Lopinavir/ritonavir

Lopinavir/ritonavir (LPV/r), sold under the brand name Kaletra among others, is a fixed-dose combination antiretroviral medication for the treatment and prevention of HIV/AIDS.[2] It combines lopinavir with a low dose of ritonavir.[2] It is generally recommended for use with other antiretrovirals.[2] It may be used for prevention after a needlestick injury or other potential exposure.[2] It is taken by mouth as a tablet, capsule, or solution.[2]

Lopinavir/ritonavir
Combination of
LopinavirProtease inhibitor
RitonavirProtease inhibitor (pharmacokinetic booster)
Clinical data
Trade namesKaletra, Aluvia
AHFS/Drugs.comMonograph
MedlinePlusa602015
License data
Pregnancy
category
  • AU: B3
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
KEGG
NIAID ChemDB
CompTox Dashboard (EPA)
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Common side effects include diarrhea, vomiting, feeling tired, headaches, and muscle pains.[2] Severe side effects may include pancreatitis, liver problems, and high blood sugar.[2] It is commonly used in pregnancy and it appears to be safe.[2] Both medications are HIV protease inhibitors.[2] Ritonavir functions by slowing down the breakdown of lopinavir.[2]

Lopinavir/ritonavir as a single medication was approved for use in the United States in 2000.[2] It is on the World Health Organization's List of Essential Medicines.[3]

Medical uses

Lopinavir/ritonavir was once a preferred combination for HIV first-line therapy in the United States.[4] But due its higher pill burden compared to than other protease inhibitor-based regimens and increased gastrointestinal intolerance, it is no longer recommended to treatment-naive patients.[5]

Adverse effects

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%.[6] Other common adverse effects include abdominal pain, asthenia, headache, vomiting and, particularly in children, rash.[6]

Raised liver enzymes and hyperlipidemia (both hypertriglyceridemia and hypercholesterolemia) are also commonly observed during lopinavir/ritonavir treatment.

Lopinavir/ritonavir is anticipated to have varying degrees of interaction with other medications that are also CYP3A and/or P-gp substrates.[7]

People with a structural heart disease, preexisting conduction system abnormalities, ischaemic heart disease, or cardiomyopathies should use lopinavir/ritonavir with caution.[8]

On 8 March 2011 the U.S. Food and Drug Administration 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.[9]

History

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.[10][11]

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).[11] 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.[11] Abbott, therefore, pursued a strategy of co-administering lopinavir with doses of ritonavir sub-therapeutic with respect to HIV inhibition; hence, lopinavir was only formulated and marketed as a fixed-dose combination medication with ritonavir.

Lopinavir/ritonavir was approved by the US Food and Drug Administration (FDA) on 15 September 2000,[12][13] and in Europe on 19 March 2001.[14] Its patent was scheduled to expire in the US on 26 June 2016.

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.[15][16][17]

Society and culture

Cost

As a result of high prices and the spread of HIV infection, the government of Thailand issued a compulsory license on 29 January 2007, to produce and/or import generic versions of lopinavir and ritonavir.[18] 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.[19] 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.[20]

Available forms

Heat-stable pellets that can be taken by mouth have been developed for children.[21]

Research
See also: Coronavirus disease 2019 § Research, and COVID-19 drug repurposing research

While data for SARS-CoV-1 looked promising, the benefit in COVID-19 is unclear as of 23 March 2020.[22] In 2020, a non-blinded, randomized trial found lopinavir/ritonavir was not useful to treat severe COVID-19.[23][22] In this trial the medication was started typically around 13 days after the start of symptoms.[22]

References
  1. "Kaletra Product information". Health Canada. 19 March 2019. Retrieved 18 March 2020.
  2. "Lopinavir and Ritonavir". The American Society of Health-System Pharmacists. Archived from the original on 20 December 2016. Retrieved 28 November 2016.
  3. 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.
  4. "Adult and Adolescent Guidelines". AIDSinfo. 4 May 2006. Archived from the original on 6 May 2006. Retrieved 6 May 2006.
  5. "What to Start: Initial Combination Regimens for the Antiretroviral-Naive Patient". AIDSinfo. 18 December 2019. p. Table 10. Antiretroviral Components or Regimens Not Recommended as Initial Therapy. Archived from the original on 31 August 2020. Retrieved 26 August 2020.
  6. "Kaletra- lopinavir and ritonavir tablet, film coated Kaletra- lopinavir and ritonavir solution". DailyMed. 26 December 2019. Retrieved 18 March 2020.
  7. Zhang L, Zhang Y, Huang SM (19 October 2009). "Scientific and regulatory perspectives on metabolizing enzyme-transporter interplay and its role in drug interactions: challenges in predicting drug interactions". Molecular Pharmaceutics. 6 (6): 1766–1774. doi:10.1021/mp900132e. PMID 19839641.
  8. "FDA Issues Safety Labeling Changes for Kaletra". Medscape. 10 April 2009. Archived from the original on 10 September 2017. Retrieved 18 March 2020.
  9. "Kaletra (lopinavir/ritonavir): Label Change - Serious Health Problems in Premature Babies". Drugs.com. Archived from the original on 11 March 2011.
  10. Foster C. "Research at Argonne helps Abbott Labs develop anti-HIV drug". Archived from the original on 22 October 2006. Retrieved 4 September 2006.
  11. Sham HL, Kempf DJ, Molla A, Marsh KC, Kumar GN, Chen CM, et al. (December 1998). "ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease". Antimicrobial Agents and Chemotherapy. 42 (12): 3218–3224. doi:10.1128/AAC.42.12.3218. PMC 106025. PMID 9835517.
  12. "Drug Approval Package: Kaletra (Lopinavir/Ritonavir) NDA #21-226 & 21-251". U.S. Food and Drug Administration (FDA). 20 November 2001. Retrieved 18 March 2020.
  13. "Generic Kaletra Availability". Drugs.com. Retrieved 18 February 2020.
  14. "Kaletra EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 18 February 2020.
  15. Bonadio E, Baldini A (1 April 2020). "Drug companies should drop their patents and collaborate to fight coronavirus". The Conversation.
  16. "Inoculating the world may mean reviving old curbs on patents". Pittsburgh Post-Gazette. Bloomberg. 14 April 2020. Retrieved 16 April 2020.
  17. Scheer S (19 March 2020). "Israel approves generic HIV drug to treat COVID-19 despite doubts". Reuters. Retrieved 16 April 2020.
  18. "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" (PDF). Archived from the original (PDF) on 17 July 2011.
  19. 'Abbott pulls HIV drug in Thai patents protest', Financial Times (14 March 2007)
  20. "People Living with HIV: Let's change the rules imposed by the pharmaceutical industry!" (PDF). AIDES. 1 July 2007. Archived from the original (PDF) on 20 October 2007.
  21. Pasipanodya B, Kuwengwa R, Prust ML, Stewart B, Chakanyuka C, Murimwa T, et al. (December 2018). "Assessing the adoption of lopinavir/ritonavir oral pellets for HIV-positive children in Zimbabwe". Journal of the International AIDS Society. 21 (12): e25214. doi:10.1002/jia2.25214. PMC 6293134. PMID 30549217.
  22. McCreary EK, Pogue JM (April 2020). "Coronavirus Disease 2019 Treatment: A Review of Early and Emerging Options". Open Forum Infectious Diseases. 7 (4): ofaa105. doi:10.1093/ofid/ofaa105. PMC 7144823. PMID 32284951.
  23. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. (May 2020). "A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19". The New England Journal of Medicine. 382 (19): 1787–1799. doi:10.1056/NEJMoa2001282. PMC 7121492. PMID 32187464. 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.
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