Pharmacokinetics and safety of the anti‐human cytomegalovirus drug letermovir in subjects with hepatic impairment
| Autor: | Valentin S. Moiseev, David McCormick, Holger Zimmermann, Dirk Kropeit, Zhanna Kobalava, Katharina Erb-Zohar, Hans-Peter Stobernack, Helga Rübsamen-Schaeff |
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| Rok vydání: | 2017 |
| Předmět: |
Adult
0301 basic medicine Human cytomegalovirus Drug medicine.medical_specialty Adolescent Metabolic Clearance Rate media_common.quotation_subject 030106 microbiology Congenital cytomegalovirus infection Administration Oral Acetates Antiviral Agents Severity of Illness Index Gastroenterology Drug Administration Schedule Russia Young Adult 03 medical and health sciences Letermovir Pharmacokinetics Internal medicine medicine Humans Pharmacology (medical) Aged media_common Pharmacology business.industry Liver Diseases Hepatic impairment Healthy subjects Middle Aged medicine.disease Confidence interval Surgery Treatment Outcome 030104 developmental biology Liver Area Under Curve Cytomegalovirus Infections Quinazolines Female business Half-Life medicine.drug |
| Zdroj: | British Journal of Clinical Pharmacology. 83:2678-2686 |
| ISSN: | 1365-2125 0306-5251 |
| DOI: | 10.1111/bcp.13376 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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