Pharmacokinetics and pharmacodynamics of rosuvastatin in subjects with hepatic impairment.
OBJECTIVE
To assess the effect of chronic hepatic impairment on rosuvastatin disposition, pharmacodynamic activity and tolerability.


METHODS
This was an open-label, non-randomised, parallel-group trial. Six subjects were enrolled in each of three hepatic-function strata: Child-Pugh class A (CP-A, mild impairment), Child-Pugh class B (CP-B, moderate impairment) and normal hepatic function; the latter two strata were age, weight, race, sex and smoking history matched. All subjects were given rosuvastatin 10 mg for 14 days.


RESULTS
In subjects with CP-A, and in four of six subjects with CP-B, rosuvastatin steady-state AUC(0-24) and C(max) were similar to subjects with normal hepatic function (geometric mean values 60.7 ng h/ml and 6.02 ng/ml, respectively). Two of six subjects with CP-B who had the highest CP scores (i.e. the highest degrees of hepatic impairment) had the highest AUC(0-24) (128 ng h/ml and 242 ng h/ml) and C(max) (23.4 ng/ml and 96.7 ng/ml) values. Low-density lipoprotein cholesterol (LDL-C) was decreased in all strata, but the response was more variable in the CP-B group. Rosuvastatin was well tolerated, and the safety profile was similar in subjects with hepatic impairment and normal hepatic function.


CONCLUSIONS
In most subjects with mild-to-moderate hepatic impairment, the steady-state pharmacokinetics of rosuvastatin were similar to subjects with normal hepatic function (more extensive hepatic impairment may increase systemic exposure to rosuvastatin), and most had LDL-C reductions similar to subjects with normal hepatic function.
Simonson
S G
SG
AstraZeneca, R&D Lund, Experimental Medicine, SE-221 87 Lund, Sweden. steven.simonson@astrazeneca.com
Martin
P D
PD
Mitchell
P
P
Schneck
D W
DW
Lasseter
K C
KC
Warwick
M J
MJ
D000328:Adult; D019540:Area Under Curve; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D005260:Female; D005464:Fluorobenzenes / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008107:Liver Diseases / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium