Letermovir

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Letermovir
Letermovir skeletal.svg
Clinical data
Trade names Prevymis
Other namesAIC246; MK-8228
AHFS/Drugs.com Monograph
MedlinePlus a618006
License data
Pregnancy
category
  • AU:B3
Routes of
administration 		By mouth, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 37% (estimate)
Protein binding 98.2%
Metabolism glucuronidation (UGT1A1/1A3) to a minor extent
Elimination half-life 12 hours
Excretion 93.3% via feces, <2% via kidneys
Identifiers
  • {(4S)-8-Fluoro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.232.644 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C29H28F4N4O4
Molar mass 572.561 g·mol−1
3D model (JSmol)
  • COc1cccc(N2CCN(C3=Nc4c(F)cccc4[C@H](CC(=O)O)N3c3cc(C(F)(F)F)ccc3OC)CC2)c1
  • InChI=1S/C29H28F4N4O4/c1-40-20-6-3-5-19(16-20)35-11-13-36(14-12-35)28-34-27-21(7-4-8-22(27)30)23(17-26(38)39)37(28)24-15-18(29(31,32)33)9-10-25(24)41-2/h3-10,15-16,23H,11-14,17H2,1-2H3,(H,38,39)/t23-/m0/s1
  • Key:FWYSMLBETOMXAG-QHCPKHFHSA-N

Letermovir (INN; brand name Prevymis) is an antiviral drug for the treatment of cytomegalovirus (CMV) infections. It has been tested in CMV infected patients with allogeneic stem cell transplants and may also be useful for other patients with a compromised immune system such as those with organ transplants or HIV infections. [1] The drug was initially developed by the anti-infective division at Bayer, which became AiCuris Anti-infective Cures AG through a spin-out and progressed the development to end of Phase 2 before the project was sold to Merck & Co for Phase 3 development and approval. [2]

Contents

The drug was granted fast track status by the US Food and Drug Administration (FDA) and orphan drug status by the European Medicines Agency. [1] It is approved for prevention of CMV infection and disease in recipients of an allogeneic stem cell transplant. [3]

The FDA considers it to be a first-in-class medication. [4]

Medical use

In the US as well as in the EU, letermovir is used for the prevention of cytomegalovirus infection and disease in adult CMV-seropositive recipients of an allogeneic stem cell transplant. The therapy is started shortly after the transplantation and typically lasts for 100 days. [5] [6] Although letermovir is a relatively new antiviral, CMV resistance has been documented in stem cell transplantation recipients; although rare, breakthrough infections of prophylactic treatment with letermovir underscores the ongoing selective pressure on CMV's viral evolution and its continued ability to evade therapeutic suppression through mutations in critical gene regions such as within the UL56 amplicon. [7] [8]

Contraindications

Combining the drug with pimozide or ergot alkaloids (such as ergotamine or methylergometrine) is contraindicated because these drugs are metabolized by the liver enzyme CYP3A4, and letermovir inhibits this enzyme. In people who also take ciclosporin, which increases letermovir concentrations in the body, combination with the cholesterol lowering drugs simvastatin and pitavastatin is also contraindicated. In Canada, this also applies to bosentan, lovastatin and rosuvastatin; and in the EU, to dabigatran, atorvastatin, and rosuvastatin. [6] [9]

Adverse effects

Side effects from the use of letermovir are uncommon, but gastrointestinal symptoms such as gastritis and nausea may occur, as can dyspnea (difficulties breathing) and hepatitis. [5] In general, side effects of the drug are comparable to those under placebo treatment. [6]

Overdose

In studies, giving the threefold therapeutic dose for 14 days resulted in no additional adverse effects. It is unknown whether the substance can be removed from the system by hemodialysis. [6]

Pharmacology

Mechanism of action

Letermovir is a viral terminase inhibitor. It specifically inhibits the CMV viral terminase complex which is encoded by the CMV genes UL56, UL51 and UL89. This inhibition has the effect of preventing cleavage of CMV DNA concatamers, resulting in long uncleaved DNA and noninfectious viral particles.[ jargon ] Letermovir is only active against CMV and has no effect on other herpesviruses. [5]

Pharmacokinetics

Letermovir is quickly absorbed from the gut, reaching its highest concentrations in the blood plasma after 1.5 to 3 hours. Its bioavailability is estimated to be 37%. Ciclosporin increases this bioavailability to about 85%. When in the bloodstream, the substance is almost completely (98.2%) bound to plasma proteins. It is mostly (96.6%) circulating in its original form; only a small proportion is metabolized by the liver enzymes UGT1A1 and UGT1A3, resulting in a glucuronide. [6]

The drug is mainly excreted via the feces (93.3%). Less than 2% is found in the urine. [6]

The glucuronide which is the main metabolite of letermovir Letermovir glucuronide.svg
The glucuronide which is the main metabolite of letermovir

Chemistry

Letermovir is used as the free acid. It is a white to off-white, amorphous powder that is slightly hygroscopic, very slightly soluble in water, and very soluble in acetonitrile, acetone, dimethylacetamide, ethanol, and 2-propanol. [10] The molecule has one asymmetric carbon atom, which is in S configuration. [10]

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References

  1. 1 2 "Neues Virostatikum Letermovir" (in German). Deutsche Apothekerzeitung. 29 August 2011.
  2. ↑ Masangkay EG (29 July 2014). "Merck Kicks Off Phase 3 Study Of CMV Drug Letermovir" . Retrieved 8 October 2014.
  3. ↑ "FDA Approves Letermovir for CMV Prophylaxis Post-Transplantation". onclive.com. 9 November 2017.
  4. ↑ New Drug Therapy Approvals 2017 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2018. Retrieved 16 September 2020.
  5. 1 2 3 El Helou G, Razonable RR (4 June 2019). "Letermovir for the prevention of cytomegalovirus infection and disease in transplant recipients: an evidence-based review". Infection and Drug Resistance. 12: 1481–1491. doi: 10.2147/IDR.S180908 . PMC   6556539 . PMID   31239725.
  6. 1 2 3 4 5 6 "Prevymis: EPAR – Product Information" (PDF). European Medicines Agency. 1 February 2021.
  7. ↑ Zamora D, Perchetti G, Biernacki M, Xie H, Castor JL, Joncas-schronce L, et al. (1 November 2021). "20. Risk Factors for Breakthrough Cytomegalovirus (CMV) Infection and De Novo Resistance in Hematopoietic Cell Transplantation (HCT) Recipients Receiving Letermovir Prophylaxis". Open Forum Infectious Diseases. 8 (Supplement_1): S13–S14. doi: 10.1093/ofid/ofab466.020 . ISSN   2328-8957. PMC   8643935 .{{cite journal}}: CS1 maint: overridden setting (link)
  8. ↑ Perchetti GA, Biernacki MA, Xie H, Castor J, Joncas-Schronce L, Ueda Oshima M, et al. (April 2023). "Cytomegalovirus breakthrough and resistance during letermovir prophylaxis". Bone Marrow Transplantation. 58 (4): 430–436. doi:10.1038/s41409-023-01920-w. PMID   36693927. S2CID   256230989.{{cite journal}}: CS1 maint: overridden setting (link)
  9. ↑ Letermovir Professional Drug Facts . Accessed 17 April 2021.
  10. 1 2 "Prevymis: EPAR – Public assessment report" (PDF). European Medicines Agency. 17 January 2018.
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