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

Article date: December 2017

By: Dirk Kropeit, David McCormick, Katharina Erb‐Zohar, Valentin S. Moiseev, Zhanna D. Kobalava, Hans‐Peter Stobernack, Holger Zimmermann, Helga Rübsamen‐Schaeff in Volume 83, Issue 12, pages 2678-2686

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.

DOI: 10.1111/bcp.13376

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