Indications
Ritonavir is prescribed in conjunction with other antiretroviral medications for the treatment of HIV-1 infection. In the United States, Europe, and Canada, ritonavir is also indicated in combination with nirmatrelvir for the treatment of mild-to-moderate COVID-19 in adults who are at high risk for severe progression, which may lead to hospitalization or death. In Europe, this indication is approved under a conditional marketing authorization.
Pharmacodynamics
Ritonavir functions as a protease inhibitor with efficacy against the Human Immunodeficiency Virus Type 1 (HIV-1). Protease inhibitors, including ritonavir, obstruct the protease enzyme essential for the proteolytic cleavage of viral polyprotein precursors into individual functional proteins, crucial for forming infectious HIV-1 particles. By binding to the protease active site, ritonavir inhibits the cleavage process, thereby disrupting the formation of functional viral particles and resulting in immature, non-infectious viruses. Often used in combination with at least two other anti-HIV drugs, modern regimens require low-dose ritonavir to enhance pharmacokinetic exposure through inhibition of the cytochrome P450 3A4 enzyme pathway.
Absorption
The absolute bioavailability of ritonavir has not yet been established. After oral administration, ritonavir reaches peak concentrations approximately 2 hours after fasting and about 4 hours after dosing under non-fasting conditions. It is important to note that ritonavir capsules and tablets are not bioequivalent.
Metabolism
Ritonavir primarily circulates in the plasma as an unchanged drug, though five metabolites have been identified. The isopropylthiazole oxidation metabolite (M-2) is the predominant metabolite present at low plasma concentrations, maintaining similar antiviral properties to the unchanged drug. The cytochrome P450 enzymes CYP3A and CYP2D6 play a significant role in the metabolism of ritonavir.
Mechanism of Action
Ritonavir functions primarily as an inhibitor of the HIV protease enzyme, a crucial factor in the viral life cycle. This enzyme is responsible for cleaving structural and replicative proteins derived from significant HIV genes, such as gag and pol. The gag gene products contribute to the viral core and nucleocapsid, while the pol gene encodes several vital enzymes, including HIV reverse transcriptase, ribonuclease H, integrase, and protease. These proteins are initially synthesized as a large precursor called the gag-pol polyprotein, which must be cleaved by the HIV protease to yield functional proteins. Ritonavir disrupts this process by inhibiting the cleavage of the gag-pol polyprotein, leading to the formation of immature, noninfectious viral particles. Additionally, Ritonavir is a potent inhibitor of the cytochrome P450 CYP3A4 isoenzyme in the intestinal tract and liver. By acting as a type II ligand, it fits precisely into the CYP3A4 active site and irreversibly binds to the heme iron through thiazole nitrogen, thereby decreasing the enzyme's redox potential and preventing its interaction with cytochrome P450 reductase. Furthermore, Ritonavir may also influence cellular transport by limiting the efflux of other protease inhibitors through P-glycoprotein and MRP efflux channels.
