Drug information of Letermovir

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Letermovir

فارسی

Letermovir recieved approval from the FDA on November 8th, 2017 for use in prophylaxis of cytomegalovirus (CMV) infection in allogeneic hematopoietic stem cell transplant patients.

Mechanism of effect

CMV relies on a DNA terminase complex consisting of multiple subunits (pUL51, pUL56, and pUL89) for processing of viral DNA. Viral DNA is produced in a single repeating strand which is then cut by the DNA terminase complex into individual viral genomes which can then be packaged into mature viral particles. Letemovir inhibits the activity of this complex to prevent production of mature viral genomes and the production of viable viral particles.

Pharmacodynamic

Letermovir inhibits the activity of the DNA terminase complex of CMV thereby preventing the cutting of viral DNA into mature length genomes for packaging into viral particles.

Pharmacokinetics

Peak plasma time, PO: 0.75-2.25 hr

Peak plasma concentration, 480 mg/day PO: 13,000 ng/mL

Time to steady-state: 9-10 days

Bioavailability

  • Healthy subjects, no cyclosporine: 94%
  • HSCT recipients, no cyclosporine: 35% (480 mg/day)
  • HSCT recipients, with cyclosporine: 85% (240 mg/day)

AUC

  • Accumulation ratio: 1.22
  • HSCT recipients
    • 480 mg/day PO, no cyclosporine: 34,400 ng·hr/mL
    • 480 mg/day IV, no cyclosporine: 100,000 ng·hr/mL
    • 240 mg/day PO, with cyclosporine: 60,800 ng·hr/mL
    • 240 mg/day IV, with cyclosporine: 70,300 ng·hr/mL
  • Healthy subjects
    • 480 mg PO/day: 71,500 ng·hr/mL

Distribution

Vd, HSCT recipients (IV): 45.5 L

Protein bound: 99% across concentration range of 0.2-50 mg/L

Blood-to-plasma ratio: 0.56 across concentration range of 0.1-10 mg/L

Metabolism

UGT1A1/1A3 (minor)

CYP3A, CYP2D6 (minor)

Elimination

Route: Hepatic uptake (OATP1B1/3)

Half-life: 12 hr (480 mg/day IV)

Excretion: 93% feces (70% unchanged); <2% urine

Dosage

Adult

Cytomegalovirus Infection Prophylaxis

480 mg PO/IV qDay; initiate between Day 0 and Day 28 posttransplantation (before or after engraftment) and continue through Day 100

Use IV only in patients unable to take oral therapy; switch to oral administration as soon as feasible

Pediatric

<18 years: Safety and efficacy not established

Alerts

Coadministration of letermovir with certain drugs may result in potentially significant drug interactions, some of which may lead to adverse reactions or reduced therapeutic effect of either drug

Drug interaction overview

  • Cyclosporine and letermovir may increase plasma concentrations of each other
  • Contraindicated drug interactions
    • Pimozide: Coadministration with pimozide may result in increased concentrations of pimozide, owing to inhibition of CYP3A4 by letermovir, which may lead to QT prolongation and torsades de pointes
    • Ergot alkaloids: Coadministration with ergot alkaloids may result in increased concentrations of ergot alkaloids (ergotamine and dihydroergotamine), owing to inhibition of CYP3A by letermovir, which may lead to ergotism
    • Pitavastatin or simvastatin when coadministered with cyclosporine: Coadministration of letermovir in combination with cyclosporine may result in significantly increased pitavastatin or simvastatin concentrations, which may lead to myopathy or rhabdomyolysis
  • Potential for other drugs to affect letermovir
    • Letermovir is a substrate of CYP3A, CYP2D6, UGT1A1, and UGT1A3, and transporters OATP1B1/3 and P-gp; oxidative metabolism is considered to be a minor elimination pathway based on in vivo human data
    • Inhibitors of OATP1B1/3 may result in increases in letermovir plasma concentrations
    • Changes in letermovir plasma concentrations due to inhibition of P-gp or UGTs are not anticipated to be clinically relevant
  • Potential for letermovir to affect other drugs
    • Letermovir is a time-dependent inhibitor and inducer of CYP3A in vitro; drug interaction studies showed a net effect of letermovir on CYP3A is moderate inhibition
    • Letermovir is a reversible inhibitor of CYP2C8 in vitro; if coadministered, plasma concentrations of CYP2C8 substrates are predicted to increase
    • Letermovir induces CYP2C9 and CYP2C19; if coadministered, plasma concentrations of CYP2C9 and CYP2C19 substrates may decrease
    • Letermovir induces CYP2B6 in vitro; clinical relevance unknown
    • Letermovir inhibits efflux transporters P-gp, breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), OAT3, and hepatic uptake transporter OATP1B1/3 in vitro; coadministration with substrates of OATP1B1/3 transporters (eg, atorvastatin, a known substrate of CYP3A, OATP1B1/3, and potentially BCRP) may result in a clinically relevant increase in plasma concentrations of OATP1B1/3 substrates
Note: There were no clinically relevant changes in plasma concentrations of digoxin, a P-gp substrate, or acyclovir, an OAT3 substrate

Points of recommendation

Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

You may take letermovir tablets with or without food.

Do not crush, chew, or break a letermovir tablet. Swallow it whole.

You can store the mixture for up to 24 hours at room temperature, or up to 48 hours in a refrigerator.

Letermovir injection must be given slowly, and the infusion can take at least 1 hour to use all of the medicine in the IV bag.

Use this medicine for the full prescribed length of time, even if you have no symptoms. Skipping doses may increase your risk of further infection that is resistant to medication.

Store letermovir tablets or unmixed injection solution in the original packaging at room temperature, away from moisture, heat, and light. Keep each tablet in the foil blister pack until you are ready to take a tablet.

Do not shake the injection solution bottle. Prepare your dose only when you are ready to give an injection. Do not use if the medicine has changed colors or has particles in it. Call your pharmacist for new medicine.

Each single-use vial (bottle) of letermovir injection is for one use only. Throw it away after one use, even if there is still medicine left inside.

Use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

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