Letermovir

Letermovir
Names
Trade namesPrevymis
Other namesAIC246; MK-8228
IUPAC name
  • {(4S)-8-Fluoro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid
Clinical data
Drug classAntiviral
Main usesPrevent cytomegalovirus (CMV) reactivation[1]
Side effectsNausea, diarrhea, vomiting[2]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: B3
  • US: N (Not classified yet)
    Routes of
    use    		By mouth, intravenous
    Typical dose480 mg OD[1]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa618006
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only)
    • US: ℞-only
    • EU: Rx-only
    Pharmacokinetics
    Bioavailability37% (estimate)
    Protein binding98.2%
    Metabolismglucuronidation (UGT1A1/1A3) to a minor extent
    Elimination half-life12 hours
    Excretion93.3% via faeces, <2% via kidneys
    Chemical and physical data
    FormulaC29H28F4N4O4
    Molar mass572.561 g·mol−1
    3D model (JSmol)
    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
    InChI
    • 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, sold under the brand name Prevymis, is an antiviral medication used to prevent cytomegalovirus (CMV) reactivation following allogeneic stem cell transplant.[1] It is used in those who are seropositive for CMV.[1] It may be taken by mouth or injection into a vein.[3]

    Common side effects include nausea, diarrhea, and vomiting.[2] Other side effects may include swelling, cough, headache, and tiredness.[3] It is a cytomegalovirus DNA terminase complex inhibitor.[1]

    Letermovir was approved for medical use in the United States in 2017 and Europe in 2018.[3][2] In the United Kingdom it costs the NHS about £7,500 for 4 weeks as of 2021.[1] This amount in the United States is about 6,200 USD.[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]

    Dosage

    It is given at a dose of 480 mg once per day for 100 days.[1] Longer treatment may sometimes be used.[1] In those on ciclosporin half that dose may be used.[1]


    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][7]

    Side 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. 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 faeces (93.3%). Less than 2% is found in the urine.[6]

    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.[8]

    The molecule has one asymmetric carbon atom, which is in S configuration.[8]

    History

    The drug was developed by Merck & Co.[9] The drug was granted fast track status by the US Food and Drug Administration (FDA) and orphan drug status by the European Medicines Agency.[10] The FDA considers it to be a first-in-class medication.[11]

    References

    1. 1 2 3 4 5 6 7 8 9 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 679. ISBN 978-0857114105.
    2. 1 2 3 "Prevymis". Archived from the original on 12 July 2021. Retrieved 21 November 2021.
    3. 1 2 3 "Letermovir Monograph for Professionals". Drugs.com. Archived from the original on 22 April 2021. Retrieved 21 November 2021.
    4. ↑ "Prevymis Prices, Coupons & Savings Tips - GoodRx". GoodRx. Retrieved 21 November 2021.
    5. 1 2 3 El Helou G, Razonable RR (2019-06-04). "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. Archived (PDF) from the original on 14 July 2021. Retrieved 1 July 2021.
    7. ↑ Letermovir Professional Drug Facts. Accessed 17 April 2021.
    8. 1 2 "Prevymis: EPAR – Public assessment report" (PDF). European Medicines Agency. 17 January 2018. Archived (PDF) from the original on 27 June 2019. Retrieved 1 July 2021.
    9. ↑ Masangkay, Estel Grace (July 29, 2014). "Merck Kicks Off Phase 3 Study Of CMV Drug Letermovir". Archived from the original on 23 October 2017. Retrieved 8 Oct 2014.
    10. ↑
    11. ↑ New Drug Therapy Approvals 2017 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2018. Archived from the original on 23 October 2020. Retrieved 16 September 2020.
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