Influence of severe renal impairment on the pharmacokinetics of clazosentan.

The purpose of this open-label, parallel-group study was to investigate the effect of severe renal impairment on the pharmacokinetics (PK), tolerability, and safety of clazosentan, an intravenous endothelin receptor antagonist. Clazosentan was administered as a continuous intravenous infusion of 1 mg/h for a period of 6 hours in 9 subjects with severe renal impairment (group A) and 8 healthy subjects (group B) (creatinine clearance <30 mL/min and >80 mL/min, respectively). The subjects in both groups were well matched for sex, body mass index, and age (±10 years). The PK parameters of clazosentan were calculated by both model-independent and model-dependent methods. The differences in the PK parameters between the subjects with severe renal impairment and healthy subjects were minor. The geometric means for area under the curve (AUC) during the infusion, AUC(0-t), (AUC from zero to time t of the last measured concentration above the limit of quantification) AUC(0-∞) (AUC from zero to infinity), and concentration at steady state were 7%, 8%, 8%, and 8%, respectively, higher in group A than in group B. The results obtained after 2-compartmental modeling were in agreement with those obtained after noncompartmental analysis. Administration of clazosentan was well tolerated in both groups. The data suggest that there is no need for dose adjustment of clazosentan in patients with renal impairment.

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

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Clazosentan is a selective endothelin A receptor antagonist, formulated for parenteral use, which is in clinical development for the treatment of aneurysmal subarachnoid haemorrhage. The human ADME study showed that most of clazosentan is excreted via the biliary route. The pharmacokinetics (PK) of clazosentan are similar in healthy subjects and those with severe renal impairment. WHAT THIS STUDY ADDS: The results of the present study showed that there was an increase in the exposure to clazosentan with increasing severity of liver impairment. Changes in PK in subjects with mild liver impairment compared with healthy subjects are unlikely to be clinically relevant. There are significant differences in the PK parameters of clazosentan in subjects with moderate and severe liver impairment compared with healthy subjects. The results of this study will allow confident dosing of clazosentan in individuals with moderate and severe liver impairment. 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.