Pharmacokinetics and safety of the anti-human cytomegalovirus drug letermovir in subjects with hepatic impairment

AimsHuman cytomegalovirus constitutes a prevalent and serious threat to immunocompromised individuals and requires new treatments. Letermovir is a novel viral-terminase inhibitor that has demonstrated prophylactic/pre-emptive activity against human cytomegalovirus in Phase 2 and 3 transplant trials. As unchanged letermovir is primarily excreted via the liver by bile, this trial aimed to assess the effect of hepatic impairment on letermovir pharmacokinetics. MethodsPhase 1, open-label, parallel-group pharmacokinetic and safety comparison of multiple once-daily oral letermovir in female subjects with hepatic impairment and healthy matched controls. For 8days, subjects with moderate hepatic impairment (n=8) and their matched healthy controls (n=9) received 60mg letermovir/day and those with severe hepatic impairment (n=8) and their matched healthy controls (n=8) received 30mg letermovir/day. Pharmacokinetic parameters were determined from blood samples. ResultsFor subjects with moderate hepatic impairment, maximal observed concentration at steady state (C-ss,C-max) and the area under the concentration vs. time curve over a dosing interval at steady state (AUC(,ss)) for total letermovir were 1.37-fold (90% confidence interval: 0.87, 2.17) and 1.59-fold (0.98, 2.57) higher, respectively, than in healthy subjects. For subjects with severe hepatic impairment, C-ss,C-max and AUC(,ss) values of total letermovir were 2.34-fold (1.91, 2.88) and 3.82-fold (2.94, 4.97) higher, respectively, compared with healthy subjects. ConclusionsModerate hepatic impairment increased exposure to letermovir <2-fold, while severe hepatic impairment increased letermovir exposure approximately 4-fold as compared with healthy subjects. Letermovir 60/30mg/day was generally well-tolerated in subjects with hepatic impairment.