Lopinavir/ritonavir

Lopinavir/ritonavir
Combination of
Lopinavir Protease inhibitor
Ritonavir Protease inhibitor (pharmacokinetic booster)
Clinical data
Trade names Kaletra, Aluvia
AHFS/Drugs.com Monograph
MedlinePlus a602015
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration		 By mouth
ATC code J05AR10 (WHO)
Legal status
Legal status
Identifiers
CAS Number 369372-47-4 N
NIAID ChemDB 003688
 NYesY (what is this?)  (verify)

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. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlestick injury or other potential exposure. It is taken by mouth as a tablet or solution.[1]

Common side effects include diarrhea, vomiting, feeling tired, headaches, and muscle pains. Severe side effects may include pancreatitis, liver problems, and high blood sugar. It is commonly used in pregnancy and it appears to be safe. Both medications are HIV protease inhibitors. 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 most important medications needed in a basic 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 200 USD for a typical month supply as of 2016.[4]

Medical uses

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

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

Lopinavir was developed by Abbott in an attempt to improve on the HIV resistance and serum protein-binding properties of the company's earlier protease inhibitor, ritonavir.[10] 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 cytochrome P450 3A4.[10] Abbott therefore pursued a strategy of co-administering lopinavir with sub-therapeutic doses of ritonavir, and lopinavir is only marketed as a co-formulation with ritonavir. It is the first multi-drug capsule to contain a drug not available individually.

Lopinavir/ritonavir was approved by the USA FDA on 15 September 2000, and in Europe in April 2001. Its patent will expire in the US on June 26, 2016.

Abbott Laboratories was one of the earliest users of the Advanced Photon Source, a national synchrotron-radiation light source at Argonne National Laboratory. One of the early research projects undertaken at the Advanced Photon Source was the Human Immunodeficiency Virus. Using X-ray crystallography, researchers found the points of attack of the HIV protease inhibitors – agents that block the breakdown of proteins. Protease inhibitors stop HIV from making new copies of itself by blocking the last step in the process, when the virus attempts to replicate – and out of that discovery came the drug Kaletra/Aluvia.[11]

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.[12] 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.[13] 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.[14]

References

  1. 1 2 3 4 "Lopinavir and Ritonavir". The American Society of Health-System Pharmacists. Retrieved 28 November 2016.
  2. ↑ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  3. ↑ "Lopinavir + Ritonavir". International Drug Price Indicator Guide. 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)
  6. 1 2 KALETRA (lopinavir/ritonavir) capsules; (lopinavir/ritonavir) oral solution. Prescribing information. April 2009
  7. ↑ Zhang, Lei; Zhang, Yuanchao; Huang, Shiew-Mei (19 October 2009). "Scientific and Regulatory Perspectives on Metabolizing Enzyme-Transporter Interplay and Its Role in Drug Interactions: Challenges in Predicting Drug Interactions". Molecular Pharmaceuticals. 6 (6): 1766–1774. Retrieved 28 April 2016.
  8. ↑ FDA Issues Safety Labeling Changes for Kaletra, 2009-04-10, Medscape Today
  9. ↑ Drugs.com: Kaletra (lopinavir/ritonavir): Label Change - Serious Health Problems in Premature Babies
  10. 1 2 Sham HL, Kempf DJ, Molla A, et al. (1998) ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrob. Agents Chemother. 42: 3218-24
  11. ↑ Foster, Catherine. "Research at Argonne helps Abbott Labs develop anti-HIV drug". Retrieved 2006-09-04.
  12. ↑ 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
  13. ↑ 'Abbott pulls HIV drug in Thai patents protest', Financial Times (14 March 2007)
  14. ↑ AIDES "People Living with HIV: Let's change the rules imposed by the pharmaceutical industry!" (July 1, 2007)
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