Lopinavir/ritonavir

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Lopinavir/ritonavir
Lopinavir and ritonavir.svg
Combination of
LopinavirProtease inhibitor
RitonavirProtease inhibitor (pharmacokinetic booster)
Clinical data
Trade namesKaletra, Aluvia
AHFS/Drugs.comMonograph
MedlinePlusa602015
License data
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
NIAID ChemDB
CompTox Dashboard (EPA)
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Lopinavir/ritonavir (LPV/r), sold under the brand name Kaletra among others, is a fixed dose combination medication for the treatment and prevention of HIV/AIDS.[1] It combines lopinavir with a low dose of ritonavir.[1] It is generally recommended for use with other antiretrovirals.[1] It may be used for prevention after a needlestick injury or other potential exposure.[1] It is taken by mouth as a tablet, capsule, or solution.[1]

Common side effects include diarrhea, vomiting, feeling tired, headaches, and muscle pains.[1] Severe side effects may include pancreatitis, liver problems, and high blood sugar.[1] It is commonly used in pregnancy and it appears to be safe.[1] Both medications are HIV protease inhibitors.[1] Ritonavir functions by slowing down the breakdown of lopinavir.[1]

Lopinavir/ritonavir as a single medication was approved for use in the United States in 2000.[1] It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system.[2] The wholesale cost in the developing world is 18.96 to 113.52 a month.[3] In the United States it is not available as a generic medication and costs more than US$200 for a typical month supply as of 2016.[4]

Medical uses[edit]

As of 2006, lopinavir/ritonavir forms part of the preferred combination for first-line therapy recommended by the US United States Department of Health and Human Services in 2006.[5]

Adverse effects[edit]

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[edit]

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 resitance 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 with ritonavir.[citation needed]

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

Society and culture[edit]

Cost[edit]

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.[14] 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.[15] 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.[16]

Available forms[edit]

Heat-stable pellets that can be taken by mouth have been developed for children.[17]

Research[edit]

Lopinavir/ritonavir is a potential treatment for MERS-CoV, SARS-CoV, and is being studied as a possible treatment for the 2019 novel coronavirus (2019-nCoV) responsible for the 2019–20 Wuhan coronavirus outbreak.[18][19][20] In late January 2020, Chinese medical researchers stated to the media that in exploratory research considering a selection of 30 drug candidates, three of them, remdesivir, chloroquine and lopinavir/ritonavir, seemed to have "fairly good inhibitory effects" on 2019-nCoV at the cellular level. Requests to start clinical testing were submitted.[21]

References[edit]

  1. ^ a b c d e f g h i j k "Lopinavir and Ritonavir". The American Society of Health-System Pharmacists. Archived from the original on 20 December 2016. Retrieved 28 November 2016.
  2. ^ 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.
  3. ^ "Lopinavir + Ritonavir". International Drug Price Indicator Guide. Archived from the original on 5 March 2017. Retrieved 28 November 2016.
  4. ^ Tarascon Pharmacopoeia 2016 Professional Desk Reference Edition. Jones & Bartlett Publishers. 2016. p. 67. ISBN 9781284095302.
  5. ^ DHHS panel. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (May 4, 2006). (Available for download from AIDSInfo Archived 2006-05-06 at the Wayback Machine)
  6. ^ a b KALETRA (lopinavir/ritonavir) capsules; (lopinavir/ritonavir) oral solution. Prescribing information. April 2009 Archived 2010-07-04 at the Wayback Machine
  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): 1766–74. doi:10.1021/mp900132e. PMID 19839641.
  8. ^ FDA Issues Safety Labeling Changes for Kaletra, 2009-04-10, Medscape Today Archived 2017-09-10 at the Wayback Machine
  9. ^ "Kaletra (lopinavir/ritonavir): Label Change - Serious Health Problems in Premature Babies". Drugs.com. Archived from the original on 2011-03-11.
  10. ^ Foster C. "Research at Argonne helps Abbott Labs develop anti-HIV drug". Archived from the original on 2006-10-22. Retrieved 2006-09-04.
  11. ^ a b c 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): 3218–24. doi:10.1128/AAC.42.12.3218. PMC 106025. PMID 9835517.
  12. ^ "Generic Kaletra Availability". FDA. Retrieved 2020-02-18.
  13. ^ "Kaletra". EMA. Retrieved 2020-02-18.
  14. ^ "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 2011-07-17.
  15. ^ 'Abbott pulls HIV drug in Thai patents protest', Financial Times (14 March 2007)
  16. ^ "People Living with HIV: Let's change the rules imposed by the pharmaceutical industry!" (PDF). July 1, 2007. Archived from the original (PDF) on October 20, 2007.
  17. ^ 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.
  18. ^ Paules CI, Marston HD, Fauci AS (January 2020). "Coronavirus Infections-More Than Just the Common Cold". JAMA. doi:10.1001/jama.2020.0757. PMID 31971553.
  19. ^ Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH, Chan KS, et al. (March 2004). "Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings". Thorax. 59 (3): 252–6. doi:10.1136/thorax.2003.012658. PMC 1746980. PMID 14985565.
  20. ^ Andersen PI, Ianevski A, Lysvand H, Vitkauskiene A, Oksenych V, Bjoras M, Telling K, Lutsar I, Dumpis U, Irie Y, Tenson T (2020). "Discovery and Development of Safe-in-Man Broad-Spectrum Antiviral Agents". Preprints. doi:10.20944/preprints201910.0144.v4.
  21. ^ Zhao Y (2020-01-30). "Three drugs fairly effective on novel coronavirus at cellular level". China News Service. Archived from the original on 2020-01-29. Retrieved 2020-02-01.
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