Pharmacokinetic and pharmacodynamic drug-drug interaction assessment between pradigastat and digoxin or warfarin

• Published in: Journal of clinical pharmacology 2014-07, Vol.54 (7), p.800-808
• Main Authors: Yan, Jing-He, Meyers, Dan, Lee, Zachary, Danis, Kate, Neelakantham, Srikanth, Majumdar, Tapan, Rebello, Sam, Sunkara, Gangadhar, Chen, Jin
• Format: Article
• Language: English
• Subjects: Acetates - administration & dosage; Acetates - adverse effects; Acetates - blood; Acetates - pharmacokinetics; Adolescent; Adult; Aminopyridines - administration & dosage; Aminopyridines - adverse effects; Aminopyridines - blood; Aminopyridines - pharmacokinetics; Cardiotonic Agents - adverse effects; Cardiotonic Agents - blood; Cardiotonic Agents - pharmacokinetics; Cohort Studies; Diacylglycerol O-Acyltransferase - antagonists & inhibitors; digoxin; Digoxin - adverse effects; Digoxin - blood; Digoxin - pharmacokinetics; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - blood; Enzyme Inhibitors - pharmacokinetics; Female; Half-Life; Humans; Hypolipidemic Agents - administration & dosage; Hypolipidemic Agents - adverse effects; Hypolipidemic Agents - blood; Hypolipidemic Agents - pharmacokinetics; interaction; International Normalized Ratio; Male; Metabolic Clearance Rate; Middle Aged; pharmacodynamics; pharmacokinetics; Prescription drugs; Prothrombin Time; Reproducibility of Results; warfarin; Warfarin - adverse effects; Warfarin - blood; Warfarin - pharmacokinetics; Young Adult
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1002/jcph.285

Pradigastat, a novel diacylglycerol acyltransferase‐1 inhibitor, was evaluated for both pharmacokinetic (PK) and pharmacodynamic (PD) drug–drug interactions when co‐administered with digoxin or warfarin in healthy subjects. This open‐label study included two parallel subject cohorts each with three sequential treatment periods. Forty subjects were enrolled in the study with 20 subjects allocated to each cohort. PK and PD (PT/INR for warfarin only) samples were collected in each period. The statistical analysis results showed that the 90% CIs of the geometric mean ratios of digoxin, R‐warfarin, and S‐warfarin PK parameters (AUC and Cmax) were all within 0.80–1.25 interval. The 90% CIs of the geometric mean ratios of pradigastat PK parameters (AUC and Cmax) were within 0.80–1.25 interval when co‐administered with warfarin; while co‐administration with digoxin slightly reduced pradigastat exposure (∼15%). The results also showed that 90% CIs of the geometric mean ratios of warfarin PD parameters (AUCPT, PTmax, AUCINR, and INRmax) were within 0.80–1.25 interval. Pradigastat and digoxin or warfarin had no relevant clinical PK or PD drug–drug interactions. Administration of pradigastat and warfarin or pradigastat and digoxin as a mono or combined treatment appears to be safe and tolerated.