Letermovir

{{Short description|Antiviral drug}} {{Use dmy dates|date=September 2023}} {{cs1 config |name-list-style=vanc |display-authors=6}} {{Infobox drug | image = Letermovir skeletal.svg | image_class = skin-invert-image | alt = | caption =

| tradename = Prevymis | Drugs.com = {{drugs.com|monograph|letermovir}} | MedlinePlus = a618006 | DailyMedID = Letermovir | pregnancy_AU = B3 | pregnancy_category= | routes_of_administration = By mouth, intravenous | ATC_prefix = J05 | ATC_suffix = AX18

| legal_AU = S4 | legal_CA = Rx-only | legal_CA_comment = <ref>{{cite web | title=Product monograph brand safety updates | website=Health Canada | date=7 July 2016 | url=https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-product-database/label-safety-assessment-update/product-monograph-brand-safety-updates.html | access-date=3 April 2024}}</ref><ref>{{cite web | title=Immune system health | website=Health Canada | date=9 May 2018 | url=https://www.canada.ca/en/services/health/drug-health-products/drug-medical-device-highlights-2017/approved-drugs/immune-system-health.html | access-date=13 April 2024}}</ref> | legal_UK =  | legal_US = Rx-only | legal_EU = Rx-only | legal_status =

| IUPAC_name = {(4''S'')-8-Fluoro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid | C=29 | H=28 | F=4 | N=4 | O=4 | smiles = COc1cccc(N2CCN(C3=Nc4c(F)cccc4[C@H](CC(=O)O)N3c3cc(C(F)(F)F)ccc3OC)CC2)c1 | StdInChI=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 | StdInChIKey = FWYSMLBETOMXAG-QHCPKHFHSA-N }}

'''Letermovir''' (INN; brand name '''Prevymis''') is an antiviral drug for the prevention 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.<ref name="DAZ">{{cite news|url=http://www.deutsche-apotheker-zeitung.de/pharmazie/news/2011/09/02/neues-virostatikum-letermovir/5205.html|title=Neues Virostatikum Letermovir|language=German|date=29 August 2011|publisher=Deutsche Apothekerzeitung|archive-date=23 September 2015|access-date=20 October 2013|archive-url=https://web.archive.org/web/20150923213949/http://www.deutsche-apotheker-zeitung.de/pharmazie/news/2011/09/02/neues-virostatikum-letermovir/5205.html|url-status=dead}}</ref> 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.<ref>{{cite web|url=http://www.clinicalleader.com/doc/merck-kicks-off-phase-study-of-cmv-drug-letermovir-0001|title=Merck Kicks Off Phase 3 Study Of CMV Drug Letermovir | vauthors = Masangkay EG | date= 29 July 2014|access-date= 8 October 2014}}</ref>

The drug was granted fast track status by the US Food and Drug Administration (FDA) and orphan drug status by the European Medicines Agency.<ref name="DAZ" /> It is approved for prevention of CMV infection and disease in recipients of an allogeneic stem cell transplant.<ref>{{cite news | title = FDA Approves Letermovir for CMV Prophylaxis Post-Transplantation | url = http://www.onclive.com/web-exclusives/fda-approves-letermovir-for-cmv-prophylaxis-posttransplantation | publisher = onclive.com | date = 9 November 2017 | archive-date = 29 March 2018 | access-date = 26 December 2017 | archive-url = https://web.archive.org/web/20180329084417/http://www.onclive.com/web-exclusives/fda-approves-letermovir-for-cmv-prophylaxis-posttransplantation | url-status = dead }}</ref>

The FDA considers it to be a first-in-class medication.<ref>{{cite report | title=New Drug Therapy Approvals 2017 | website=U.S. Food and Drug Administration (FDA) | date=January 2018 | url=https://www.fda.gov/media/110526/download | archive-url=https://web.archive.org/web/20190914090907/https://www.fda.gov/media/110526/download | url-status=dead | archive-date=14 September 2019 | format=PDF | access-date=16 September 2020}}</ref>

== 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.<ref name="El Helou">{{cite journal | vauthors = El Helou G, Razonable RR | title = Letermovir for the prevention of cytomegalovirus infection and disease in transplant recipients: an evidence-based review | journal = Infection and Drug Resistance | volume = 12 | pages = 1481–1491 | date = 4 June 2019 | pmid = 31239725 | pmc = 6556539 | doi = 10.2147/IDR.S180908 | doi-access = free }}</ref><ref name="AC">{{cite web|title=Prevymis: EPAR – Product Information|publisher=European Medicines Agency|date=1 February 2021|url=https://www.ema.europa.eu/en/documents/product-information/prevymis-epar-product-information_en.pdf}}</ref> 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 protein, which is a component of CMV terminase.<ref>{{Cite journal| vauthors = Zamora D, Perchetti G, Biernacki M, Xie H, Castor JL, Joncas-schronce L, Blazevic R, Leisenring W, Huang ML, Jerome K, Martin PJ, Boeckh M, Greninger AL |date=1 November 2021|title=20. Risk Factors for Breakthrough Cytomegalovirus (CMV) Infection and De Novo Resistance in Hematopoietic Cell Transplantation (HCT) Recipients Receiving Letermovir Prophylaxis|journal=Open Forum Infectious Diseases|volume=8|issue=Supplement_1|pages=S13–S14|doi=10.1093/ofid/ofab466.020|issn=2328-8957|doi-access=free|pmc=8643935}}</ref><ref>{{cite journal | vauthors = Perchetti GA, Biernacki MA, Xie H, Castor J, Joncas-Schronce L, Ueda Oshima M, Kim Y, Jerome KR, Sandmaier BM, Martin PJ, Boeckh M, Greninger AL, Zamora D | title = Cytomegalovirus breakthrough and resistance during letermovir prophylaxis | journal = Bone Marrow Transplantation | volume = 58 | issue = 4 | pages = 430–436 | date = April 2023 | pmid = 36693927 | doi = 10.1038/s41409-023-01920-w | s2cid = 256230989 }}</ref>

== 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.<ref name="AC" /><ref>Letermovir {{drugs.com|PPA|letermovir}}. Accessed 17 April 2021.</ref>

== 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.<ref name="El Helou" /> In general, side effects of the drug are comparable to those under placebo treatment.<ref name="AC" />

== 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.<ref name="AC" />

== 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.{{Technical inline|date=April 2021}} Letermovir is only active against CMV and has no effect on other herpesviruses.<ref name="El Helou" />

=== 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.<ref name="AC" />

The drug is mainly excreted via the feces (93.3%). Less than 2% is found in the urine.<ref name="AC" />

[[File:Letermovir glucuronide.svg|thumb|left|class=skin-invert-image|The glucuronide which is the main metabolite of letermovir]] {{clear left}}

== 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.<ref name="assessment report">{{cite web|title=Prevymis: EPAR – Public assessment report|publisher=European Medicines Agency|date=17 January 2018|url=https://www.ema.europa.eu/en/documents/assessment-report/prevymis-epar-public-assessment-report_en.pdf}}</ref> The molecule has one asymmetric carbon atom, which is in ''S'' configuration.<ref name="assessment report" />

== References == {{reflist}}

== External links == * {{cite web | title=Letermovir Injection | website=MedlinePlus | url=https://medlineplus.gov/druginfo/meds/a618007.html }}

Category:Anti-herpes virus drugs Category:CYP3A4 inducers Category:Phenylpiperazines Category:Drugs developed by Merck & Co. Category:Carboxylic acids Category:Fluoroarenes Category:Methoxy compounds Category:Orphan drugs Category:(Trifluoromethyl)benzene derivatives