Influence of different degrees of liver impairment on the pharmacokinetics of clazosentan

AIM

To investigate the effect of mild, moderate and severe liver impairment on the pharmacokinetics (PK), tolerability and safety of clazosentan, an intravenous endothelin receptor antagonist.

METHODS

Healthy subjects with normal liver function (n = 8), subjects with mild (Child Pugh A, n = 8), and with moderate (Child-Pugh B, n = 8) liver impairment received a continuous intravenous infusion of 1 mg h⁻¹ and subjects with severe liver impairment (Child Pugh C, n = 8) received a continuous intravenous infusion of 0.5 mg h⁻¹ clazosentan for a duration of 6 h. The pharmacokinetic (PK) parameters of clazosentan were determined by both model-independent and model-dependent methods.

RESULTS

Mean plasma concentrations of clazosentan increased with increasing severity of liver impairment. Geometric means of area under the plasma concentration–time curve from 0 to infinity (AUC_(0,∞)) were 1.41- (90% CI 1.04, 1.90), 2.37- (90% CI 1.75, 3.19), and 3.79- (90% CI 2.81, 5.11) fold higher in subjects with mild, moderate and severe liver impairment, respectively, compared with healthy subjects. Similar results were obtained by non-compartmental and two-compartmental analysis. A significant positive correlation between clazosentan AUC_(0,∞) and Child-Pugh score (r = 0.83), bilirubin (r = 0.78) and prothrombin time (r = 0.62), and a significant negative correlation with albumin concentrationl (r = 0.71) was observed. Administration of clazosentan was well tolerated in all groups.

CONCLUSIONS

The increase in exposure to clazosentan in Child-Pugh A patients is not expected to be clinically relevant and no dose adjustment for these patients is proposed. It is recommended to reduce the dose of clazosentan to half in Child-Pugh B and to one fourth in Child-Pugh C patients.