Common side effects of ritonavir include nausea, vomiting, loss of appetite, diarrhea, and numbness of the hands and feet.[7] Serious side effects include liver complications,pancreatitis,allergic reactions, andarrhythmias.[7] Serious interactions may occur with a number of other medications includingamiodarone andsimvastatin.[7] At low doses, it is considered to be acceptable for use during pregnancy.[11] Ritonavir is of the protease inhibitor class.[7] However, it is also commonly used to inhibit the enzyme that metabolizes other protease inhibitors.[12] This inhibition allows lower doses of these latter medications to be used.[12]
This sectionneeds expansion with: a lead sentence that better describes the very important (pharmacokinetic-pharmakodynamic) PK-PD observations for this first-in-class inhibitor design, and its initial application. You can help byadding missing information.(February 2020)
Ritonavir isindicated in combination with other antiretroviral agents for the treatment of HIV-1-infected patients.[3][4][7] 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.[18][19] Ritonavir is effective in preventing the replication of HIV-1. Protease inhibitors, including ritonavir, effectively blockHIV-1 protease, a crucial enzyme in the reproductive cycle of HIV-1.[20]
Ritonavir exhibits hepatic activity.[28] It inducesCYP1A2 and inhibitsCYP3A4 andCYP2D6. Concomitant therapy of ritonavir with a variety of medications may result in serious and sometimes fataldrug interactions.[29]
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.[8]
This sectionneeds expansion with: with an accurate description of both its HIV protease and CYP3A4 binding characteristics and structural details. You can help byadding missing information.(February 2020)
Ritonavir (center) bound to the active site of HIV protease[citation needed]
Ritonavir is rarely used for its own antiviral activity but remains widely used as a booster of otherprotease inhibitors. More specifically, ritonavir is used to inhibit a particular enzyme, in intestines, liver, and elsewhere, that normallymetabolizes 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.[34][35]. 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§ Adverse drug reactions above.[8][36]
Ritonavir at a 200 mg dose reaches maximum plasma concentration in about 3 hours and has a half life of 3–4 hours.[5][6] Importantly, the pharmacokinetics of Ritonavir are not linear—the half life increases at higher doses or under repeated dosing.[5] For instance, the half life of a 500 mg tablet is 4–6 hours rather than 3–4 hours for a 200 mg tablet.[5] The drug has high bioavailability but about 20% is lost due tofirst-pass metabolism.[5] Rivonavir capsules are not absorbed as quickly as Ritonavir tablets and may exhibit different bioavailability.[7]
Ritonavir was demonstrated to have anin vitro potency of EC50=0.02 μM on HIV-1 protease and highly sustained concentration in plasma after oral administration in several species.[37]
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.[37]
Full details of the synthesis of ritonavir were first published by scientists fromAbbott Laboratories.
New HIV infections and deaths, before and after the FDA approval of "highly active antiretroviral therapy",[39] of which saquinavir and ritonavir were key as the first two protease inhibitors.[medical citation needed] As a result of the new therapies, HIV deaths in the United States fell dramatically within two years.[39]
Ritonavir is sold as Norvir byAbbVie, Inc.[3][4] The USFood and Drug Administration (FDA) approved ritonavir on March 1, 1996,[40][41] 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.[39]
After the start of the COVID pandemic in 2020, many antivirals, including protease inhibitors in general and ritonavir in particular, wererepurposed in an effort to treat the new infection.Lopinavir/ritonavir was found not to work in severeCOVID-19.[42] Virtual screening followed by molecular dynamics analysis predicted ritonavir blocks the binding of the SARS-CoV-2 spike (S) protein to the humanangiotensin-converting enzyme 2 (hACE2) receptor, which is critical for the virus entry into human cells.[43]
Finally in 2021, acombination of ritonavir with nirmatrelvir, a newly developed orally active3C-likeprotease inhibitor, was developed for the treatment of COVID-19.[44][45][46][47] Ritonavir serves to slow down metabolism of nirmatrelvir bycytochrome enzymes to maintain higher circulating concentrations of the main drug.[48] In November that year, Pfizer announced positive phase 2/3 results, including 89% reduction in hospitalizations when given within three days after symptom onset.[49][50]
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.[51] However, like many drugs, crystalline ritonavir can exhibitpolymorphism, 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 thebioavailability can vary in the different arrangements, and this was observed for forms I and II of ritonavir.[52]
During development—ritonavir was introduced in 1996—only the crystal form now called form I was found; however, in 1998, a lowerfree energy,[53] more stable polymorph, form II, was discovered. This more stable crystal form was less soluble, which resulted in significantly lowerbioavailability. The compromised oral bioavailability of the drug led to temporary removal of the oral capsule formulation from the market.[52] 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.[51] Abbott (now AbbVie) withdrew the capsules from the market, and prescribing physicians were encouraged to switch to a Norvir suspension.[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 ofdisappearing polymorphs.[54]
The company's research and development teams ultimately solved the problem by replacing the capsule formulation with a refrigerated gelcap.[when?][citation needed] In 2000, Abbott (now AbbVie) received FDA-approval for a tablet formulation oflopinavir/ritonavir (Kaletra) which contained a preparation of ritonavir that did not require refrigeration.[55] Ritonavir tablets produced in a solid dispersion by melt-extrusion was found to remain in form I, and was re-introduced commercially in 2010.[56]
In 2003, Abbott (AbbVie, Inc.) raised the price of a Norvir course fromUS$1.71 per day toUS$8.57 per day, leading to claims ofprice gouging by patients' groups and some members of Congress. Consumer groupEssential 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.[57]
^abcd"Norvir EPAR".European Medicines Agency (EMA). September 17, 2018.Archived from the original on October 2, 2018. RetrievedAugust 20, 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^abDanner SA, Carr A, Leonard JM, Lehman LM, Gudiol F, Gonzales J, Raventos A, Rubio R, Bouza E, Pintado V, Aguado AG, Garcia de Lomas J, Delgado R, Borleffs JC, Hsu A, Valdes JM, Boucher CA, Cooper DA (December 1995). "A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease. European-Australian Collaborative Ritonavir Study Group".The New England Journal of Medicine.333 (23):1528–1533.doi:10.1056/NEJM199512073332303.hdl:2445/121979.PMID7477167.
^abcdefghij"Ritonavir". The American Society of Health-System Pharmacists.Archived from the original on October 17, 2015. RetrievedOctober 23, 2015.
^World Health Organization (2019).World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization.hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^World Health Organization (2021).World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization.hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
^Carpenter M, Berry H, Pelletier AL (May 2019). "Clinically Relevant Drug-Drug Interactions in Primary Care".American Family Physician.99 (9):558–564.PMID31038898.
^abWO 1994014436, Kempf DJ, Norbeck DW, Sham HL, Zhao C, Sowin TJ, Reno DS, Haight AR, Cooper AJ, "Retroviral protease inhibiting compounds", published July 7, 1994, assigned to Abbott Laboratories.
^Kempf DJ, Norbeck DW, Codacovi L, Wang XC, Kohlbrenner WE, Wideburg NE, et al. (October 1990). "Structure-based, C2 symmetric inhibitors of HIV protease".Journal of Medicinal Chemistry.33 (10):2687–2689.doi:10.1021/jm00172a002.PMID2213822.
^Merry C, Barry MG, Mulcahy F, Ryan M, Heavey J, Tjia JF, et al. (March 1997). "Saquinavir pharmacokinetics alone and in combination with ritonavir in HIV-infected patients".AIDS.11 (4):F29–F33.doi:10.1097/00002030-199704000-00001.PMID9084785.
^abKempf DJ, Sham HL, Marsh KC, Flentge CA, Betebenner D, Green BE, et al. (February 1998). "Discovery of ritonavir, a potent inhibitor of HIV protease with high oral bioavailability and clinical efficacy".Journal of Medicinal Chemistry.41 (4):602–617.doi:10.1021/jm970636+.PMID9484509.
Chemburkar SR, Bauer J, Deming K, Spiwek H, Patel K, Morris J, et al. (2000). "Dealing with the Impact of Ritonavir Polymorphs on the Late Stages of Bulk Drug Process Development".Organic Process Research & Development.4 (5):413–417.doi:10.1021/op000023y.
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