Therapeutic Category: Antivirals; Protease Inhibitors (PIs)

Indications And Use: Atazanavir sulfate is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. This indication is based on analyses of plasma HIV-1 RNA levels and CD4 cell counts from controlled studies of 48 weeks duration in antiretroviral-naive patients and a controlled study of 24 weeks duration in antiretroviral-treatment-experienced patients. In antiretroviral-treatment-experienced patients, the use of atazanavir sulfate may be considered for adults with HIV strains that are expected to be susceptible to atazanavir sulfate as assessed by genotypic and/or phenotypic testing.

Warnings: Anti-HIV medicines like REYATAZ contribute to the progression of liver disease.

Description: REYATAZ (atazanavir sulfate), an azapeptide inhibitor of HIV-1 protease, is the first once-daily PI approved by the Food and Drug Administration (FDA). REYATAZ has a unique lipid profile and does not appear to increase cholesterol or triglyceride levels as other PIs do. 

Pharmacodynamics:
Mechanism of Action- Atazanavir is an azapeptide HIV-1 protease inhibitor. 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.
Absorption- Atazanavir is rapidly absorbed with a Tmax of approximately 2.5 hours. The drug demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in systemic bioavailability (AUC) and Cmax values over the dose range of 200-800 mg once daily. Steady-state is achieved between days 4 and 8, with an accumulation of approximately 2.3-fold.
Distribution/Protein binding- Atazanavir is 86% bound to human serum proteins and protein binding is independent of concentration. The drug binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively). In a multiple-dose study in HIV-infected patients dosed with atazanavir sulfate 400 mg once daily with a light meal for 12 weeks, atazanavir was detected in the cerebrospinal fluid and semen. The cerebrospinal fluid/plasma ratio for atazanavir (n=4) ranged between 0.0021 and 0.0226 and seminal fluid/plasma ratio (n=5) ranged between 0.11 and 4.42.
Metabolism- Atazanavir is extensively metabolized in humans. The major biotransformation pathways of this drug in humans consisted of monooxygenation and dioxygenation. Other minor biotransformation pathways for atazanavir or its metabolites consisted of glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation. Two minor metabolites of atazanavir in plasma have been characterized. Neither metabolite demonstrated in vitro antiviral activity. In vitro studies using human liver microsomes suggested that atazanavir is metabolized by cytochrome P450 liver enzyme CYP3A.

Elimination- Following a single 400 mg dose of 14C-atazanavir, 79% and 13% of the total radioactivity was recovered in the feces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the feces and urine, respectively. The mean elimination half-life of atazanavir in healthy volunteers (n=214) and HIV-infected adult patients (n=13) was approximately 7 hours at steady state following a dose of 400 mg daily with a light meal.

Adverse Effects:
Body as a Whole- Allergic reaction, angioedema, asthenia, burning sensation, chest pain, dysphasia, edema, facial atrophy, generalized edema, headache, heat sensitivity, infection, jaundice, malaise, overdose, pallor, peripheral edema, photosensitivity, rash, substernal chest pain, sweating. REYATAZ with nucleoside analogues may cause lactic acidosis and if taken with PIs glucose abnormalities can occur. REYATAZ containing regimens also have the following adverse nutritional effects: abdominal pain, depression, diarrhea, nausea and vomiting. 
 

Nutrition Considerations:
Administration of atazanavir sulfate with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single 400 mg dose of atazanavir sulfate with a light meal (357 kcal, 8.2 grams (gm) fat, 10.6 gm protein) resulted in a 70% increase in AUC and 57% increase in Cmax relative to the fasting state. Administration of a single 400 mg dose of atazanavir sulfate with a high-fat meal (721 kcal, 37.3 gm fat, 29.4 gm protein) resulted in a mean increase in AUC of 35% with no change in Cmax relative to the fasting state. Atazanavir sulfate taken with either a light meal or high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately one half compared to the fasting state. 

Drug Interactions:
Herb Interactions- Based on in vitro tests, St. John’s Wort, echinacea, milk thistle, garlic and possibly other herbs may alter REYATAZ levels in the bloodstream so patients should consult with their health care provider before using them.