Lopinavir

Lopinavir

Clinical data
Pronunciation	/loʊˈpɪnəvɪər/ loh-PIN-ə-veer
Other names	ABT-378
AHFS/Drugs.com	International Drug Names
MedlinePlus	a602015
License data	US  DailyMed:  Lopinavir
Routes of administration	By mouth
ATC code	J05AR10 ( WHO )(with ritonavir)
Legal status
Legal status	UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	Unknown
Protein binding	98-99%
Metabolism	Liver
Elimination half-life	5 to 6 hours
Excretion	Mostly fecal
Identifiers
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
CAS Number	192725-17-0  Y
PubChem CID	92727
DrugBank	DB01601  Y
ChemSpider	83706  Y
UNII	2494G1JF75
KEGG	D01425  Y
ChEMBL	ChEMBL729  Y
CompTox Dashboard (EPA)	DTXSID8046456
ECHA InfoCard	100.281.362
Chemical and physical data
Formula	C37H48N4O5
Molar mass	628.814 g·mol−1
3D model (JSmol)	Interactive image
SMILES 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 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 Y Key:KJHKTHWMRKYKJE-SUGCFTRWSA-N Y
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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

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

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

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]

References

1. "FDA Approved Drug Products: Kaletra". Archived from the original on 26 January 2008. Retrieved 30 April 2004.
2. Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 510. ISBN   9783527607495.
3. Perazzolo S, Zhu, Lin W, Nguyen A, Ho RJ (2021). "Systems and Clinical Pharmacology of COVID-19 Therapeutic Candidates: A Clinical and Translational Medicine Perspective". J Pharm Sci. 110 (3): 1002–1017. Bibcode:2021JPhmS.110.1002P. 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 Archived 22 March 2014 at the Wayback Machine 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.