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Lopinavir

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Lopinavir
Clinical data
Other namesABT-378
AHFS/Drugs.comInternational Drug Names
MedlinePlusa602015
License data
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityUnknown
Protein binding98-99%
MetabolismLiver
Elimination half-life5 to 6 hours
ExcretionMostly fecal
Identifiers
  • (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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.281.362 Edit this at Wikidata
Chemical and physical data
FormulaC37H48N4O5
Molar mass628.814 g·mol−1
3D model (JSmol)
  • O=C(N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](NC(=O)[C@@H](N2C(=O)NCCC2)C(C)C)Cc3ccccc3)COc4c(cccc4C)C
  • InChI=1S/C37H48N4O5/c1-25(2)34(41-20-12-19-38-37(41)45)36(44)39-30(21-28-15-7-5-8-16-28)23-32(42)31(22-29-17-9-6-10-18-29)40-33(43)24-46-35-26(3)13-11-14-27(35)4/h5-11,13-18,25,30-32,34,42H,12,19-24H2,1-4H3,(H,38,45)(H,39,44)(H,40,43)/t30-,31-,32-,34-/m0/s1 checkY
  • Key:KJHKTHWMRKYKJE-SUGCFTRWSA-N checkY
  (verify)

Lopinavir is an antiretroviral of the protease inhibitor class. It is used against HIV infections as a fixed-dose combination with another protease inhibitor, ritonavir (lopinavir/ritonavir).[1]

It was patented in 1995 and approved for medical use in 2000.[2] Considered now as second-line therapy in the West, it is still prescribed in LMIC, especially among children living with HIV. Lopinavir and ritonavir can be taken as a tablet or an oral solution, a preferred option in children. In the early stages of COVID-19 pandemics, lopinavir was repurposed against the SARS-CoV-2 virus in the hope of disturbing its protease activity.[3]

Side effects

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Side effects, interactions, and contraindications have only been evaluated in the drug combination lopinavir/ritonavir. They include nausea, vomiting, and stomach aches.[citation needed]

Pharmacology

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Lopinavir is highly bound to plasma proteins (98–99%).[4]

Reports are contradictory regarding lopinavir penetration into the cerebrospinal fluid (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.[5]

Research

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A 2014 study indicates that lopinavir is effective against the human papilloma virus (HPV). The study used the equivalent of one tablet twice a day applied topically to the cervices of women with high-grade and low-grade precancerous conditions. After three months of treatment, 82.6% of the women who had high-grade disease had normal cervical conditions, confirmed by smears and biopsies.[6] Lopinavir has been shown to impair protein synthesis via AMP-activated protein kinase (AMPK) and eEF2 kinase (eEF2K) activation, a mechanism that is similar to the antiviral effect of protein phosphatase 1 inhibitors.[7][8]

Lopinavir was found to inhibit MERS-CoV replication in the low-micromolar range in cell cultures.[9] In 2020, lopinavir/ritonavir was found not to work in severe COVID-19. In this trial the medication was started typically around 13 days after the start of symptoms.[10]

A long-acting injectable formulation of lopinavir is under clinical trial aiming at monthly dosing (NCT05850728).

References

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  1. ^ "FDA Approved Drug Products: Kaletra". Retrieved 30 April 2004.
  2. ^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 510. ISBN 9783527607495.
  3. ^ Perazzolo, Simone; Zhu; Lin, Weixian; Nguyen, Alexander; Ho, Rodney JY (2021). "Systems and Clinical Pharmacology of COVID-19 Therapeutic Candidates: A Clinical and Translational Medicine Perspective". J Pharm Sci. 110 (3): 1002–1017. doi:10.1016/j.xphs.2020.11.019. PMC 7689305. PMID 33248057.
  4. ^ Kaletra (lopinavir/ritonavir) capsules; (lopinavir/ritonavir) oral solution. Prescribing information. April 2009
  5. ^ Capparelli EV, Holland D, Okamoto C, Gragg B, Durelle J, Marquie-Beck J, et al. (June 2005). "Lopinavir concentrations in cerebrospinal fluid exceed the 50% inhibitory concentration for HIV". AIDS. 19 (9): 949–52. doi:10.1097/01.aids.0000171409.38490.48. PMID 15905676. S2CID 3162858.
  6. ^ HIV drug used to reverse effects of virus that causes cervical cancer University of Manchester, 17 February 2014.
  7. ^ Stecher C, Marinkov S, Mayr-Harting L, Katic A, Kastner MT, Rieder-Rommer FJ, et al. (2021). "Protein phosphatase 1 regulates Human Cytomegalovirus protein translation by restraining AMPK signaling". Frontiers in Microbiology. 12: 698603. doi:10.3389/fmicb.2021.698603. ISSN 1664-302X. PMC 8320725. PMID 34335531.
  8. ^ Ammosova T, Platonov M, Ivanov A, Kont YS, Kumari N, Kehn-Hall K, et al. (November 2014). "1E7-03, a low MW compound targeting host protein phosphatase-1, inhibits HIV-1 transcription". British Journal of Pharmacology. 171 (22): 5059–75. doi:10.1111/bph.12863. PMC 4253456. PMID 25073485.
  9. ^ de Wilde AH, Jochmans D, Posthuma CC, Zevenhoven-Dobbe JC, van Nieuwkoop S, Bestebroer TM, et al. (August 2014). "Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture". Antimicrobial Agents and Chemotherapy. 58 (8): 4875–84. doi:10.1128/AAC.03011-14. PMC 4136071. PMID 24841269.
  10. ^ Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. (May 2020). "A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19". The New England Journal of Medicine. 382 (19): 1787–1799. doi:10.1056/NEJMoa2001282. PMC 7121492. PMID 32187464.
[edit]
  • "Lopinavir". Drug Information Portal. U.S. National Library of Medicine.
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