Influence of hepatic impairment on everolimus pharmacokinetics: Implications for dose adjustment

Objective: We assessed the influence of hepatic impairment on the pharmacok inetics of the immunosuppressant everolimus to provide dose recommendations for clinical use. Methods: In this open-label, single-dose, case-control study, 8 subjects wi th liver cirrhosis classed as moderate hepatic impairment (Child-Pugh score , 7-9) and 8 demographically matched healthy control subjects received a si ngle oral 2-mg dose of everolimus. Routine safety assessments were made, an d blood samples were taken for determination of everolimus concentrations a nd protein binding. Results: The apparent clearance of everolimus was significantly reduced by 53% in subjects with moderate hepatic impairment compared with healthy subj ects (9.1 +/- 3.1 versus 19.4 +/- 5.8 L/h). This was manifested by a 115% h igher area under the blood concentration-time curve (AUC) (245 +/- 91 versu s 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 o f everolimus was not altered by hepatic impairment on the basis of the maxi mum blood concentration (C-max) and time to reach C-max (t(max)). Protein b inding 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 l evel (r = 0.86) and a significant negative correlation with albumin concent ration (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 Chil d-Pugh classification. Therapeutic monitoring would be a helpful adjunct to subsequent titration of everolimus exposure in this subpopulation. Everoli mus has not been assessed in patients with severe hepatic impairment.