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

British Journal of Clinical Pharmacology

5 years ago

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

Zhanna D. Kobalava, Katharina Erb-Zohar, Helga Rübsamen-Schaeff, Valentin S. Moiseev, Holger Zimmermann, Hans-Peter Stobernack, Dirk Kropeit, David McCormick

Aims Human 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. Methods Phase 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 8 days, subjects with moderate hepatic impairment (n = 8) and their matched healthy controls (n = 9) received 60 mg letermovir/day and those with severe hepatic impairment (n = 8) and their matched healthy controls (n = 8) received 30 mg letermovir/day. Pharmacokinetic parameters were determined from blood samples. Results For subjects with moderate hepatic impairment, maximal observed concentration at steady state (Css,max) and the area under the concentration vs. time curve over a dosing interval at steady state (AUCτ,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, Css,max and AUCτ,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. Conclusions Moderate hepatic impairment increased exposure to letermovir <2-fold, while severe hepatic impairment increased letermovir exposure approximately 4-fold as compared with healthy subjects. Letermovir 60/30 mg/day was generally well-tolerated in subjects with hepatic impairment.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/bcp.13376