期刊
CLINICAL PHARMACOLOGY & THERAPEUTICS
卷 70, 期 5, 页码 425-430出版社
MOSBY, INC
DOI: 10.1016/S0009-9236(01)15633-X
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Objective: We assessed the influence of hepatic impairment on the pharmacokinetics of the immunosuppressant everolimus to provide dose recommendations for clinical use. Methods: In this open-label, single-dose, case-control study, 8 subjects with liver cirrhosis classed as moderate hepatic impairment (Child-Pugh score, 7-9) and 8 demographically matched healthy control subjects received a single oral 2-mg dose of everolimus. Routine safety assessments were made, and blood samples were taken for determination of everolimus concentrations and protein binding. Results: The apparent clearance of everolimus was significantly reduced by 53% in subjects with moderate hepatic impairment compared with healthy subjects (9.1 +/- 3.1 versus 19.4 +/- 5.8 L/h). This was manifested by a 115% higher area under the blood concentration-time curve (AUC) (245 +/- 91 versus 114 +/- 45 ng (.) h/ml) and 84% prolonged half-life (79 +/- 42 versus 43 +/- 18 hours) in subjects with hepatic impairment. The rate of absorption of everolimus was not altered by hepatic impairment on the basis of the maximum blood concentration (C-max) and time to reach C-max (t(max)). Protein binding was similar in the two groups (73.8% +/- 3.6% versus 73.5% +/- 2.4%). A significant positive correlation of the everolimus AUC with bilirubin level (r = 0.86) and a significant negative correlation with albumin concentration (r = 0.72) was observed. Conclusions: The dose of everolimus should initially be reduced by half in patients with mild and moderate hepatic impairment on the basis of the Child-Pugh classification. Therapeutic monitoring would be a helpful adjunct to subsequent titration of everolimus exposure in this subpopulation. Everolimus has not been assessed in patients with severe hepatic impairment.
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