Lopinavir

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Lopinavir
File:Lopinavir.svg
Systematic (IUPAC) name
(2S)-N-[(2S,4S,5S)-5-[2-(2,6-dimethylphenoxy)acetamido]-4-hydroxy-1,6-diphenylhexan-2-yl]-3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanamide
Clinical data
Pregnancy
category
Routes of
administration		 Oral
Legal status
Legal status
  • ℞-only (U.S.), POM (UK)
Pharmacokinetic data
Bioavailability Unknown
Protein binding 98-99%
Metabolism Hepatic
Biological half-life 5 to 6 hours
Excretion Mostly fecal
Identifiers
CAS Number 192725-17-0
ATC code J05AE06 (WHO)
PubChem CID 92727
DrugBank EXPT00388
Chemical data
Formula C37H48N4O5
Molar mass 628.810 g/mol[[Script error: No such module "String".]]
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Lopinavir (ABT-378) is an antiretroviral of the protease inhibitor class. It is marketed by Abbott as Kaletra (high-income countries) and Aluvia (low-income countries), both of which represent a co-formulation with a sub-therapeutic dose of ritonavir, as a component of combination therapy to treat HIV/AIDS. The Kaletra formulation has also been used successfully as monotherapy in some studies.[1]

As of 2006, lopinavir/ritonavir forms part of the preferred combination for first-line therapy recommended by the US DHHS.[2] It is available as capsules, tablets and oral solution.

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.[3] 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.[3] 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 US 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.[4]

Pharmacology

Lopinavir is highly bound to plasma proteins (98-99%).[5]

There are contradictory reports regarding lopinavir penetration into the CSF. Anecdotal reports state that lopinavir cannot be detected in the CSF; however, a study of paired CSF-plasma samples from 26 patients receiving lopinavir/ritonavir found lopinavir CSF levels above the IC50 in 77% of samples.[6]

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.

As reported at the 2009-04-10 patients with a structural heart disease, preexisting conduction system abnormalities, ischaemic heart disease, or cardiomyopathies should use Kaletra (lopinavir/ritonavir) with caution [7].

Access

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.[8] 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.[9] 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.[10]

References

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External links

Antiviral drugs: antiretroviral drugs used against HIV (primarily J05)
Entry/fusion inhibitors
(Discovery & development)
Reverse transcriptase
inhibitors (RTIs)
(1st gen) Efavirenz°# · Nevirapine#  · Loviride◊ · Delavirdine◊ ·
(2nd gen) diarylpyrimidines (Etravirine, Rilpivirine†)  · Lersivirine†
Integrase inhibitors
Raltegravir · Elvitegravir† · Globoidnan A (experimental)  · MK-2048†  · GSK-572†
Maturation inhibitors
Bevirimat† · Vivecon†
Protease Inhibitors (PI)
(Discovery and development)
Atazanavir° · Fosamprenavir° · Lopinavir°# · Darunavir · Nelfinavir# · Ritonavir# · Saquinavir# · Tipranavir · Amprenavir◊ · Indinavir◊#
Combined formulations
Experimental agents
TRIM5alpha (gene)
Other
Failed agents
°DHHS preferred first-line agent. ◊Formerly or rarely used agent.
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  1. ↑ Aidsmap | Kaletra monotherapy as effective as triple therapy for at least 18 months
  2. ↑ DHHS panel. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (May 4, 2006). (Available for download from AIDSInfo)
  3. ↑ 3.0 3.1 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
  4. ↑ Foster, Catherine. "Research at Argonne helps Abbott Labs develop anti-HIV drug". Retrieved 2006-09-04. 
  5. ↑ 5.0 5.1 5.2 KALETRA (lopinavir/ritonavir) capsules; (lopinavir/ritonavir) oral solution. Prescribing information. April 2009
  6. ↑ Capparelli E, Holland D, Okamoto C; et al. (2005). "Lopinavir concentrations in cerebrospinal fluid exceed the 50% inhibitory concentration for HIV". AIDS (London, England). 19 (9). 
  7. ↑ FDA Issues Safety Labeling Changes for Kaletra, 2009-04-10, Medscape Today
  8. ↑ 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
  9. ↑ 'Abbott pulls HIV drug in Thai patents protest', Financial Times (14 March 2007)
  10. ↑ AIDES "People Living with HIV: Let's change the rules imposed by the pharmaceutical industry!" (July 1st, 2007)
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