Title:
Effects of hepatic impairment on the pharmacokinetics of everolimus: a single-dose, open-label, parallel-group study.

Abstract:
Although the pharmacokinetics of everolimus, an oral mammalian target of rapamycin inhibitor, have been characterized in patients with moderate hepatic impairment, they have not been assessed in those with mild or severe hepatic impairment.
The goal of this study was to assess the pharmacokinetics and safety of everolimus in healthy volunteers with normal hepatic function and patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment in otherwise good health to inform dosing in the clinical setting.
A multicenter, open-label, Phase I study in which all enrollees received a single, 10-mg, oral everolimus dose was conducted. Blood samples for pharmacokinetic assessment were collected at predetermined time points up to 168 hours postdosing. Safety was also assessed. Proposed dose recommendations based on Child-Pugh status at baseline and day 8 were calculated based on AUC0-∞ geometric mean ratios and their associated 90% CIs. Post hoc analysis of the relationship between pharmacokinetic parameters and markers of hepatic function was also performed to identify thresholds for dose adjustment.
Thirteen subjects with normal hepatic function and 7 patients with mild, 8 patients with moderate, and 6 patients with severe hepatic impairment were enrolled. Compared with normal subjects, everolimus AUC0-∞ for patients with mild, moderate, and severe hepatic impairment increased by 1.60-, 3.26-, and 3.64-fold, respectively. Based on Child-Pugh classification at day 8, the everolimus doses required to adjust the exposure of patients with mild, moderate, and severe hepatic impairment to that of normal subjects were 6.25, 3.07, and 2.75 mg, respectively. Thresholds for 2-fold everolimus dose reduction were 15.0 μmol/L for bilirubin, 43.1 g/L for albumin, and 1.1 for the international normalized ratio; using these thresholds could lead to underdosing or overdosing in some patients. Most adverse events were of grade 1 severity, ≤1 day in duration, and not everolimus related.
Everolimus exposure after a single 10-mg dose was influenced by the degree of hepatic impairment. Child-Pugh classification was found to be the most conservative means of guiding dose adjustment in patients with hepatic impairment. Based on these data, as well as previously reported data for patients with moderate hepatic impairment, everolimus once-daily dosing should be 7.5 mg and 5 mg in patients with mild and moderate impairment, respectively. Everolimus is not recommended in patients with severe hepatic impairment unless benefits outweigh risks; in that case, 2.5 mg once daily should not be exceeded. ClinicalTrials.gov identifier: NCT00968591.