Lopinavir/ritonavir

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222px
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)
Legal status
Routes of
administration		 Oral
Identifiers
CAS Number 369372-47-4 N
ATC code J05AR10 (WHO)
NIAID ChemDB 003688
 NYesY (what is this?)  (verify)

Lopinavir/ritonavir is a fixed dose combination drug for the treatment of HIV/AIDS. It combines lopinavir with low doses of ritonavir into a single pill.

As of 2006, lopinavir/ritonavir forms part of the preferred combination for first-line therapy recommended by the US DHHS.[1] It is available as capsules, tablets and oral solution. It has also been used successfully as a monotherapy in some studies.[2]

It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[3] As of 2015 the cost for a typical month of medication in the United States is more than 200 USD.[4]

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%.[5] Other common adverse effects include abdominal pain, asthenia, headache, vomiting and, particularly in children, rash.[5]

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

Kaletra is anticipated to have varying degrees of interaction with other medications that are also CYP3A and/or P-gp substrates.[6]

Patients with a structural heart disease, preexisting conduction system abnormalities, ischaemic heart disease, or cardiomyopathies should use lopinavir/ritonavir with caution.[7]

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.[8]

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.[9] 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.[9] 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.[10]

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.[11] 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.[12] 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.[13]

References

  1. ↑ DHHS panel. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (May 4, 2006). (Available for download from AIDSInfo)
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ 5.0 5.1 KALETRA (lopinavir/ritonavir) capsules; (lopinavir/ritonavir) oral solution. Prescribing information. April 2009
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ FDA Issues Safety Labeling Changes for Kaletra, 2009-04-10, Medscape Today
  8. ↑ Drugs.com: Kaletra (lopinavir/ritonavir): Label Change - Serious Health Problems in Premature Babies
  9. ↑ 9.0 9.1 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
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ 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
  12. ↑ 'Abbott pulls HIV drug in Thai patents protest', Financial Times (14 March 2007)
  13. ↑ AIDES "People Living with HIV: Let's change the rules imposed by the pharmaceutical industry!" (July 1, 2007)
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