BACKGROUND AND OBJECTIVE: Pradigastat, a diacylglycerol acyltransferase1 inhibitor, is being developed for the treatment of familial chylomicronemia syndrome. The primary objective of this clinical study was to evaluate the effect of renal impairment on the pharmacokinetics of pradigastat. METHODS: In an open-label, parallel-group study, the single-dose (40 mg) pharmacokinetics of pradigastat were evaluated in patients with mild (n = 9), moderate (n = 10) and severe renal impairment (n = 9) compared with matched healthy subjects (n = 28). The protein binding and urinary excretion of pradigastat were also assessed in this study. RESULTS: In patients with mild and moderate renal impairment the geometric means of the maximum plasma concentration (C max) and the area under the plasma concentration-time curve from time zero to infinity (AUC inf) of pradigastat were similar as compared with healthy subjects. In patients with severe renal impairment, the geometric means of the C max and AUC inf increased by 40 % [geometric mean ratio 1.41; 90 % confidence interval (CI) 0.92-2.14] and 18 % (geometric mean ratio 1.18; 90 % CI 0.68-2.05), respectively. There was no significant correlation between renal function (measured by creatinine clearance) and C max or AUC inf. Protein binding values were >99 % and the urinary excretion of pradigastat was minimal in all subjects. There were no severe adverse events in the study and mild transient diarrhoea was the most common adverse event. The safety profile was similar between patients with renal impairment and healthy subjects. CONCLUSION: There was no change in the pharmacokinetics of pradigastat in patients with mild and moderate renal impairment. In patients with severe renal impairment, the mean exposure C max and AUC inf of pradigastat were increased by 40 and 18 %, respectively.
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BACKGROUND AND OBJECTIVE: Pradigastat, a diacylglycerol acyltransferase1 inhibitor, is being developed for the treatment of familial chylomicronemia syndrome. The primary objective of this clinical study was to evaluate the effect of renal impairment on the pharmacokinetics of pradigastat. METHODS: In an open-label, parallel-group study, the single-dose (40 mg) pharmacokinetics of pradigastat were evaluated in patients with mild (n = 9), moderate (n = 10) and severe renal impairment (n = 9) compared with matched healthy subjects (n = 28). The protein binding and urinary excretion of pradigastat were also assessed in this study. RESULTS: In patients with mild and moderate renal impairment the geometric means of the maximum plasma concentration (C max) and the area under the plasma concentration-time curve from time zero to infinity (AUC inf) of pradigastat were similar as compared with healthy subjects. In patients with severe renal impairment, the geometric means of the C max and AUC inf increased by 40 % [geometric mean ratio 1.41; 90 % confidence interval (CI) 0.92-2.14] and 18 % (geometric mean ratio 1.18; 90 % CI 0.68-2.05), respectively. There was no significant correlation between renal function (measured by creatinine clearance) and C max or AUC inf. Protein binding values were >99 % and the urinary excretion of pradigastat was minimal in all subjects. There were no severe adverse events in the study and mild transient diarrhoea was the most common adverse event. The safety profile was similar between patients with renal impairment and healthy subjects. CONCLUSION: There was no change in the pharmacokinetics of pradigastat in patients with mild and moderate renal impairment. In patients with severe renal impairment, the mean exposure C max and AUC inf of pradigastat were increased by 40 and 18 %, respectively.