Lopinavir

drugbox
IUPAC_name = (2"S")-"N"- [(2S,4S,5S)-5-{ [2-(2,6-dimethylphenoxy)
acetyl] amino}-4-hydroxy-1,6-diphenyl-hexan-2-yl] -
3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanamide

---

CAS_number = 192725-17-0
ATC_prefix = J05
ATC_suffix = AE06
PubChem = 92727
DrugBank = EXPT00388
C = 37 |H = 48 |N = 4 |O = 5
molecular_weight = 628.810 g/mol
smiles = O=C(COc1c(C)cccc1C)NC(Cc1ccccc1)C(O)CC(Cc1ccccc1)NC(=O)C(C(C)C)N1CCCNC1=O
bioavailability = Unknown
protein_bound = 98-99%
metabolism = Hepatic
elimination_half-life = 5 to 6 hours
excretion = Mostly fecal
pregnancy_category = C (U.S.)
legal_status = ℞-only (U.S.), POM (UK)
routes_of_administration = Oral

Lopinavir (ABT-378) is an antiretroviral of the protease inhibitor class. It is marketed by Abbott as Kaletra (capsules) and Aluvia (non-refrigerated tablets), 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. [ [http://www.aidsmap.com/en/news/4140714E-EFE1-45FD-9E77-E230D787542E.asp Aidsmap | "Kaletra" monotherapy as effective as triple therapy for at least 18 months ] ]

As of 2006, lopinavir/ritonavir forms part of the preferred combination for first-line therapy recommended by the US DHHS.DHHS panel. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (May 4, 2006). (Available for download from [http://www.aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=7&ClassID=1 AIDSInfo] )] 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. [http://aac.asm.org/cgi/reprint/42/12/3218?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&searchid=1&FIRSTINDEX=0&volume=42&firstpage=3218&resourcetype=HWCIT 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] ] 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. 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.

Pharmacology

Lopinavir is highly bound to plasma proteins (98-99%). [http://www.rxabbott.com/pdf/kaletrapi.pdf KALETRA (lopinavir/ritonavir) capsules; (lopinavir/ritonavir) oral solution. Prescribing information. April 2005] ]

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. [cite journal | title=Lopinavir concentrations in cerebrospinal fluid exceed the 50% inhibitory concentration for HIV | author=Capparelli E, Holland D, Okamoto C, "et al." | journal=AIDS (London, England) | year=2005 | volume=19 | issue=9 ]

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

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

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. [ [http://www.cptech.org/ip/health/c/thailand/thai-cl-kaletra_en.pdf 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] ] 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. [ [http://www.ft.com/cms/s/a2e81cc8-d1d1-11db-b921-000b5df10621,_i_rssPage=d7e814a8-3012-11da-ba9f-00000e2511c8.html 'Abbott pulls HIV drug in Thai patents protest', Financial Times (14 March 2007)] ] 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. [ [http://www.aides.org/rapport/people-livin-with-hiv-lets-change-the-rule-imposed-by-industry.pdf AIDES "People Living with HIV: Let's change the rules imposed by the pharmaceutical industry!" (July 1st, 2007)] ]

References

External links

* [http://www.kaletra.com/ Abbott: Kaletra (lopinavir/ritonavir) tablets]