+VE DRUGWATCH

A new pi: atazanavir

Within a few months, there is likely to be a new antiretroviral on the market. Tracy Barnes reports on the findings from clinical trials so far.

Drug Name: Atazanavir

Drug Class: Protease inhibitors (PIs)

Brand Name: Reyataz™

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How atazanavir works

Atazanavir is a new form of protease inhibitor, referred to as an azapeptide protease inhibitor. This class of drug combats viral replication of HIV by competitively inhibiting HIV’s protease protein. This protein or enzyme is used by HIV to break up large viral proteins into smaller particles from which new HIV particles can be formed. PIs ensure that these new particles are immature and incapable of infecting new cells, thus inhibiting the HIV replication process.

Combination therapy

Atazanavir is being developed in a number of possible combinations. Firsltly as an unboosted single agent, in combination with nucleoside reverse transcriptase inhibitors (NRTIs), secondly boosted with saquinavir, in combination with other antiretroviral agents and thirdly boosted with ritonavir and in combination with other antiretroviral agents.

Dosing

Dosing of atazanavir will depend on what combination it is prescribed. As an unboosted agent a 400mg daily dose will be required. In combination with saquinavir a 400mg dose alongside 1200mg saquinavir dose will be required (other doses of this combination will be investigated). Boosted with ritonavir a 300mg dose alongside 100mg ritonavir will be required. Currently no paediatric doses are recommended. An oral powder is under development. There are currently no weight-based dose adjustments for adults. All doses will be taken once daily and with food.

Dosing restrictions

Atazanavir is metabolised by the liver and moderately inhibits the CYP3A4 enzyme. Atazanavir should not be administered with any drug that has a narrow therapeutic window and is a substrate of CYP3A4. Any drug that inhibits or accelerates the metabolic process is likely to impact on the levels of atazanavir in the blood. Sub-optimal levels of atazanavir in the blood increase the risk of resistance developing. Similarly any drug that shares this metabolic pathway is likely to be affected by the co-administration of atazanavir, for this reason there are a likely to be a number of dosing restrictions or recommended dose modifications.

Non-nucleoside reverse transcriptase inhibitors:

Efavirenz: if atazanavir is to be co-administered with efavirenz, which decreases atazanavir levels, a 300 mg dose with 100mg ritonavir be co-administered with 600mg efavirenz 600 mg (all as a single daily dose with food), atazanavir without ritonavir should not be co-administered with efavirenz.

Protease inhibitors:

Indinavir: Co-administration of atazanavir and indinavir is not recommended.

Ritonavir: once daily co-administration of 300mg atazanavir and 100mg ritonavir in healthy subjects resulted in approximately a 3.4-fold increase in exposure compared to atazanavir 300mg once daily.

Saquinavir (soft gelatine capsules): a reduction in the total daily dose of saquinavir to 1,200mg once daily is recommended when 400mg atazanavir and saquinavir are coadministered.

Other medicinal products:

Antacids and medications containing buffers reduce the concentrations of atazanavir, possibly due to increased gastric pH. Atazanavir should be administered 2 hours before or 1 hour after any antacids, including buffered medications.

Calcium channel blockers:

Dose modification of diltiazem by 50% should be made when co-administered with atazanavir. No dose modification of atazanavir is necessary.

Concomitant use of atazanavir with simvastatin and lovastatin is not recommended due to an increased risk of muscle disorders.

The risk of muscle disorders may also be increased when protease inhibitors, including atazanavir are used in combination with atorvastatin or cerivastatin.

Stomach acid inhibitors:

Drugs that inhibit stomach acids such as lansoperazole (Zoton®) reduce concentrations of atazanavir and should be co-administered with caution.

Antibiotics:

A dose reduction of clarithromycin by 50% should be considered when it is co-administered with atazanavir.

Oral contraceptives:

Concentrations of active ingredients may be increased if co-administered atazaniavir. The lowest, effective dose of oral contraceptive is recommended.

Rifabutin:

No dose adjustment is needed for atazanavir. A rifabutin dose reduction of up to 75% is recommended when administered with atazanavir.

Sildenafil (Viagra®):

Sildenafil levels are increased in the presence of atazanavir, a reduced dose of sildenafil is recommended.

Warfarin:

Co-administration with atazanavir has the potential to produce serious and/or life-threatening bleeding and has not been studied. It is recommended that patients are closely monitored.

Side effects

The most common side effects of atazanavir include:

Jaundice
Headache;
Insomnia;
Abdominal pain;
Diarrhoea;
Dyspepsia;
Nausea;
Vomiting;
Rash;
Malaise/fatigue.

Some patients receiving atazanavir have experienced raised bilirubin levels, resulting in jaundice. For patients whose total bilirubin is more than 5 times normal levels alternative antiretroviral therapy to atazanavir should be considered.

Pre-existing conditions

Atazanavir is primarily metabolised by the liver. Some patients with liver impairment have experienced raised levels of atazanavir. Patients with chronic hepatitis B or C or who have marked increases in transaminase levels prior to treatment may be at increased risk of further transaminases elevations.

Patients with heart block should use atazanavir with caution and only if benefits outweigh risk.

Paediatric use

Atazanavir is not currently recommended for use in children. Studies for its use are still ongoing.

Use during pregnancy

There are no adequate and well-controlled studies of atazanavir in pregnant women. For this reason atazanavir should only be used during pregnancy if the benefits justify any potential risks.

atazanavir-resisitant HIV

In vitro studies reveal that patients who are protease inhibitor naïve and develop the 150L mutation do not develop cross-resistance to other PIs and in fact have increased sensitivity to other PIs.

Once again in vitro studies show that patients who are treatment experienced and have three or more mutations in protease inhibitors lose susceptibility to atazanavir.