Ritonavir

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| _datapage = Ritonavir (data page) | _vaccine_target={{#ifeq: | vaccine | | _type_not_vaccine }} | _legal_all=S4Rx-onlyPOMRx-onlyRx-only | _ATC_prefix_supplemental=J05 | _has_EMA_link = yes | CAS_number=155213-67-5 | PubChem=392622 | ChemSpiderID=347980 | ChEBI=45409 | ChEMBL=163 | DrugBank=DB00503 | KEGG=D00427 | _hasInChI_or_Key={{#if:1S/C37H48N6O5S2/c1-24(2)33(42-36(46)43(5)20-29-22-49-35(40-29)25(3)4)34(45)39-28(16-26-12-8-6-9-13-26)18-32(44)31(17-27-14-10-7-11-15-27)41-37(47)48-21-30-19-38-23-50-30/h6-15,19,22-25,28,31-33,44H,16-18,20-21H2,1-5H3,(H,39,45)(H,41,47)(H,42,46)/t28-,31-,32-,33-/m0/s1NCDNCNXCDXHOMX-XGKFQTDJSA-N |yes}} | UNII=O3J8G9O825 | _hasJmol02 = |_hasMultipleCASnumbers = |_hasMultiplePubChemCIDs = |_hasMultipleChEBIs =

| _countSecondIDs={{#invoke:ParameterCount |main |CAS_number2 |ATC_prefix2 |PubChem2 |PubChemStructure2 |IUPHAR_ligand2 |DrugBank2 |ChemSpiderID2 |UNII2 |KEGG2 |ChEBI2 |ChEMBL2 |PDB_ligand2 |NIAID_ChemDB2 |SMILES2 |smiles2 |StdInChI2 |StdInChIKey2 |DTXCID2}} | _countIndexlabels={{#invoke:ParameterCount |main |index_label |index2_label}} | _trackListSortletter= |QID = |QID2 = |Verifiedfields= |Watchedfields= |verifiedrevid=}} Ritonavir, sold under the brand name Norvir, is an antiretroviral medication used along with other medications to treat HIV/AIDS.<ref name="Norvir FDA label" /><ref name="Norvir EPAR" /><ref name=AHFS2015>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> This combination treatment is known as highly active antiretroviral therapy (HAART).<ref name=AHFS2015/> Ritonavir is a protease inhibitor, though it now mainly serves to boost the potency of other protease inhibitors.<ref name=AHFS2015/><ref name="StatPearls">Template:Cite book</ref> It may also be used in combination with other medications to treat hepatitis C and COVID-19.<ref name=FDA-ucm427530 /><ref name="pmid36423149">Template:Cite journal</ref> It is taken by mouth.<ref name=AHFS2015/>

Common side effects of ritonavir include nausea, vomiting, loss of appetite, diarrhea, and numbness of the hands and feet.<ref name=AHFS2015/> Serious side effects include liver complications, pancreatitis, allergic reactions, and arrhythmias.<ref name=AHFS2015/> Serious interactions may occur with a number of other medications including amiodarone and simvastatin.<ref name=AHFS2015/> At low doses, it is considered to be acceptable for use during pregnancy.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Ritonavir is of the protease inhibitor class.<ref name=AHFS2015/> However, it is also commonly used to inhibit the enzyme that metabolizes other protease inhibitors.<ref name=BNF69/> This inhibition allows lower doses of these latter medications to be used.<ref name=BNF69>Template:Cite book</ref>

Ritonavir was patented in 1989 and came into medical use in 1996.<ref>Template:Cite book</ref><ref name=Fis2006>Template:Cite book</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO21st">Template:Cite book</ref><ref name="WHO22nd">Template:Cite book</ref> Ritonavir capsules were approved as a generic medication in the United States in 2020.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Medical uses

HIV

Ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1-infected patients.<ref name="Norvir FDA label" /><ref name="Norvir EPAR">{{#invoke:citation/CS1|citation |CitationClass=web }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref><ref name=AHFS2015/> Though initially developed as an independent antiviral treatment, it is most commonly used as a pharmacokinetic enhancer, in order to increase the plasma concentrations of other antiretrovirals.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

COVID-19

Two SARS-CoV-2 3CL^pro inhibitors are prepackaged with ritonavir to enhance their blood concentration.<ref name=Zhu2023/>

In December 2021, the combination of nirmatrelvir and ritonavir was granted emergency use authorization by the US Food and Drug Administration (FDA) for the treatment of coronavirus disease COVID-19.<ref name="Paxlovid FDA label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="FDA PR 20211222" /><ref name="Pfizer PR 20211222">Template:Cite press release</ref> The co-packaged medications are sold under the brand name Paxlovid.<ref name="FDA PR 20211222">Template:Cite press release</ref><ref name="Pfizer PR 20211222" /><ref name="EUA FAQ">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="FDA PR 20211222" /> On December 31, 2021, the UK Medicines and Healthcare products Regulatory Agency (MHRA) approved the same combination "for people with mild to moderate COVID-19 who are at high risk of developing severe COVID-19".<ref name="MHRA PR 20211231">Template:Cite press release</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

In January 2023, simnotrelvir/ritonavir was conditionally approved by China's National Medical Products Administration (NMPA) for COVID-19.<ref name=Zhu2023>Template:Cite journal</ref>

Other uses

The use of ritonavir as a CYP3A inhibitor is also seen in the Hepatitis C medication ombitasvir/paritaprevir/ritonavir.<ref name="StatPearls"/>

Side effects

When administered at the initially tested higher doses effective for anti-HIV therapy, the side effects of ritonavir are those shown below.<ref name="Norvir FDA label" />

• Asthenia, malaise
• Diarrhea
• Nausea and vomiting
• Abdominal pain
• Dizziness
• Insomnia
• Kidney failure
• Sweating
• Taste abnormality
• Metabolic effects, including
  • Hypercholesterolemia
  • Hypertriglyceridemia
  • Elevated transaminases
  • Elevated creatine kinase

Adverse drug reactions

Ritonavir exhibits hepatic activity.<ref name=Yeh2006>Template:Cite journal</ref> 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.<ref>Template:Cite news</ref>

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.<ref name="pmid32556272">Template:Cite journal</ref><ref name="pmid31038898">Template:Cite journal</ref> The FDA has issued a boxed warning for this type of drug interactions.<ref name=StatPearls/>

CYP3A4 inducers can counteract the inhibiting effects of ritonavir and lead to drastically reduced levels of "boosted" drugs, increasing the risk of developing drug resistance. Other CYP3A4 inhibitors may have an additive effect with ritonavir, causing increased drug levels.<ref name=StatPearls/>

Pharmacology

File:HIV protesase with ritonavir.png

Ritonavir (center) bound to the active site of HIV protease.Template:Citation needed

Pharmacodynamics

Ritonavir was originally developed as an inhibitor of HIV protease,<ref name = "WO1994014436">Template:Cite patent</ref> one of a family of pseudo-C₂-symmetric small molecule inhibitors.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>. 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 Template:Section link above.<ref name="StatPearls"/><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Pharmacokinetics

Ritonavir at a 200 mg dose reaches maximum plasma concentration in about 3 hours and has a half life of 3–4 hours.<ref name="pharmk1"/><ref name="pharmk2"/> Importantly, the pharmacokinetics of Ritonavir are not linear—the half life increases at higher doses or under repeated dosing.<ref name="pharmk1"/> For instance, the half life of a 500 mg tablet is 4–6 hours rather than 3–4 hours for a 200 mg tablet.<ref name="pharmk1"/> The drug has high bioavailability but about 20% is lost due to first-pass metabolism.<ref name="pharmk1"/> Rivonavir capsules are not absorbed as quickly as Ritonavir tablets and may exhibit different bioavailability.<ref name=AHFS2015/>

Ritonavir was demonstrated to have an in vitro potency of EC₅₀=0.02 μM on HIV-1 protease and highly sustained concentration in plasma after oral administration in several species.<ref name="pmid9484509">Template:Cite journal</ref>

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.<ref name="pmid9484509" />

Full details of the synthesis of ritonavir were first published by scientists from Abbott Laboratories.

File:Ritonavir synthesis.svg

In the first step shown, an aldehyde derived from phenylalanine is treated with zinc dust in the presence of vanadium(III) chloride. This results in a pinacol coupling reaction which dimerizes the material to provide an intermediate which is converted to its epoxide and then reduced to (2S,3S,5S)-2,5-diamino-1,6-diphenylhexan-3-ol. Importantly, this retains the absolute stereochemistry of the amino acid precursor. The diamine is then treated sequentially with two thiazole derivatives, each linked by an amide bond, to provide ritonavir.<ref name = "WO1994014436" /><ref>Template:Cite book</ref>

History

File:HIV new infections and deaths 1981-2008.jpg

New HIV infections and deaths, before and after the FDA approval of "highly active antiretroviral therapy",<ref name=MMWR0621/> of which saquinavir and ritonavir were key as the first two protease inhibitors.Template:Medical citation needed As a result of the new therapies, HIV deaths in the United States fell dramatically within two years.<ref name="MMWR0621">Template:Cite journal</ref>

Ritonavir is sold as Norvir by AbbVie, Inc.<ref name="Norvir FDA label" /><ref name="Norvir EPAR" /> The US Food and Drug Administration (FDA) approved ritonavir on March 1, 1996,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="MMWR0621" />

In 2014, the FDA approved a combination of ombitasvir/paritaprevir/ritonavir for the treatment of hepatitis C virus (HCV) genotype 4.<ref name=FDA-ucm427530>Template:Cite press release</ref>

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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Ritonavir serves to slow down metabolism of nirmatrelvir by cytochrome enzymes to maintain higher circulating concentrations of the main drug.<ref>Template:Cite news</ref> In November that year, Pfizer announced positive phase 2/3 results, including 89% reduction in hospitalizations when given within three days after symptom onset.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref name="bauer">Template:Cite journal</ref> 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.<ref name="morissette">Template:Cite journal</ref>

During development—ritonavir was introduced in 1996—only the crystal form now called form I was found; however, in 1998, a lower free energy,<ref>Template:Cite journal</ref> 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.<ref name="morissette"/> As a consequence of the fact that even a trace amount of form II can result in the conversion of the more bioavailable form I into form II, the presence of form II threatened the ruin of existing supplies of the oral capsule formulation of ritonavir; and indeed, form II was found in production lines, effectively halting ritonavir production.<ref name="bauer"/> Abbott (now AbbVie) withdrew the capsules from the market, and prescribing physicians were encouraged to switch to a Norvir suspension.Template:Citation needed 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.<ref>Template:Cite journal</ref>

The company's research and development teams ultimately solved the problem by replacing the capsule formulation with a refrigerated gelcap.Template:WhenTemplate:Citation needed In 2000, Abbott (now AbbVie) received FDA-approval for a tablet formulation of lopinavir/ritonavir (Kaletra) which contained a preparation of ritonavir that did not require refrigeration.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Ritonavir tablets produced in a solid dispersion by melt-extrusion was found to remain in form I, and was re-introduced commercially in 2010.<ref>Template:Cite journal</ref>

Society and culture

Economics

In 2003, Abbott (AbbVie, Inc.) raised the price of a Norvir course from Template:US$ per day to Template:US$ 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.<ref>Template:Cite news</ref>

Further reading

• Template:Cite journal