아타자나비어

Pharmacologic interaction with bepridil (potential for serious and/or life-threatening adverse effects). Concomitant use of bepridil and atazanavir not recommended.

Pharmacokinetic interaction with antiarrhythmic agents (i.e., amiodarone, systemic lidocaine, quinidine). Potential for serious and/or life-threatening adverse effects. Monitor plasma concentrations of these antiarrhythmic agents if used concomitantly with atazanavir.

Potential pharmacokinetic interaction (increased plasma concentration of the tricyclic antidepressant). Potential for serious and/or life-threatening adverse effects. Monitor plasma concentrations of these tricyclic antidepressants agents if used concomitantly with atazanavir.

Pharmacokinetic interaction with rifampin (substantial decrease (90%) in the peak plasma concentration and area under the concentration-time curve (AUC) of HIV protease inhibitors). Concomitant use of atazanavir and rifampin not recommended.

For more Interactions (Complete) data for ATAZANAVIR (34 total), please visit the HSDB record page.

Atazanavir can cause several forms of liver injury including transient serum enzyme elevations, indirect hyperbilirubinemia, idiosyncratic acute liver injury and exacerbation of underlying chronic viral hepatitis.；Some degree of serum aminotransferase elevations occurs in a high proportion of patients taking atazanavir containing antiretroviral regimens. Moderate-to severe elevations in serum aminotransferase levels (>5 times the upper limit of normal) are found in 3% to 10% of patients, although rates may be higher in patients with HIV-HCV coinfection. These elevations are usually asymptomatic and self-limited and can resolve even with continuation of the medication.；Atazanavir therapy (similar to indinavir) also causes increases in unconjugated (indirect) and total serum bilirubin that can manifest as jaundice in up to 10% of patients. These elevations are due to the inhibition of UDP glucuronyl transferase, the hepatic enzyme responsible for conjugation of bilirubin that is deficient in Gilbert syndrome. The hyperbilirubinemia is usually mild, the increases averaging 0.3-0.5 mg/dL, but can be more marked in patients with Gilbert syndrome with increases of 1.5 mg/dL or more and clinical jaundice. The jaundice, however, is not indicative of hepatic injury.；Clinically apparent acute liver injury due to atazanavir is rare and the clinical pattern of liver injury, latency and recovery have not been well defined. The liver injury is idiosyncratic and rare and probably similar to the injury that is caused by other HIV protease inhibitors. The liver injury typically arises 1 to 8 weeks after starting the protease inhibitor and has variable patterns of liver enzyme elevation, from hepatocellular to cholestatic. Signs of hypersensitivity (fever, rash, eosinophilia) are rare, as is autoantibody formation. The acute liver injury is usually self-limited and resolves within a few weeks of stopping the antiretroviral agent (Case 1).；In addition, initiation of atazanavir based antiretroviral therapy can lead to exacerbation of an underlying chronic hepatitis B or C in coinfected individuals, typically arising 2 to 12 months after starting therapy, and associated with a hepatocellular pattern of serum enzyme elevations and increases in serum levels of hepatitis B virus (HBV) DNA or hepatitis C virus (HCV) RNA. Atazanavir therapy has not been clearly linked to lactic acidosis and acute fatty liver that is reported in association with several nucleoside analogue reverse transcriptase inhibitors.；Likelihood score: D (possible, rare cause of clinically apparent liver injury).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 3.8X10+7(SRC), determined from a structure estimation method(2), indicates that atazanavir is expected to be immobile in soil(SRC). Volatilization of atazanavir from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 3.6X10-32 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Atazanavir is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.0X10-26 mm Hg(SRC), determined from a fragment constant method(4). Biodegradation data were not available(SRC, 2005).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 3.8X10+7(SRC), determined from a structure estimation method(2), indicates that atazanavir is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 3.6X10-32 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 7.4(SRC), from an estimated log Kow of 2.9(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Hydrolysis may occur however the predicted rate indicates that the reaction would be very slow with half lives corresponding to 10,000 and 100,000 years for pH 8 and 7, respectively(8). These estimated rates suggest that hydrolysis is not expected to be an important fate process. Biodegradation data were not available(SRC,2005).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), atazanavir, which has an estimated vapor pressure of 1.0X10-26 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the atmosphere. Particulate-phase atazanavir may be removed from the air by wet and dry deposition(SRC). Based on other biphenyl compounds(3), atazanavir is not expected to absorb at >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

Common adverse effects of atazanavir include hyperbilirubinemia (35% to 49% in adults and 16% in children), rash (up to 21%), hypercholesterolemia (6% to 25%), hyperamylasemia (14% to 33%), jaundice (5% to 9% in adults and 13% to 15% in children), nausea (3% to 14%), cough (21% in children), and fever (2% in adults and 18% to 19% in children). Severe adverse effects include Stevens-Johnson syndrome, toxic skin eruptions, erythema multiforme, angioedema, cholecystitis, pancreatitis, interstitial nephritis, diabetic ketoacidosis, and AV block. Additional potential adverse effects include nephrolithiasis, cholelithiasis, hyperlipidemia, hypertriglyceridemia, bleeding, pancreatitis, exacerbation of diabetes mellitus or hyperglycemia, and lactic acidosis when used in combination with nucleoside analogs.；Although immune reconstitution inflammatory syndrome (IRIS) is not a direct adverse effect of atazanavir, it is noteworthy that a pathological inflammatory response may occur after initiating antiretroviral treatment for HIV infection. There have been reports of up to a 75% mortality rate in IRIS cases associated with tuberculosis in the central nervous system. Although there have been suggestions that successful treatment with antiretroviral drugs enables the recovery of immune function, it may also exacerbate existing opportunistic infections (paradoxical IRIS) or reveal previously undetected opportunistic infections (unmasking IRIS).；Clinical symptoms may vary based on the type of opportunistic infections, but a common feature includes acute generalized or local inflammatory responses, such as fever or localized tissue edema. Therefore, the timing of initiating antiretroviral therapy is crucial to prevent IRIS.；Drug-Drug Interactions；Atazanavir is metabolized through the CYP3A4 pathway and has inhibitory effects on CYP3A4, CYP1A2, and CYP2C9 enzymes. Therefore, patients taking medications that inhibit or are substrates of these enzymes, especially those with a narrow therapeutic index, should avoid atazanavir. Significant drug interactions may arise with warfarin, irinotecan, diltiazem, simvastatin, lovastatin, phosphodiesterase inhibitors, St John's wort, and tenofovir.

Currently, no specific antidote exists for atazanavir toxicity. Patients should receive symptomatic and supportive care from healthcare staff while regularly monitoring their vital signs and looking for signs of respiratory distress. Electrocardiogram monitoring of the patient is recommended, as atazanavir may exacerbate AV block due to PR interval prolongation. In cases where a simultaneous overdose with nucleoside reverse transcriptase inhibitors is suspected, clinicians should carefully monitor patients for symptoms of lactic acidosis.

Using a structure estimation method based on molecular connectivity indices(1), the Koc for atazanavir can be estimated to be 3.8X10+7(SRC). According to a classification scheme(2), this estimated Koc value suggests that atazanavir is expected to be immobile in soil.

/SIGNS AND SYMPTOMS/ At high doses that lead to high drug exposures, jaundice due to indirect (unconjugated) hyperbilirubinemia (without associated liver function test changes) or PR interval prolongation may be observed.

/SIGNS AND SYMPTOMS/ ... Stevens-Johnson syndrome and erythema multiforme have been reported in patients receiving atazanavir.

/CASE REPORTS/ A single self-administered overdose of 29.2 g of /atazanavir/ in an HIV-infected patient (73 times the recommended dose) was associated with asymptomatic bifascicular block and PR interval prolongation. These events resolved spontaneously.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

atazanavir

DILI Positive

Oral

DOI:10.1016/j.drudis.2019.09.022

An estimated BCF of 7.4 was calculated for atazanavir(SRC), using an estimated log Kow of 2.9(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Henry's Law constant for atazanavir is estimated as 3.6X10-32 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that atazanavir is expected to be essentially nonvolatile from moist soil(SRC) and water surfaces(2). Atazanavir is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.0X10-26 mm Hg(SRC), determined from a fragment constant method(3).

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl atazanavir sulfate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Atazanavir Sulfate/

Human immunodeficiency virus (HIV) infection (treatment). Atazanavir sulfate is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. /Atazanavir Sulfate/

Medication

Use (kg; approx.) in Germany (2009): >500；Consumption (g per capita; approx.) in Germany (2009): 0.00611；Excretion rate: 0.3；Calculated removal (%): 4.8

While data specific to atazanavir were not available(SRC, 2005), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through subsoils into aquifers(1).