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.
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.
Authors: D R Kaul; S Stoelben; E Cober; T Ojo; E Sandusky; P Lischka; H Zimmermann; H Rubsamen-Schaeff Journal: Am J Transplant Date: 2011-05 Impact factor: 8.086
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Authors: Stephen Ph Alexander; Eamonn Kelly; Neil Marrion; John A Peters; Helen E Benson; Elena Faccenda; Adam J Pawson; Joanna L Sharman; Christopher Southan; Jamie A Davies Journal: Br J Pharmacol Date: 2015-12 Impact factor: 8.739
Authors: J Reefschlaeger; W Bender; S Hallenberger; O Weber; P Eckenberg; S Goldmann; M Haerter; I Buerger; J Trappe; J A Herrington; D Haebich; H Ruebsamen-Waigmann Journal: J Antimicrob Chemother Date: 2001-12 Impact factor: 5.790
Authors: Roy F Chemaly; Andrew J Ullmann; Susanne Stoelben; Marie Paule Richard; Martin Bornhäuser; Christoph Groth; Hermann Einsele; Margarida Silverman; Kathleen M Mullane; Janice Brown; Horst Nowak; Katrin Kölling; Hans P Stobernack; Peter Lischka; Holger Zimmermann; Helga Rübsamen-Schaeff; Richard E Champlin; Gerhard Ehninger Journal: N Engl J Med Date: 2014-05-08 Impact factor: 91.245
Authors: Christopher Southan; Joanna L Sharman; Helen E Benson; Elena Faccenda; Adam J Pawson; Stephen P H Alexander; O Peter Buneman; Anthony P Davenport; John C McGrath; John A Peters; Michael Spedding; William A Catterall; Doriano Fabbro; Jamie A Davies Journal: Nucleic Acids Res Date: 2015-10-12 Impact factor: 16.971
Authors: Markus Wild; Friedrich Hahn; Benedikt Grau; Lars Herrmann; Aischa Niesar; Martin Schütz; Melanie M Lorion; Lutz Ackermann; Svetlana B Tsogoeva; Manfred Marschall Journal: Int J Mol Sci Date: 2020-08-04 Impact factor: 5.923