vascor)
 * Cisapride (Propulsid)
 * Ergot derivatives (Cafergot and others)
 * Midazolam (Versed)
 * Triazolam (Halcion)

Close patient monitoring and/or dose adjustments have been recommended when amprenavir is given with drugs such as:


 * Amiodarone (Cordarone)
 * Felodipine (Plendil), nifedipine (Adalat)
 * Cyclosporine (Neoral)
 * Warfarin
 * Ketoconazole (Nizoral)
 * Atorvastatin (Lipitor)
 * Rifabutin (Mycobutin)
 * Sildenafil (Viagra)

On the other hand, anticonvulsants such as carbamazepine (Tegretol) and phenytoin (Dilantin) increase the activity of CYP3A4 and may reduce the effectiveness of amprenavir.

Amprenavir is more effective when taken one hour before or after antacids.

Some have advocated consuming grapefruit juice to increase the availability of amprenavir. However, studies have shown that, unlike other drugs metabolized via CYP3A4, grapefruit juice does not affect circulating levels of amprenavir.

Effectiveness
When taken in combination with other anti-HIV drugs, amprenavir is very effective at reducing the "viral load" or level of circulating virus. One study showed that 1200 mg amprenavir taken daily with lamivudine (Pivir) and zidovudine (Retrovir) significantly reduced viral load in 86% of patients after 60 weeks of treatment.

Alternatives
Glaxo, the manufacturer of Agenerase, has created a new drug called fosamprenavir (which is marketed under the tradename Lexiva). Fosamprenavir is the "pro-drug" form of amprenavir, which means that fosamprenavir is converted into amprenavir in the body. The advantage of taking a pro-drug like fosamprenavir is the reduced dosing requirements.

Protease inhibitors other than amprenavir and fosamprenavir are available on the market as well. In addition, other classes of antiretroviral drugs are available, including non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, and fusion inhibitors.