Lopinavir Explained

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.

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]

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

External links

Notes and References

  1. Web site: FDA Approved Drug Products: Kaletra. 30 April 2004 .
  2. Book: Fischer J, Ganellin CR . Analogue-based Drug Discovery . 2006 . John Wiley & Sons . 9783527607495 . 510 .
  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 . 10.1016/j.xphs.2020.11.019. 33248057 . 7689305 .
  4. http://www.rxabbott.com/pdf/kaletratabpi.pdf 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, van den Brande G, Ellis R, Letendre S . 6 . Lopinavir concentrations in cerebrospinal fluid exceed the 50% inhibitory concentration for HIV . AIDS . 19 . 9 . 949–52 . June 2005 . 15905676 . 10.1097/01.aids.0000171409.38490.48 . 3162858 . free .
  6. http://www.manchester.ac.uk/aboutus/news/display/?id=11595 HIV drug used to reverse effects of virus that causes cervical cancer
  7. Stecher C, Marinkov S, Mayr-Harting L, Katic A, Kastner MT, Rieder-Rommer FJ, Lin X, Nekhai S, Steininger C . 6 . 2021. Protein phosphatase 1 regulates Human Cytomegalovirus protein translation by restraining AMPK signaling . Frontiers in Microbiology . 12. 698603 . 10.3389/fmicb.2021.698603. 34335531 . 8320725 . 1664-302X. free.
  8. Ammosova T, Platonov M, Ivanov A, Kont YS, Kumari N, Kehn-Hall K, Jerebtsova M, Kulkarni AA, Uren A, Kovalskyy D, Nekhai S . 6 . 1E7-03, a low MW compound targeting host protein phosphatase-1, inhibits HIV-1 transcription . British Journal of Pharmacology . 171 . 22 . 5059–75 . November 2014 . 25073485 . 4253456 . 10.1111/bph.12863 .
  9. de Wilde AH, Jochmans D, Posthuma CC, Zevenhoven-Dobbe JC, van Nieuwkoop S, Bestebroer TM, van den Hoogen BG, Neyts J, Snijder EJ . 6 . 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 . August 2014 . 24841269 . 4136071 . 10.1128/AAC.03011-14 . free .
  10. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, Li X, Xia J, Chen N, Xiang J, Yu T, Bai T, Xie X, Zhang L, Li C, Yuan Y, Chen H, Li H, Huang H, Tu S, Gong F, Liu Y, Wei Y, Dong C, Zhou F, Gu X, Xu J, Liu Z, Zhang Y, Li H, Shang L, Wang K, Li K, Zhou X, Dong X, Qu Z, Lu S, Hu X, Ruan S, Luo S, Wu J, Peng L, Cheng F, Pan L, Zou J, Jia C, Wang J, Liu X, Wang S, Wu X, Ge Q, He J, Zhan H, Qiu F, Guo L, Huang C, Jaki T, Hayden FG, Horby PW, Zhang D, Wang C . 6 . A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19 . The New England Journal of Medicine . 382 . 19 . 1787–1799 . May 2020 . 32187464 . 7121492 . 10.1056/NEJMoa2001282 . free .

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