Ritonavir

Uses

Ritonavir is an HIV protease inhibitor used in combination with other antivirals in the treatment of HIV infection.

Indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.

Ritonavir is also used to associated treatment for these conditions: Human Immunodeficiency Virus (HIV) Infections

How Ritonavir works

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 .

Toxicity

Human experience of acute overdose with ritonavir is limited. One patient in clinical trials took ritonavir 1500 mg/day for two days. The patient reported paresthesias which resolved after the dose was decreased. A post-marketing case of renal failure with eosinophilia has been reported with ritonavir overdose. The approximate lethal dose was found to be greater than 20 times the related human dose in rats and 10 times the related human dose in mice. Oral LD value in rats is >2500 mg/kg. Adverse effects of ritonavir may arise from drug-drug interactions. Other effects include hepatotoxicity, pancreatitis, and allergic reactions/hypersensitivity.

Food Interaction

• Avoid St. John's Wort. Co-administration may reduce serum concentrations of ritonavir and interfere with virologic efficacy.

[Moderate] ADJUST DOSING INTERVAL: Administration with food may modestly affect the bioavailability of ritonavir from the various available formulations.

When the oral solution was given under nonfasting conditions, peak ritonavir concentrations decreased 23% and the extent of absorption decreased 7% relative to fasting conditions.

Dilution of the oral solution (within one hour of dosing) with 240 mL of chocolate milk or a nutritional supplement (Advera or Ensure) did not significantly affect the extent and rate of ritonavir absorption.

When a single 100 mg dose of the tablet was administered with a high-fat meal (907 kcal; 52% fat, 15% protein, 33% carbohydrates), approximately 20% decreases in mean peak concentration (Cmax) and systemic exposure (AUC) were observed relative to administration after fasting.

Similar decreases in Cmax and AUC were reported when the tablet was administered with a moderate-fat meal.

In contrast, the extent of absorption of ritonavir from the soft gelatin capsule formulation was 13% higher when administered with a meal (615 KCal; 14.5% fat, 9% protein, and 76% carbohydrate) relative to fasting.

MANAGEMENT: Ritonavir should be taken with meals to enhance gastrointestinal tolerability.

Ritonavir Cholesterol interaction

[Moderate] Hyperlipidemia has been observed in 10% of patients receiving ritonavir during clinical trials.

Increases of 30% to 40% from baseline have been reported for total cholesterol and 200% to 300% or more for triglycerides.

These effects have also been reported during postmarketing experience with other protease inhibitors (PIs) but may be the most dramatic with ritonavir.

The clinical significance of these elevations is unclear.

Severe hyperlipidemia is known to sometimes cause pancreatitis.

In addition, some patients have reportedly developed symptomatic atherosclerosis and coronary artery disease after initiating PI treatment.

Patients with preexisting hyperlipidemia may require closer monitoring during PI therapy, and adjustments made accordingly in their lipid-lowering regimen.

PI therapy should be administered cautiously in patients with coronary artery disease or a history of ischemic heart disease.

Ritonavir Drug Interaction

Major: etravirine, atorvastatin, oxycodoneModerate: emtricitabine / tenofovir alafenamide, metoprolol, atazanavir, emtricitabine / tenofovirMinor: raltegravir, dolutegravirUnknown: aspirin, heparin, arginine, pregabalin, acetaminophen, nirmatrelvir / ritonavir, darunavir, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol

Ritonavir Disease Interaction

Major: hemophilia, hepatotoxicityModerate: hyperglycemia, hyperlipidemia, heart block

Volume of Distribution

The estimated volume of distribution of ritonavir is 0.41 ± 0.25 L/kg.

Elimination Route

The absolute bioavailability of ritonavir has not been determined. Following oral administration, peak concentrations are reached after approximately 2 hours and 4 hours (T_max) after dosing under fasting and non-fasting conditions, respectively. It should be noted that ritonavir capsules and tablets are not considered bioequivalent.

Half Life

The approximate half-life of ritonavir is 3-5 hours.

Clearance

The apparent oral clearance at steady-state is 8.8 ± 3.2 L/h. Renal clearance is minimal and estimated to be 7

Elimination Route

Ritonavir is primarily eliminated in the feces. Following oral administration of a single 600mg dose of radiolabeled ritonavir, approximately 11.3 ± 2.8% of the dose was excreted into the urine, of which 3.5 ± 1.8% was unchanged parent drug. The same study found that 86.4 ± 2.9% of the dose was excreted in the feces, of which 33.8 ± 10.8% was unchanged parent drug.

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