Key result
A single 200 mg dose of sacubitril/valsartan resulted in increased systemic exposures correlated with liver disease severity, including a 19-109% increase in valsartan AUC.
Why the study?
Does mild to moderate hepatic impairment alter the pharmacokinetics and protein binding of a single oral dose of sacubitril/valsartan compared to healthy subjects?
Does mild to moderate hepatic impairment alter the pharmacokinetics and protein binding of a single oral dose of sacubitril/valsartan compared to healthy subjects?
Systemic exposure to sacubitril/valsartan analytes increases with the severity of hepatic impairment, though a single 200 mg dose remains safe and well-tolerated in mild to moderate disease.
Increased exposures in hepatic impairment suggest PK-guided dosing caution; leaves open dedicated outcome trials in liver disease.
OBJECTIVES: To assess the protein binding and pharmacokinetics of sacubitril/valsartan analytes (sacubitril, sacubitrilat, and valsartan) in an open-label, single oral dose (200 mg), parallel-group study in patients with mild and moderate hepatic impairment (Child-Pugh class A and B) and matched healthy subjects. METHODS: This study enrolled 32 subjects (n = 8 in each hepatic impairment and matched healthy subjects groups). Blood samples were collected at pre-determined time points to assess pharmacokinetics of sacubitril, sacubitrilat, and valsartan. Subjects with severe hepatic impairment were excluded as valsartan exposure is expected to be substantially increased in these patients. RESULTS: was unchanged. Valsartan AUC increased in patients with mild and moderate hepatic impairment by 19 - 109%, respectively. CONCLUSIONS: The increase in systemic exposures to all sacubitril/valsartan analytes correlated with the severity of liver disease. The plasma unbound fraction of sacubitrilat in patients with moderate hepatic impairment was slightly higher than in matched healthy subjects. This difference was not considered clinically significant. Safety assessments showed that sacubitril/valsartan was safe and well tolerated across all the study groups. .
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Kulmatycki et al. (2017) studied Mild and moderate hepatic impairment (n=32). Sacubitril/valsartan (LCZ696) vs. Matched healthy subjects was evaluated on Protein binding and pharmacokinetics of sacubitril/valsartan analytes. A single 200 mg dose of sacubitril/valsartan resulted in increased systemic exposures correlated with liver disease severity, including a 19-109% increase in valsartan AUC.
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