B1, BSEP, OCT1, OCT2, or OAT1 in vitro.Table 5: Drug Interactions: Changes in Pharmacokinetics of Letermovir in the Presence of Co-administered DrugCo-administered DrugRegimen of Co-administered DrugLetermovir RegimenGeometric Mean Ratio [90% CI] of Letermovir PK with/without Co-administered Drug (No Effect=1.00)AUCCmaxC24hrC12hr for tacrolimusAbbreviations: PO= oralImmunosuppressantscyclosporine200 mg single dose PO240 mg once daily PO2.11(1.97, 2.26)1.48(1.33, 1.65)2.06(1.81, 2.35)mycophenolate mofetil1 g single dose PO480 mg once daily PO1.18(1.04, 1.32)1.11(0.93, 1.34)1.39(1.12, 1.74)tacrolimus5 mg single dose PO80 mg twice daily PO1.02(0.97, 1.07)0.92(0.84, 1.00)1.02(0.93, 1.12)Table 6: Drug Interactions: Changes in Pharmacokinetics for Co-administered Drug in the Presence of LetermovirCo-administered DrugRegimen of Co-administered DrugLetermovir RegimenGeometric Mean Ratio [90% CI] of Co-administered Drug PK with/without Letermovir(No Effect=1.00)AUCCmaxC24hrC12hr reported for voriconazole.Abbreviations: PO=oralCYP3A Substratesmidazolam1 mg single dose IV240 mg once daily PO1.47(1.37, 1.58)1.05(0.94, 1.17)2.74(2.16, 3.49)2 mg single dose PO240 mg once daily PO2.25(2.04, 2.49)1.72(1.54, 1.92)Not availableP-gp Substratesdigoxin0.5 mg single dose PO240 mg twice daily PO0.88(0.80, 0.96)0.75(0.63, 0.89)0.90(0.84, 0.96)Immunosuppressantscyclosporine50 mg single dose PO240 mg once daily PO1.66(1.51, 1.82)1.08(0.97, 1.19)2.19(1.80, 2.66)mycophenolate mofetil1 g single dose PO480 mg once daily PO1.08(0.97, 1.20)0.96(0.82, 1.12)1.04(0.86, 1.27)tacrolimus5 mg single dose PO480 mg once daily PO2.42(2.04, 2.88)1.57(1.32, 1.86)2.53(2.12, 3.03)sirolimus2 mg single dose PO480 mg once daily PO3.40(3.01, 3.85)2.76(2.48, 3.06)3.15(2.80, 3.55)Antifungals and Antiviralsacyclovir400 mg single dose PO480 mg once daily PO1.02(0.87, 1.2)0.82(0.71, 0.93)1.13(0.94, 1.36)posaconazole300 mg single dose PO480 mg once daily PO0.98(0.82, 1.17)1.11(0.95, 1.29)1.10(0.94, 1.30)voriconazole200 mg twice daily PO480 mg once daily PO0.56(0.51, 0.62)0.61(0.53, 0.71)0.49(0.42, 0.57)HMG-CoA Reductase Inhibitorsatorvastatin20 mg single dose PO480 mg once daily PO3.29(2.84, 3.82)2.17(1.76, 2.67)3.62(2.87, 4.55)Oral Contraceptivesethinyl estradiol (EE) /levonorgestrel (LNG)0.03 mg EE single dose PO480 mg once daily PO1.42(1.32, 1.52)0.89(0.83, 0.96)1.57(1.45, 1.70)0.15 mg LNG single dose PO1.36(1.30, 1.43)0.95(0.86, 1.04)1.38(1.32, 1.46)
Mechanism of ActionLetermovir inhibits the CMV DNA terminase complex (pUL51, pUL56, and pUL89) which is required for viral DNA processing and packaging. Biochemical characterization and electron microscopy demonstrated that letermovir affects the production of proper unit length genomes and interferes with virion maturation. Genotypic characterization of virus resistant to letermovir confirmed that letermovir targets the terminase complex.
Antiviral ActivityThe median EC50 value of letermovir against a collection of clinical CMV isolates in a cell-culture model of infection was 2.1 nM (range = 0.7 nM to 6.1 nM, n = 74). There was no significant difference in EC50 value by CMV gB genotype (gB1=29; gB2=27; gB3=11; and gB4=3).
Combination Antiviral ActivityNo antagonism of the antiviral activity was seen when letermovir was combined with CMV DNA polymerase inhibitors (cidofovir, foscarnet, or ganciclovir).
Viral Resistance
In Cell Cul |
