Atazanavir an azapeptide inhibitor of HIV-1 protease

Atazanavir an azapeptide inhibitor of HIV-1 protease

Atazanavir sulfate is an azapeptide inhibitor of HIV-1 protease. The chemical name for atazanavir sulfate is (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, sulfate (1:1).

Its molecular formula is C38H52N6O7•H2SO4, which corresponds to a molecular weight of 802.9 (sulfuric acid salt). The free base molecular weight is 704.9 Atazanavir sulfate is a white to pale yellow crystalline powder. It is slightly soluble in water (4–5mg/mL, free base equivalent) with the pH of a saturated solution in water being about 1.9 at 24 ± 3° C.

Mechanism of Action

Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI). The compound selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions.

Antiviral Activity In Vitro

Atazanavir exhibits anti-HIV-1 activity with a mean 50% effective concentration (EC50) in the absence of human serum of 2 to 5 nM against a variety of laboratory and clinical HIV-1 isolates grown in peripheral blood mononuclear cells, macrophages, CEM-SS cells, and MT-2 cells. ATV has activity against HIV-1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. ATV has variable activity against HIV-2 isolates (1.9 to 32 nM), with EC50 values above the EC50 values of failure isolates.

Two-drug combination studies with ATV showed additive to antagonistic antiviral activity in vitro with abacavir and the NNRTIs (delavirdine, efavirenz, and nevirapine) and additive antiviral activity in vitro with the PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NRTIs (didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine), the HIV-1 fusion inhibitor enfuvirtide, and two compounds used in the treatment of viral hepatitis, adefovir and ribavirin, without enhanced cytotoxicity.


Absorption: Rapidly absorbed (increased by food). Distribution: Enters cerebrospinal fluid and semen. Metabolism and Excretion: 80% metabolized (CYP3A); 13% excreted unchanged in urine. Half-life: 7 hr.


Contraindicated in: Hypersensitivity; Severe hepatic impairment; Concurrent use of ergot derivatives, midazolam (PO), pimozide, triazolam, alfuzosin, sildenafil (Revatio), rifampin, irinotecan, lovastatin, simvastatin, indinavir, or St. John’s wort; Pediatric: risk of kernicterus in infants below 3months.

Use Cautiously in: Mild to moderate hepatic impairment; Pre-existing conduction system disease (marked first-degree AV block or second- or third-degree AV block) or concurrent use of other drugs that increase the PR interval (especially those metabolized by CYP3A4, including verapamil or diltiazem); Diabetes mellitus; Hemophilia (increased risk of bleeding); Pediatric: Children below 6 years (safety not established); Breast feeding is not recommended if HIV-infected.

Side Effects

• Common side effects may include nausea, vomiting, diarrhea, abdominal pain, and headache. These effects may diminish within the first month of treatment. You may also experience some fatigue, dizziness, weakness, body ache or rash/allergy. Contact your doctor or pharmacist if any side effects occur and remain persistent.

• Atazanavir will cause an increase in your bilirubin levels that usually does not cause symptoms or affect liver function. However, contact your doctor, if you experience persistent abdominal pain and/or have signs of jaundice (eg. yellowing of the skin or whites of your eyes).

• Atazanavir has not been shown to increase blood fat levels (LDL cholesterol, triglyceride) to the same degree as some of the other currently available protease inhibitors.

• In studies, some Atazanavir patients experienced a change in their heart rhythm (ECG), which did not cause symptoms. However caution should be taken if you have a history of abnormal heart rhythm or are taking other medications that may alter heart rhythm, such as certain anti-histamines, anti-fungals, macrolide antibiotics and anti-arrhythmic heart medications.

Adverse Effects

Atazanavir competitively inhibits an enzyme responsible for the glucuronidation of bilirubin, which frequently causes a mild, asymptomatic indirect hyperbilirubinemia; occasionally this leads to overt icterus, which is not dangerous, but may be disturbing to patients.

Jaundice, when it occurs, will resolve after discontinuation of atazanavir. Atazanavir can crystalize in the urinary or biliary tract and cause nephrolithiasis or cholelithiasis.

It can also cause an increase in the PR interval of the electrocardiogram, mild-moderate gastrointestinal symptoms such as nausea and diarrhea. Rarely, patients taking atazanavir will develop rash or elevation of hepatic aminotransferase levels. Ritonavir-boosted atazanavir can worsen serum lipid parameters, though is better in this regard than earlier-generation protease inhibitors.

Use in Pregnancy

In the HHS Perinatal Guidelines section Recommendations for Use of Antiretroviral Drugs During Pregnancy (last updated October 19, 2017), ritonavir-boosted atazanavir plus a preferred two-NRTI backbone is designated as one of the Preferred Protease Inhibitor Regimens in the category Preferred Initial Regimens in Pregnancy. In pregnancy, atazanavir cannot be administered with proton pump inhibitors.


• The usual adult dose is atazanavir 300 mg (1 x 300 mg capsule OR 2 x 150 mg capsules) once daily

• The medication should be taken with food (i.e. a light meal) to increase absorption.

• Swallow the capsules or tablets whole (do NOT chew).

• Atazanavir absorption can be significantly lowered by medications that decrease stomach acidity (eg ranitidine (ZantacÒ), cimetidine (TagametÒ), famotidine (PepcidÒ), omeprazole (LosecÒ), and pantoprazole (PantolocÒ)).

Talk to your pharmacist or doctor, if you are taking these medications. Antacids or antacid containing products may be used but must be taken at least 1 hr before or 2 hrs after your dose of atazanavir.

Alcohol is not recommended in the first 4 weeks of therapy and should be used with caution thereafter.


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