title: Effect of Renal Impairment on the Pharmacokinetics of Pradigastat, a Novel Diacylglycerol Acyltransferase1 (DGAT1) Inhibitor.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Novartis Pharma K.K., Tokyo, Japan.
authors: Sachiko
authors: S
authors: Mita
authors: Dan
authors: D
authors: Meyers
authors: Parasar
authors: P
authors: Pal
authors: TsuHan
authors: T
authors: Lin
authors: Tapan
authors: T
authors: Majumdar
authors: Sam
authors: S
authors: Rebello
authors: Gangadhar
authors: G
authors: Sunkara
authors: Jin
authors: J
authors: Chen
mesh_terms: D000085:Acetates / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D000368:Aged; D000631:Aminopyridines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D015992:Body Mass Index; D016022:Case-Control Studies; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008072:Hyperlipoproteinemia Type I / Q000188:drug therapy / Q000378:metabolism / Q000652:urine; D008297:Male; D008875:Middle Aged; D011485:Protein Binding; D051437:Renal Insufficiency / Q000378:metabolism* / Q000652:urine
chemical_list: D000085:Acetates; D000631:Aminopyridines; D004791:Enzyme Inhibitors; C000594809:pradigastat; C494881:DGAT1 protein, human; D051048:Diacylglycerol O-Acyltransferase
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