|Other names||AIC246; MK-8228|
|Main uses||Prevent cytomegalovirus (CMV) reactivation|
|Side effects||Nausea, diarrhea, vomiting|
|By mouth, intravenous|
|Typical dose||480 mg OD|
|Metabolism||glucuronidation (UGT1A1/1A3) to a minor extent|
|Elimination half-life||12 hours|
|Excretion||93.3% via faeces, <2% via kidneys|
|Chemical and physical data|
|Molar mass||572.561 g·mol−1|
|3D model (JSmol)|
Letermovir, sold under the brand name Prevymis, is an antiviral medication used to prevent cytomegalovirus (CMV) reactivation following allogeneic stem cell transplant. It is used in those who are seropositive for CMV. It may be taken by mouth or injection into a vein.
Letermovir was approved for medical use in the United States in 2017 and Europe in 2018. In the United Kingdom it costs the NHS about £7,500 for 4 weeks as of 2021. This amount in the United States is about 6,200 USD.
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.
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.
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. In general, side effects of the drug are comparable to those under placebo treatment.
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 explanation needed] Letermovir is only active against CMV and has no effect on other herpesviruses.
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.
The drug is mainly excreted via the faeces (93.3%). Less than 2% is found in the urine.
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.
The drug was developed by Merck & Co. The drug was granted fast track status by the US Food and Drug Administration (FDA) and orphan drug status by the European Medicines Agency. The FDA considers it to be a first-in-class medication.
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- 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.