ATAZOR-R-300/100

Indications

• HIV infection
• HIV-1 in combination therapy

Dosage

Children: Refer to the BNF for Children for specific paediatric dosing recommendations based on age and weight.

Adults: Refer to the BNF for specific adult dosing recommendations, which may vary based on concurrent medications and patient-specific factors.

Mechanism of action

Atazanavir selectively inhibits the HIV-1 protease enzyme. By blocking this enzyme, atazanavir prevents the cleavage of viral polyproteins into functional proteins, which is necessary for the assembly and maturation of infectious HIV particles. This leads to the production of immature, non-infectious viral particles, thereby reducing the viral load in the body.

Pharmacodynamics

Atazanavir exhibits dose-dependent antiviral activity against HIV-1. Its potency is influenced by factors such as pH levels, as atazanavir requires an acidic environment for optimal absorption and bioavailability. The drug has a relatively long half-life, allowing for once-daily dosing in many cases. The therapeutic efficacy of atazanavir is often assessed by measuring viral load and CD4 cell counts in patients undergoing treatment.

Pharmacokinetics

Atazanavir is well absorbed after oral administration, with peak plasma concentrations occurring approximately 1-2 hours after dosing. The bioavailability of atazanavir is significantly increased when taken with food. It is primarily metabolized in the liver by cytochrome P450 3A4 and has a half-life of about 7-10 hours. Atazanavir is excreted mainly via the feces and to a lesser extent in urine. Its pharmacokinetics can be affected by concurrent use of other medications that induce or inhibit CYP3A4 enzymes.

Contra-indications

• Severe hepatic impairment
• Concomitant use with certain medications (e.g., strong CYP3A4 inducers or inhibitors)
• Hypersensitivity to atazanavir or any component of the formulation

Adverse effects

• Hyperbilirubinemia
• Nausea
• Rash
• Abdominal pain
• Diarrhea
• Fatigue
• Headache
• Elevated liver enzymes

Interactions

• May interact with drugs that are metabolized by CYP3A4
• Concomitant use with proton pump inhibitors may reduce atazanavir levels
• Use with rifampicin or other strong CYP3A4 inducers may decrease efficacy

Precautions

• Use with caution in patients with a history of liver disease
• Monitor for signs of liver toxicity
• Assess for potential drug interactions prior to initiation
• Consider patient adherence to treatment regimen

Pregnancy

Atazanavir is classified as pregnancy category B. Limited data is available, and it should be used during pregnancy only if clearly needed.

Breast-feeding

Atazanavir is excreted in breast milk; caution should be exercised when administering to nursing mothers.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Oral capsules
• Oral tablet
• Oral suspension

Indications

• HIV infection in combination with other antiretroviral drugs

Dosage

Children: For children over 2 years of age

Adults: The typical adult dose of ritonavir is 100–200 mg taken 1–2 times a day. For high-dose ritonavir used as a booster, the recommended dose is 800/200 mg once daily, but this should only be used in patients with an HIV strain that has fewer than 3 mutations to protease inhibitors.

Mechanism of action

Ritonavir inhibits the HIV protease enzyme, which is crucial for the cleavage of the viral polyprotein precursors into functional proteins essential for the formation of infectious HIV particles. By binding to the active site of the protease, ritonavir prevents this cleavage, leading to the production of non-infectious viral particles. Additionally, ritonavir is a potent inhibitor of the cytochrome P450 CYP3A4 isoenzyme, which enhances the pharmacokinetic profile of other protease inhibitors by reducing their metabolism.

Pharmacodynamics

Ritonavir exhibits antiviral activity specifically against HIV-1 by preventing the function of the viral protease. This inhibition disrupts the normal life cycle of HIV, resulting in immature viral particles that cannot propagate infection. Ritonavir is generally administered in conjunction with other antiretroviral therapies to achieve a synergistic effect, enhancing the overall antiviral activity and therapeutic success.

Pharmacokinetics

Ritonavir is well-absorbed when taken orally, with peak plasma concentrations occurring approximately 2 to 4 hours post-administration. Its bioavailability is influenced by food intake. The drug is extensively metabolized in the liver, primarily by the CYP3A4 enzyme. Ritonavir has a half-life of about 3 to 5 hours in adults, requiring multiple daily doses to maintain effective plasma levels. The drug is excreted mainly in feces, with minimal renal excretion.

Contra-indications

• Severe hepatic impairment
• Severe renal impairment
• History of pancreatitis

Adverse effects

• Nausea
• Diarrhea
• Vomiting
• Abdominal pain
• Increased risk of infections
• Pancreatitis
• Hyperlipidemia
• Fat redistribution
• Liver enzyme elevation
• Cardiac conduction disorders
• Visual impairment
• Peripheral neuropathy
• Hypersensitivity reactions

Interactions

• Ritonavir + antipsychotics (second-generation): Severe (affects exposure)
• Ritonavir + clozapine: Severe (affects exposure)
• Ritonavir + benzodiazepines: Severe (increases exposure)
• Ritonavir + diazepam: Severe (increases exposure)
• Ritonavir + flurazepam: Severe (increases exposure)
• Ritonavir + clopidogrel: Severe (decreases efficacy)
• Ritonavir + glecaprevir: Severe (increases exposure)
• Ritonavir + opioids: Severe (increases risk of central nervous system toxicity)
• Ritonavir + pethidine: Severe (increases risk of central nervous system toxicity)
• Ritonavir + tepotinib: Severe (increases exposure)

Precautions

• Monitor liver function tests regularly
• Use with caution in patients with a history of cardiac conduction disorders
• Evaluate signs of pancreatitis, discontinue if diagnosed
• Avoid use in severe impairment of hepatic or renal function
• Consider potential for drug interactions due to CYP3A4 inhibition

Pregnancy

Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. Ritonavir is classified as Category B.

Breast-feeding

Ritonavir is excreted in breast milk. Weigh the benefits of breastfeeding against the potential risks of HIV transmission or adverse effects to the infant.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Ritonavir 50 mg tablets

Mechanism of action

Ritonavic inhibits the HIV viral proteinase enzyme that normally cleaves the structural and replicative proteins that arise from major HIV genes, such as *gag* and *pol*. *Gag* encodes proteins involved in the core and the nucleocapsid, while *pol* encodes the the HIV reverse transcriptase, ribonuclease H, integrase, and protease. The *pol*-encoded proteins are initially translated in the form of a larger precursoe polypeptide, *gag-pol*, and needs to be cleaved by HIV protease to form other complement proteins. Ritonavir prevents the cleavage of the *gag-pol* polyprotein, which results in noninfectious, immature viral particles. Ritonavir is a potent inhibitor of cytochrome P450 CYP3A4 isoenzyme present both in the intestinal tract and liver. It is a type II ligand that perfectly fits into the CYP3A4 active site cavity and irreversibly binds to the heme iron via the thiazole nitrogen, which decreases the redox potential of the protein and precludes its reduction with the redox partner, cytochrome P450 reductase. Ritonavir may also play a role in limiting cellular transport and efflux of other protease inhibitors via the P-glycoprotein and MRP efflux channels. Unlike nucleoside antiretroviral agents, the antiviral activity of ritonavir does not depend on intracellular conversion to an active metabolite. Ritonavir and other HIV protease inhibitors (e.g., amprenavir, indinavir, lopinavir, nelfinavir, saquinavir) act at a different stage of the HIV replication cycle than nucleoside and nonnucleoside reverse transcriptase inhibitors, and results of in vitro studies indicate that the antiretroviral effects of HIV protease inhibitors and some nucleoside or nonnucleoside antiretroviral agents may be additive or synergistic. Ritonavir is a selective, competitive, reversible inhibitor of HIV protease. HIV protease, an aspartic endopeptidase that functions as a homodimer, plays an essential role in the HIV replication cycle and the formation of infectious virus. During HIV replication, HIV protease cleaves viral polypeptide products of the gag and gag-pol genes (i.e., p55 and p160) to form structural proteins of the virion core (i.e., p17, p24, p9, and p7) and essential viral enzymes (i.e., reverse transcriptase, integrase, and protease). By interfering with the formation of these essential proteins and enzymes, ritonavir blocks maturation of the virus and causes formation of nonfunctional, immature, noninfectious virions. Ritonavir is active in both acutely and chronically infected cells since it targets the HIV replication cycle after translation and before assembly. Thus, the drug is active in chronically infected cells (e.g., monocytes and macrophages) that generally are not affected by nucleoside reverse transcriptase inhibitors (e.g., didanosine, lamivudine, stavudine, zalcitabine, zidovudine). Ritonavir does not affect early stages of the HIV replication cycle; however, the drug interferes with production of infectious HIV and limits further infectious spread of the virus. While the complete mechanisms of antiviral activity of ritonavir have not been fully elucidated, ritonavir apparently inhibits replication of retroviruses, including human immunodeficiency virus type 1 (HIV-1) and 2 (HIV-2), by interfering with HIV protease. The drug, therefore, exerts a virustatic effect against retroviruses by acting as an HIV protease inhibitor.

Pharmacodynamics

Ritonavir is a protease inhibitor with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Protease inhibitors block the part of HIV called protease. HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Ritonavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs. Modern protease inhibitors require the use of low-dose ritonavir to boost pharmacokinetic exposure through inhibition of metabolism via the cytochrome P450 3A4 enzyme pathway.