Influence of hepatic impairment on everolimus pharmacokinetics: implications for dose adjustment.
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.
Kovarik
J M
JM
Novartis Pharmaceuticals, Basel, Switzerland.
Sabia
H D
HD
Figueiredo
J
J
Zimmermann
H
H
Reynolds
C
C
Dilzer
S C
SC
Lasseter
K
K
Rordorf
C
C
D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D016022:Case-Control Studies; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D000068338:Everolimus; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000502:physiology; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*
D007166:Immunosuppressive Agents; D003577:Cytochrome P-450 Enzyme System; D000068338:Everolimus; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D020123:Sirolimus