Jump to content

Letermovir: Difference between revisions

From Wikipedia, the free encyclopedia
Browse history interactively
← Previous edit
Content deleted Content added
VisualWikitext
added UNII
update infobox
 
(59 intermediate revisions by 28 users not shown)
Line 1: Line 1:
{{Short description|Antiviral drug}}
{{Drugbox
{{Use dmy dates|date=September 2023}}
⚫
| 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
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox drug
| image = Letermovir skeletal.svg
| image = Letermovir skeletal.svg
| alt =
| alt =
| caption =
| caption =


<!-- Clinical data -->
<!-- Clinical data -->
| tradename =
| tradename = Prevymis
| Drugs.com =
| Drugs.com = {{drugs.com|monograph|letermovir}}
| MedlinePlus =
| MedlinePlus = a618006
| DailyMedID = Letermovir
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_AU = B3
| pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_category=
| pregnancy_category=
⚫
| routes_of_administration = [[Oral administration|By mouth]], [[intravenous]]
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
⚫
| ATC_prefix = J05
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
⚫
| 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 = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM -->
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM -->
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_US = Rx-only
| legal_EU = Rx-only
| legal_status = Investigational
| legal_status =
⚫
| routes_of_administration = Oral


<!-- Pharmacokinetic data -->
<!-- Pharmacokinetic data -->
| bioavailability =
| bioavailability = 37% (estimate)
| protein_bound =
| protein_bound = 98.2%
| metabolism =
| metabolism = [[glucuronidation]] ([[UGT1A1]]/[[UGT1A3|1A3]]) to a minor extent
| elimination_half-life =
| elimination_half-life = 12 hours
| excretion =
| excretion = 93.3% via feces, <2% via kidneys


<!-- Identifiers -->
<!-- Identifiers -->
| CAS_number =
| CAS_number = 917389-32-3
⚫
| ATCvet =
⚫
| ATC_prefix = None
⚫
| ATC_suffix =
| PubChem = 45138674
| PubChem = 45138674
⚫
| DrugBank = DB12070
| UNII_Ref = {{fdacite|correct|FDA}}
⚫
| UNII = 1H09Y5WO1F
⚫
| DrugBank =
| ChemSpiderID = 26352849
| ChemSpiderID = 26352849
⚫
| UNII = 1H09Y5WO1F
⚫
| KEGG = D10801
| ChEMBL = 1241951
| ChEMBL = 1241951
| synonyms = AIC246
| synonyms = AIC246; MK-8228


<!-- Chemical data -->
<!-- Chemical data -->
⚫
| 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
| 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
| molecular_weight = 572.55 g/mol
| smiles = COC1=C(C=C(C=C1)C(F)(F)F)N2[C@H](C3=C(C(=CC=C3)F)N=C2N4CCN(CC4)C5=CC(=CC=C5)OC)CC(=O)O
| 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
| 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
| StdInChIKey = FWYSMLBETOMXAG-QHCPKHFHSA-N
}}
}}
⚫
'''Letermovir''' ([[International Nonproprietary Name|INN]]) is an antiviral drug that is being developed for the treatment of [[cytomegalovirus]] (CVM) infections. It has been tested in CMV infected patients with [[allogeneic stem cell transplant]]s and may also be useful for other patients with a compromised immune system such as those with organ transplants or [[HIV infection]]s.<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=2011-08-29|publisher=Deutsche Apothekerzeitung}}</ref>


⚫
'''Letermovir''' ([[International Nonproprietary Name|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 infection]]s.<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}}</ref> The drug was initially [[drug development|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.|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 has been granted [[FDA Fast Track Development Program|fast track status]] by the [[US Food and Drug Administration]] (FDA) and [[orphan drug]] status by the [[European Medicines Agency]].<ref name="DAZ" />


The drug was granted [[FDA Fast Track Development Program|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}}</ref>
The drug candidate is under development by [[Merck & Co.]], Inc as investigative compound MK-8828.<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 |last= Masangkay |first=Estel Grace| date= July 29, 2014|accessdate= 8 Oct 2014}}</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 | format=PDF | access-date=16 September 2020}}</ref>


==References==
== 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 [[amplicon]].<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>
⚫
{{reflist}}


== Contraindications ==
Combining the drug with [[pimozide]] or [[ergot alkaloid]]s (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 ==
⚫
[[Category:Anti-herpes virus drugs]]
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 ==
{{antiinfective-drug-stub}}
=== 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 protein]]s. 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|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 [[Cahn–Ingold–Prelog priority rules|''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 }}

{{DNA antivirals}}
{{Portal bar | Medicine}}
{{Authority control}}

⚫
[[Category:Anti-herpes virus drugs]]
[[Category:CYP3A4 inducers]]
[[Category:Trifluoromethyl compounds]]
[[Category:Phenylpiperazines]]
[[Category:Drugs developed by Merck & Co.]]
[[Category:Carboxylic acids]]
[[Category:Fluoroarenes]]
[[Category:Orphan drugs]]

Latest revision as of 03:35, 14 April 2024

Letermovir
Clinical data
Trade namesPrevymis
Other namesAIC246; MK-8228
AHFS/Drugs.comMonograph
MedlinePlusa618006
License data
Pregnancy
category
  • AU: B3
Routes of
administration		By mouth, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability37% (estimate)
Protein binding98.2%
Metabolismglucuronidation (UGT1A1/1A3) to a minor extent
Elimination half-life12 hours
Excretion93.3% 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 InfoCard100.232.644 Edit this at Wikidata
Chemical and physical data
FormulaC29H28F4N4O4
Molar mass572.561 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.[3] 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.[4]

The drug was granted fast track status by the US Food and Drug Administration (FDA) and orphan drug status by the European Medicines Agency.[3] It is approved for prevention of CMV infection and disease in recipients of an allogeneic stem cell transplant.[5]

The FDA considers it to be a first-in-class medication.[6]

Medical use

[edit]

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.[7][8] 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.[9][10]

Contraindications

[edit]

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.[8][11]

Adverse effects

[edit]

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.[7] In general, side effects of the drug are comparable to those under placebo treatment.[8]

Overdose

[edit]

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.[8]

Pharmacology

[edit]

Mechanism of action

[edit]

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.[7]

Pharmacokinetics

[edit]

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.[8]

The drug is mainly excreted via the feces (93.3%). Less than 2% is found in the urine.[8]

The glucuronide which is the main metabolite of letermovir

Chemistry

[edit]

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.[12] The molecule has one asymmetric carbon atom, which is in S configuration.[12]

References

[edit]
  1. ^ "Product monograph brand safety updates". Health Canada. 7 July 2016. Retrieved 3 April 2024.
  2. ^ "Immune system health". Health Canada. 9 May 2018. Retrieved 13 April 2024.
  3. ^ a b "Neues Virostatikum Letermovir" (in German). Deutsche Apothekerzeitung. 29 August 2011.
  4. ^ Masangkay EG (29 July 2014). "Merck Kicks Off Phase 3 Study Of CMV Drug Letermovir". Retrieved 8 October 2014.
  5. ^ "FDA Approves Letermovir for CMV Prophylaxis Post-Transplantation". onclive.com. 9 November 2017.
  6. ^ New Drug Therapy Approvals 2017 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2018. Retrieved 16 September 2020.
  7. ^ a b c 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.
  8. ^ a b c d e f "Prevymis: EPAR – Product Information" (PDF). European Medicines Agency. 1 February 2021.
  9. ^ 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.
  10. ^ 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.
  11. ^ Letermovir Professional Drug Facts. Accessed 17 April 2021.
  12. ^ a b "Prevymis: EPAR – Public assessment report" (PDF). European Medicines Agency. 17 January 2018.
[edit]
Retrieved from "https://en.wikipedia.org/w/index.php?title=Letermovir&oldid=1218833878"