Letermovir is an oral antiviral drug approved for preventing CMV infection in at-risk adult patients. It works by inhibiting the CMV terminase complex, differing from other antivirals that target the viral polymerase. Letermovir has high oral bioavailability and no significant drug interactions except when used with cyclosporine, requiring a dose reduction. Common side effects are mild gastrointestinal issues. It is the first prophylactic treatment approved to prevent CMV infection in at-risk transplant patients.

1. LETERMOVIR
- Dr Nikita Ingale
- JR2
- Dept of Pharmacology
- GMCH Nagpur
PG GUIDE
- Dr Vijay Motghare
- Professor & head
- Dept of Pharmacology
- GMCH Nagpur

2. 2
- Letermovir (Prevymis) is an orally or intravenously administered cytomegalovirus (CMV) DNA
terminase complex inhibitor being developed by Merck & Co. ltd
- Letermovir has been approved in Canada and the USA for the prophylaxis of CMV infection
and disease in adult CMV-seropositive recipients of an allogeneic haematopoietic stem cell
transplant (HSCT)
- For the same indication, letermovir is undergoing regulatory review in Japan and other countries
Letermovir…
Letermovir – drug review

3. 3
- Cytomegalovirus (CMV) is a prevalent herpes virus that affects nearly one in three
children by 5 years of age and more than half of adults by 40 years of age in the USA
- Primary CMV infections often go unrecognized because they tend to cause mild,
nonspecific symptoms or no symptoms at all [ fatigue, fever, sore throat ]
- CMV infection is not a serious health problem for most healthy people, but in
severely immunocompromised individuals it can lead to serious morbidity and
mortality [HIV, bone marrow transplants]
- It is transmitted by direct contact with infectious body fluids [ blood, tears, saliva]
Cytomegaloviral infections…
Letermovir – drug review

4. 4
Cytomegaloviral infections…
Letermovir – drug review
- Without prophylaxis, 80% of CMV- seropositive recipients of an allogeneic
haematopoietic stem cell transplant (HSCT) develop CMV reactivation
- Treatment options for this patient population (e.g. ganciclovir, valganciclovir,
foscarnet and cidofovir) are limited by significant adverse events [e.g. bone
marrow suppression, renal toxicity] and emerging drug resistance

5. 5
Letermovir – drug review
- CMV DNA polymerase inhibitors (ganciclovir, foscarnet and cidofovir) are
fully active against viral populations with resistance to letermovir, and
letermovir is fully active against viral populations with resistance to CMV DNA
polymerase inhibitors
- The mechanism of action of letermovir (viral terminase inhibitor) differs from
that of other approved antivirals for CMV (which are DNA polymerase
inhibitors)
Mechanism of action…
1.No Mechanism based
side effects
2. Do not allow mature
virion particles to detach
3.

6. 6
Mechanism of action…
Letermovir – drug review

7. 7
Pharmacokinetics…
- letermovir has rapid absorption
- high absolute bioavailability (94% over an oral dose)
- high protein binding [99%]
- time to steady state of 9–10 days.
- volume of distribution following intravenous letermovir administration was 45.5L
Letermovir – drug review

8. 8
Pharmacokinetics…
- The recommended dosage of letermovir is 480 mg once daily, orally (with or without food)
- OR
- Intravenous infusion to be initiated between day 0–28 post-transplantation and administered
through 100 days post-transplantation
- The infusion should be used only in patients unable to take oral therapy, and patients should be
switched to oral letermovir as soon as they are able to take oral medications (no dosage
adjustment is required when switching).
- SAME ORAL AND PARENTRAL DOSAGE
Letermovir – drug review

9. 9
Pharmacokinetics…
- Letermovir is eliminated via hepatic metabolism being a minor pathway.
- Following the administration of a single dose of radiolabelled oral letermovir, the
majority (93%) of the dose was recovered in the faeces, with unchanged letermovir
accounting for 70%, and <2% was recovered in the urine
- The half-life with intravenous letermovir 480 mg once daily is 12 hrs
Letermovir – drug review

10. 10
Missed doses…
- Patients miss a dose of PREVYMIS  take it as soon as they remember.
- If do not remember until the next dose skip the missed dose and go back to the
regular schedule
- Patients should not double their next dose or take more than the prescribed one.
Letermovir – drug review

11. 11
Drug interactions…
Letermovir – drug review
- Cyclosporin (an inhibitor of OATP1B1/3 and other transporters) alters letermovir pharmacokinetics
- The dosage of letermovir should be reduced to 240 mg once daily when co-administered with
cyclosporin
OATP1B1 and OATP1B3 are known to play an important role in
transporting drugs across the basolateral membrane in hepatocytes, for
excretion in bile
Reduce
the dose
to half

12. 12
Dose adjustments…
Letermovir – drug review
- If PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be
decreased to 240 mg once daily
- If cyclosporine is initiated after starting PREVYMIS, the next dose of PREVYMIS should be
decreased to 240 mg once daily.
- If cyclosporine is discontinued after starting PREVYMIS, the next dose of PREVYMIS should
be increased to 480 mg once daily.
- If cyclosporine dosing is temporarily interrupted due to high cyclosporine levels, no dose
adjustment of PREVYMIS is needed.

13. 13
Letermovir – drug review
Drug interactions…
- Rifampin, a general inducer, may decrease letermovir concentrations and
coadministration is not recommended.
- Letermovir is a moderate inhibitor of CYP3A and inhibitor of CYP2C8 and may
increase the plasma concentrations of those substrates
- Significant drug-drug interactions include between letermovir and amiodarone
(substrate of CYP3A), antidiabetic agents , HMG- CoA reductase inhibitors,
warfarin and phenytoin (CYP2C8/19 substrates), proton pump inhibitors, and the
immuno- suppressants cyclosporin

14. 14
Letermovir – drug review
Drug interactions…
Hepatic impairment
No dose adjustment is required based on mild to moderate hepatic impairment. PREVYMIS is not
recommended for patients with severe hepatic impairment
Renal impairment
No dose adjustment is recommended for patients with mild, moderate, or severe renal impairment.
Efficacy and safety has not been demonstrated for patients with End stage renal disease
Combined hepatic and renal impairment
not recommended in patients with moderate hepatic impairment combined with moderate or severe
renal impairment
There are no data in subjects aged <18 years and about the safety in pregnancy

15. 15
- Gastrointestinal Adverse Events most common
- Most common Adverse Events were nausea, diarrhoea (24%), vomiting (14%), cough
(10%), peripheral oedema ( 9%), headache (9%), fatigue (11%) and abdominal pain (9%).
- Cardiac Adverse Events, of which tachycardia (4%) and atrial fibrillation (1%) occurred,
mostly mild or moderate in severity .
- No myelotoxicity or nephrotoxicity was observed.
- Letermovir is expected not to have mechanism based adverse effects because it
targets the CMV DNA terminase complex, which does not have a mammalian
counterpart
Adverse effects…
Letermovir – drug review

16. 16
Current status…
- Letermovir received its first global approval on 1 November 2017 in Canada and on
8 November 2017 in the USA for the prophylaxis of CMV infection and disease in
adult CMV-seropositive recipients of an allogeneic Haematopoetic Stem Cell
Transplant
Letermovir – drug review

17. 17
Summary…
Letermovir – drug review

18. 18
Letermovir – drug review
- Esther S. Kim , Letermovir: First Global Approval , Drugs 2017
- Kropeit D, Scheuenpflug J, Erb-Zohar K, Halabi A, Stobernack HP, Hulskotte
EGJ, van Schanke A, Zimmermann H, Rubsamen-Schaeff H: Pharmacokinetics
and safety of letermovir, a novel anti-human cytomegalovirus drug, in patients
with renal impairment. Br J Clin Pharmacol. 2017 dec;83(9):1944-1953. doi:
10.1111/bcp.13292.
- Melendez DP, Razonable RR: Letermovir and inhibitors of the terminase
complex: a promising new class of investigational antiviral drugs against human
cytomegalovirus. Infect Drug Resist. 2017 nov 5;8:269-77. doi: 10.2147
References…

19. Last PG activity for
this term:
-Group discussion
-29/09/18 saturday