Ritonavir

Absorption

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

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.

Description

Ritonavir (brand name: Norvir) was launched in Germany, the UK and US for treatment of advanced HIV in combination with antiretroviral nucleoside analogs in a record 72 days by the FDA. It is an inhibitor of HIV aspartic protease which is critical in the processing of a propeptide into the gag, gag-pol gene products and the protease itself. This inhibition results in the release of non-infectous immature virus particles. It is greater than 500-fold more selective for viral aspartic protease than the human version, has good oral bioavailability and may increase the bioavailability of other protease inhibitors. Ritonavir was able to increase the CD4 and CD8 lymphocyte count as well as reduce viral RNA. It is more potent than saqunavir and comparible in potency to zidovudine and lamivudine.

The Uses of Ritonavir

Ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1-infected patients. Ritonivir is an HIV protease inhibitor (EC50 = 25 nM) that also inhibits CYP3A4, the primary cytochrome P450 isoform that metabolizes protease inhibitors. Through CYP3A4 inhibition, low doses of ritonivir can reduce the metabolism of concomitantly administered protease inhibitiors, enhancing their bioavailability and efficacy.

What are the applications of Application

Ritonavir is an inhibitor of HIV-1 protease

Indications

Ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.
In the US, Europe, and Canada, ritonavir, in combination with nirmatrelvir, is indicated for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults who are at high risk for progression to severe COVID-19, including hospitalization or death. In Europe, this therapeutic indication is approved under conditional marketing authorization.

Background

Ritonavir is an HIV protease inhibitor that interferes with the reproductive cycle of HIV. Although it was initially developed as an independent antiviral agent, it has been shown to possess advantageous properties in combination regimens with low-dose ritonavir and other protease inhibitors. It is now more commonly used as a booster of other protease inhibitors and is available in both liquid formulations and as capsules.
While ritonavir is not an active antiviral agent against hepatitis C virus (HCV) infection, it is added in combination therapies indicated for the treatment of HCV infections as a booster. Ritonavir is a potent CYP3A inhibitor that increases peak and trough plasma drug concentrations of other protease inhibitors such as Paritaprevir and overall drug exposure. American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) guidelines recommend ritonavir-boosted combination therapies as first-line therapy for HCV Genotype 1a/b and 4 treatment-na?ve patients with or without cirrhosis.
Ritonavir is found in a fixed-dose combination product with Ombitasvir, Dasabuvir, and Paritaprevir as the FDA-approved product Viekira Pak. First approved in December 2014, Viekira Pak is indicated for the treatment of HCV genotype 1b without cirrhosis or with compensated cirrhosis, and when combined with Ribavirin for the treatment of HCV genotype 1a without cirrhosis or with compensated cirrhosis.
Ritonavir is also available as a fixed-dose combination product with Ombitasvir and Paritaprevir as the FDA- and Health Canada-approved product Technivie. First approved in July 2015, Technivie is indicated in combination with Ribavirin for the treatment of patients with genotype 4 chronic hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis.
In Canada, ritonavir is also available as a fixed-dose combination product with Ombitasvir, Dasabuvir, and Paritaprevir as the Health Canada-approved, commercially available product Holkira Pak. First approved in January 2015, Holkira Pak is indicated for the treatment of HCV genotype 1b with or without cirrhosis, and when combined with Ribavirin for the treatment of HCV genotype 1a with or without cirrhosis. The inclusion of ritonavir can select for HIV-1 protease inhibitor resistance-associated substitutions. Any HCV/HIV-1 co-infected patients treated with ritonavir-containing combination therapies should also be on a suppressive antiretroviral drug regimen to reduce the risk of HIV-1 protease inhibitor drug resistance.
Ritonavir is combined with other drugs to treat coronavirus disease 2019 (COVID-19) in patients at risk for progressing into a severe form of the disease, such as nirmatrelvir.

Pharmacokinetics

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.

Metabolism

Ritonavir circulates in the plasma predominantly as unchanged drug. Five metabolites have been identified. The isopropylthiazole oxidation metabolite (M-2) is the major metabolite in low plasma concentrations and retains similar antiviral activity to unchanged ritonavir. The cytochrome P450 enzymes CYP3A and CYP2D6 are the enzymes primarily involved in the metabolism of ritonavir.