Lopinavir/ritonavir

Lopinavir/ritonavir was once a preferred combination for HIV first-line therapy in the United States.{{cite web | title=Adult and Adolescent Guidelines | website=AIDSinfo | date=4 May 2006 | url=http://aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=7&ClassID=1 | archive-url=https://web.archive.org/web/20060506193229/http://aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=7&ClassID=1 | archive-date=6 May 2006 | url-status=dead | access-date=6 May 2006}} But due to its higher pill burden compared to other protease inhibitor-based regimens and increased gastrointestinal intolerance, it is no longer recommended to treatment-naive patients.{{cite web |title=What to Start: Initial Combination Regimens for the Antiretroviral-Naive Patient |url=https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/11/what-to-start |website=AIDSinfo |access-date=26 August 2020 |page=Table 10. Antiretroviral Components or Regimens Not Recommended as Initial Therapy |date=18 December 2019 |archive-date=31 August 2020 |archive-url=https://web.archive.org/web/20200831213445/https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/11/what-to-start |url-status=dead }}

The most common adverse effects observed with lopinavir/ritonavir are diarrhea and nausea. In key clinical trials, moderate or severe diarrhea occurred in up to 27% of patients, and moderate/severe nausea in up to 16%. Other common adverse effects include abdominal pain, asthenia, headache, vomiting and, particularly in children, rash.{{cite web | title=Kaletra- lopinavir and ritonavir tablet, film coated Kaletra- lopinavir and ritonavir solution | website=DailyMed | date=26 December 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8290add3-4449-4e58-6c97-8fe1eec972e3 | access-date=18 March 2020}}

Lopinavir/ritonavir is anticipated to have varying degrees of interaction with other medications that are also CYP3A and/or P-gp substrates.{{cite journal | vauthors = Zhang L, Zhang Y, Huang SM | title = Scientific and regulatory perspectives on metabolizing enzyme-transporter interplay and its role in drug interactions: challenges in predicting drug interactions | journal = Molecular Pharmaceutics | volume = 6 | issue = 6 | pages = 1766–1774 | date = 19 October 2009 | pmid = 19839641 | doi = 10.1021/mp900132e }}

People with a structural heart disease, preexisting conduction system abnormalities, ischaemic heart disease, or cardiomyopathies should use lopinavir/ritonavir with caution.{{cite web | title=FDA Issues Safety Labeling Changes for Kaletra | website=Medscape | date=10 April 2009 | url=http://www.medscape.com/viewarticle/590940 | archive-url=https://web.archive.org/web/20170910144125/http://www.medscape.com/viewarticle/590940 | archive-date=10 September 2017 | url-status=live | access-date=18 March 2020}}

In March 2011, the US Food and Drug Administration (FDA) notified healthcare professionals of serious health problems that have been reported in premature babies receiving lopinavir/ritonavir oral solution, probably because of its propylene glycol content. They recommend the use should be avoided in premature babies.{{cite web | work = Drugs.com | url = https://www.drugs.com/fda/kaletra-lopinavir-ritonavir-label-change-serious-health-problems-premature-babies-12919.html | title = Kaletra (lopinavir/ritonavir): Label Change - Serious Health Problems in Premature Babies | archive-url = https://web.archive.org/web/20110311020411/http://www.drugs.com/fda/kaletra-lopinavir-ritonavir-label-change-serious-health-problems-premature-babies-12919.html | archive-date=11 March 2011 }}

Abbott Laboratories (now, via spinoff, Abbvie) was one of the earliest users of the Advanced Photon Source (APS), a national synchrotron-radiation light source at Argonne National Laboratory. One of the early research projects undertaken at the APS focused on proteins from the human immunodeficiency virus (HIV). Using the APS beam line for X-ray crystallography, researchers determined viral protein structures that allowed them to determine their approach to the development of HIV protease inhibitors, a key enzyme target that processes HIV polyproteins after infection, the function of which allows the lifecycle of the virus to proceed. As a result of this structure-based drug design approach using the Argonne APS, Abbott was able to develop new products that inhibit the protease, and therefore stop virus replication.{{cite web | vauthors = Foster C | title = Research at Argonne helps Abbott Labs develop anti-HIV drug |url = http://www.physorg.com/news76606766.html |access-date = 4 September 2006 |url-status = live |archive-url = https://web.archive.org/web/20061022054830/http://www.physorg.com/news76606766.html |archive-date = 22 October 2006 }}

Lopinavir was developed by Abbott in an attempt to improve upon the company's earlier protease inhibitor, ritonavir, specifically with regard to its serum protein-binding properties (reducing the interference by serum on protease enzyme inhibition) and its HIV resistance profile (reducing the ability of virus to evolve resistance to the drug).{{cite journal | vauthors = Sham HL, Kempf DJ, Molla A, Marsh KC, Kumar GN, Chen CM, Kati W, Stewart K, Lal R, Hsu A, Betebenner D, Korneyeva M, Vasavanonda S, McDonald E, Saldivar A, Wideburg N, Chen X, Niu P, Park C, Jayanti V, Grabowski B, Granneman GR, Sun E, Japour AJ, Leonard JM, Plattner JJ, Norbeck DW | title = ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease | journal = Antimicrobial Agents and Chemotherapy | volume = 42 | issue = 12 | pages = 3218–3224 | date = December 1998 | pmid = 9835517 | pmc = 106025 | doi = 10.1128/AAC.42.12.3218 }} Administered alone, lopinavir has insufficient bioavailability; however, like several HIV protease inhibitors, its blood levels are greatly increased by low doses of ritonavir, a potent inhibitor of intestinal and hepatic cytochrome P450 3A4, which would otherwise reduce drug levels through catabolism.

Lopinavir/ritonavir was approved by the US Food and Drug Administration (FDA) in September 2000,{{cite web | title=Drug Approval Package: Kaletra (Lopinavir/Ritonavir) NDA #21-226 & 21-251 | website=U.S. Food and Drug Administration (FDA) | date=20 November 2001 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-226_Kaletra.cfm | access-date=18 March 2020}}{{cite web|url=https://www.drugs.com/availability/generic-kaletra.html|publisher=Drugs.com|title=Generic Kaletra Availability|access-date=18 February 2020}} and in the European Union in March 2001.{{cite web|url=https://www.ema.europa.eu/en/medicines/human/EPAR/kaletra|publisher=European Medicines Agency (EMA) |title=Kaletra EPAR |date=17 September 2018 |access-date=18 February 2020}}

In March 2020, during the COVID-19 pandemic, the Israeli government announced that it would force AbbVie to license its patents for lopinavir/ritonavir. In response, AbbVie announced that it would cease enforcing its patents on the drug entirely.{{cite web|url=https://theconversation.com/drug-companies-should-drop-their-patents-and-collaborate-to-fight-coronavirus-135241|title=Drug companies should drop their patents and collaborate to fight coronavirus| vauthors = Bonadio E, Baldini A |publisher=The Conversation|date=1 April 2020}}{{cite news | title=Inoculating the world may mean reviving old curbs on patents | website=Pittsburgh Post-Gazette | date=14 April 2020 | url=https://www.msn.com/en-us/news/world/inoculating-the-world-may-mean-reviving-old-curbs-on-patents/ar-BB12e2Q1 | access-date=16 April 2020 | agency=Bloomberg }}{{cite news | vauthors = Scheer S | title=Israel approves generic HIV drug to treat COVID-19 despite doubts | website=Reuters | date=19 March 2020 | url=https://www.reuters.com/article/us-health-coronavirus-israel-drug-idUSKBN216237 | access-date=16 April 2020}}

As a result of high prices and the spread of HIV infection, the government of Thailand issued a compulsory license in January 2007, to produce and/or import generic versions of lopinavir and ritonavir.{{cite web | url = http://www.cptech.org/ip/health/c/thailand/thai-cl-kaletra_en.pdf | title = Decree of Department of Disease Control, Ministry of Public Health, regarding exploitation of patent on drugs & medical supplies by the government on combination drug between lopinavir & ritonavir | archive-url = https://web.archive.org/web/20110717191941/http://www.cptech.org/ip/health/c/thailand/thai-cl-kaletra_en.pdf | archive-date=17 July 2011 }} In response, Abbott Laboratories withdrew its registration for lopinavir and seven of their other new drugs in Thailand, citing the Thai government's lack of respect for patents.[http://www.ft.com/cms/s/a2e81cc8-d1d1-11db-b921-000b5df10621,_i_rssPage=d7e814a8-3012-11da-ba9f-00000e2511c8.html 'Abbott pulls HIV drug in Thai patents protest', Financial Times (14 March 2007)] Abbott's attitude has been denounced by several NGOs worldwide, including a netstrike initiated by Act Up-Paris and a public call to boycott all of Abbott's medicines by the French NGO AIDES.{{cite web | url = http://www.aides.org/rapport/people-livin-with-hiv-lets-change-the-rule-imposed-by-industry.pdf | title = People Living with HIV: Let's change the rules imposed by the pharmaceutical industry! | date = 1 July 2007 | archive-url = https://web.archive.org/web/20071020044146/http://www.aides.org/rapport/people-livin-with-hiv-lets-change-the-rule-imposed-by-industry.pdf | archive-date=20 October 2007 | work = AIDES }}

Heat-stable pellets that can be taken by mouth have been developed for children.{{cite journal | vauthors = Pasipanodya B, Kuwengwa R, Prust ML, Stewart B, Chakanyuka C, Murimwa T, Brophy J, Salami O, Mushavi A, Apollo T | title = Assessing the adoption of lopinavir/ritonavir oral pellets for HIV-positive children in Zimbabwe | journal = Journal of the International AIDS Society | volume = 21 | issue = 12 | pages = e25214 | date = December 2018 | pmid = 30549217 | pmc = 6293134 | doi = 10.1002/jia2.25214 }}

{{see also|Coronavirus disease 2019#Research|COVID-19 drug repurposing research}}

While data for SARS-CoV-1 looked promising, the benefit in COVID-19 is unclear as of March 2020.{{cite journal | vauthors = McCreary EK, Pogue JM | title = Coronavirus Disease 2019 Treatment: A Review of Early and Emerging Options | journal = Open Forum Infectious Diseases | volume = 7 | issue = 4 | pages = ofaa105 | date = April 2020 | pmid = 32284951 | pmc = 7144823 | doi = 10.1093/ofid/ofaa105 | doi-access = free }} In 2020, a non-blinded, randomized trial found lopinavir/ritonavir was not useful to treat severe COVID-19.{{cite journal | vauthors = Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, Li X, Xia J, Chen N, Xiang J, Yu T, Bai T, Xie X, Zhang L, Li C, Yuan Y, Chen H, Li H, Huang H, Tu S, Gong F, Liu Y, Wei Y, Dong C, Zhou F, Gu X, Xu J, Liu Z, Zhang Y, Li H, Shang L, Wang K, Li K, Zhou X, Dong X, Qu Z, Lu S, Hu X, Ruan S, Luo S, Wu J, Peng L, Cheng F, Pan L, Zou J, Jia C, Wang J, Liu X, Wang S, Wu X, Ge Q, He J, Zhan H, Qiu F, Guo L, Huang C, Jaki T, Hayden FG, Horby PW, Zhang D, Wang C | title = A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19 | journal = The New England Journal of Medicine | volume = 382 | issue = 19 | pages = 1787–1799 | date = May 2020 | pmid = 32187464 | pmc = 7121492 | doi = 10.1056/NEJMoa2001282 | quote = This randomized trial found that lopinavir–ritonavir treatment added to standard supportive care was not associated with clinical improvement or mortality in seriously ill patients with Covid-19 different from that associated with standard care alone. | doi-access = free }} In this trial the medication was started typically around 13 days after the start of symptoms.

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• {{cite web | title=Fact sheet on lopinavir and ritonavir (Lpv/R) oral pellets | website=World Health Organization (WHO) | url=https://www.who.int/hiv/pub/toolkits/iatt-factsheet-lopinavir-ritonavir/en/ | archive-url=https://web.archive.org/web/20151121102208/http://www.who.int/hiv/pub/toolkits/iatt-factsheet-lopinavir-ritonavir/en/ | url-status=dead | archive-date=21 November 2015 }}

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