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Ritonavir, sold under the brand name Norvir, is an antiretroviral medication used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). It may also be used in combination with other medications to treat hepatitis C and COVID-19. It is taken by mouth. Ritonavir is of the protease inhibitor class.
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Ritonavir was patented in 1989 and came into medical use in 1996. It is on the World Health Organization's List of Essential Medicines. Ritonavir capsules were approved as a generic medication in the United States in 2020.
Medical uses
HIV
Ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1-infected patients. Ritonavir is effective in preventing the replication of HIV-1. Protease inhibitors, including ritonavir, effectively block HIV-1 protease, a crucial enzyme in the reproductive cycle of HIV-1.
COVID-19
Two SARS-CoV-2 3CL<sup>pro</sup> inhibitors are prepackaged with ritonavir to enhance their blood concentration. The co-packaged medications are sold under the brand name Paxlovid. Paxlovid is not authorized for the pre-exposure or post-exposure prevention of COVID-19 or for initiation of treatment in those requiring hospitalization due to severe or critical COVID-19.
In January 2023, simnotrelvir/ritonavir was conditionally approved by China's National Medical Products Administration (NMPA) for COVID-19.
Other uses
The use of ritonavir as a CYP3A inhibitor is also seen in the hepatitis C medication ombitasvir/paritaprevir/ritonavir. It induces CYP1A2 and inhibits CYP3A4 and CYP2D6. Concomitant therapy of ritonavir with a variety of medications may result in serious and sometimes fatal drug interactions.
Due to it being a strong inhibitor (that causes at least a five-fold increase in the plasma AUC values, or more than 80% decrease in clearance) of both cytochrome P450 enzymes CYP2D6 and CYP3A4, ritonavir can severely potentiate and prolong the half-life and/or increase the blood concentration of phenobarbital, primidone, carbamazepine, phenytoin, PDE5 inhibitors like sildenafil, opioids such as hydrocodone, oxycodone, pethidine and fentanyl, antiarrhythmic agents such as amiodarone, propafenone and disopyramide, immunosuppressants such as tacrolimus, voclosporin and sirolimus, neuroleptics like lurasidone and pimozide, as well as some chemotherapeutic agents, benzodiazepines and some ergot derivatives. The FDA has issued a boxed warning for this type of drug interactions. one of a family of pseudo-C-symmetric small molecule inhibitors.
Ritonavir is rarely used for its own antiviral activity but remains widely used as a booster of other protease inhibitors. More specifically, ritonavir is used to inhibit a particular enzyme, in intestines, liver, and elsewhere, that normally metabolizes protease inhibitors, cytochrome P450-3A4 (CYP3A4). The drug binds to and inhibits CYP3A4, so a low dose can be used to enhance other protease inhibitors. This discovery drastically reduced the adverse effects and improved the efficacy of protease inhibitors and HAART.<!-- ; it was first communicated in an article published in the journal AIDS in 1997 by researchers at the University of Liverpool -->.<!-- NOTE TO EDITORS ON THE HIDING OF THIS PRIMARY SOURCE-BASED CLAIM: A primary source cannot be the basis of a claim for primacy of discovery—to try this is to allow authors to say "I did this first" without confirmation by the secondary literature. It is inappropriate for any editor at WP to rely in such a claim from a primary source (and it is disallowed by its WP:VERIFY guidelines (even if the primary source makes the claim for itself) --> However, because of the general role of CYP3A4 in xenobiotic metabolism, dosing with ritonavir also affects the efficacy of numerous other medications, adding to the challenge of prescribing drugs concurrently. See above.
Pharmacokinetics
Ritonavir at a 200 mg dose reaches maximum plasma concentration in about 3 hours and has a half life of 3–4 hours.
Chemistry
Ritonavir was initially derived from a moderately potent and orally bioavailable small molecule, A-80987. The P3 and P2′ heterocyclic groups of A-80987 were redesigned to create an analogue, now known as ritonavir, with improved pharmacokinetic properties to the original.
History
class=skin-invert-image|thumb|alt=|New HIV infections and deaths, before and after the FDA approval of "highly active antiretroviral therapy", As a result of the new therapies, HIV deaths in the United States fell dramatically within two years.
Ritonavir is sold as Norvir by AbbVie, Inc. As a result of the introduction of "highly active antiretroviral thearap[ies]" the annual U.S. HIV-associated death rate fell from over 50,000 to about 18,000 over a period of two years.
After the start of the COVID pandemic in 2020, many antivirals, including protease inhibitors in general and ritonavir in particular, were repurposed in an effort to treat the new infection. Lopinavir/ritonavir was found not to work in severe COVID-19. Virtual screening followed by molecular dynamics analysis predicted ritonavir blocks the binding of the SARS-CoV-2 spike (S) protein to the human angiotensin-converting enzyme 2 (hACE2) receptor, which is critical for the virus entry into human cells.
Finally in 2021, a combination of ritonavir with nirmatrelvir, a newly developed orally active 3C-like protease inhibitor, was developed for the treatment of COVID-19. Ritonavir serves to slow down metabolism of nirmatrelvir by cytochrome enzymes to maintain higher circulating concentrations of the main drug. In November that year, Pfizer announced positive phase 2/3 results, including 89% reduction in hospitalizations when given within three days after symptom onset.
Polymorphism and temporary market withdrawal
Ritonavir was originally dispensed as a capsule that did not require refrigeration. This contained a crystal form of ritonavir that is now called form I. However, like many drugs, crystalline ritonavir can exhibit polymorphism, i.e., the same molecule can crystallize into more than one crystal type, or polymorph, each of which contains the same repeating molecule but in different crystal packings/arrangements. The solubility and hence the bioavailability can vary in the different arrangements, and this was observed for forms I and II of ritonavir.
During development—ritonavir was introduced in 1996—only the crystal form now called form I was found; however, in 1998, a lower free energy, more stable polymorph, form II, was discovered. This more stable crystal form was less soluble, which resulted in significantly lower bioavailability. The compromised oral bioavailability of the drug led to temporary removal of the oral capsule formulation from the market. It has been estimated that Abbott lost more than US$250 million as a result, and the incident is often cited as a high-profile example of disappearing polymorphs.
In 1999, the company's research and development teams ultimately solved the problem by replacing the capsule formulation with a refrigerated gelcap. In 2000, Abbott received FDA-approval for a tablet formulation of lopinavir/ritonavir (Kaletra) which contained a preparation of ritonavir that did not require refrigeration. Ritonavir tablets produced in an amorphous (non-crystalline) solid dispersion by melt-extrusion were introduced commercially in 2010.
Society and culture
Economics
In 2003, Abbott (AbbVie, Inc.) raised the price of a Norvir course from per day to per day, leading to claims of price gouging by patients' groups and some members of Congress. Consumer group Essential Inventions petitioned the NIH to override the Norvir patent, but the NIH announced on August 4, 2004, that it lacked the legal right to allow generic production of Norvir.