Singapore Drugs Database

Indication

For use in prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant (HSCT) [FDA Label].

Mechanism of Action

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 [A31289]. Letemovir inhibits the activity of this complex to prevent production of mature viral genomes and the production of viable viral particles. The exact nature of Letemovir's binding to this complex is not currently known. Initially, the observation of resistance-causing mutations in pUL56 suggested this subunit was the location of Letemovir binding [A31290]. However, resistance mutations have now been observed in pUL51, pUL56, and pUL89 [A31291]. It is possible that changes in amino acid sequence in one subunit could result in conformational changes to interacting subunits affecting Letemovir binding or that Letemovir interacts with multiple subunits of the complex but evidence towards either of these distinctions has not yet been seen. pUL89 is known to contain the endonuclease activity of the complex but because all members of the complex are necessary for targeting as well as protection from proteosomal degradation, it is difficult to discern if Letemovir inhibits pUL89's activity directly [A31292].

Pharmacokinetics

Absorption

Letermovir has a bioavailability of 94% in healthy subjects when administered without cyclosporin, 35% in HSCT recipients when administered without cyclosporin, and 85% in HSCT recipients when administered with cyclosporin [FDA Label]. Letermovir's Tmax is 45 min to 2.25 h [FDA Label]. Time to steady state has been observed to be 9-10 days. Taking Letermovir with food increases Cmax by an average of 129.82% (range of 104.35%-161.50%) [FDA Label]. No significant effect on AUC has been observed .

Distribution

The mean steady state volume of distrubution is 45.5L [FDA Label]

Metabolism

Letermovir undergoes a minor degree of metabolism through UGT1A1/1A3 [FDA Label].

Elimination

Clearance

The mean clearance is 11.25 L/h in healthy subjects [A31281]

Toxicity

There is no human data on the safety of Letemovir in pregnancy [FDA Label]. Embryo-fetal toxicity and malformations have been observed in rats at exposures 11 times the human exposure at the recommended human dose (RHD) of Letemovir. No such toxicity was noted in rats at 3 times human exposure at the RHD or in rabbits at values less than human exposure with the RHD. Total litter loss was observed in 21.7% of female rats at 2 times human exposure at RHD. This did not occur at values similar to human exposure at RHD. No human data is available regarding lactation [FDA Label]. Letemovir has been observed in the milk of lactating rats and in the blood of their nursing pups. No data is available concerning the effect of Letemovir on human fertility [FDA Label]. Testicular toxicity leading to reduced fertility has been observed in male rats. No antidote exists for Letemovir overdosage [FDA Label]. The effectiveness of dialysis in clearing plasma of Letemovir is unknown.

Active Ingredient/Synonyms

Letermovir | Letermovir |