title: A population pharmacokinetic model that describes multiple peaks due to enterohepatic recirculation of ezetimibe.
abstract: BACKGROUND
  Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, is in clinical development for the treatment of hypercholesterolemia. It is rapidly absorbed and glucuronidated in the intestine. The parent compound and its conjugated metabolite undergo enterohepatic recirculation, resulting in multiple peaks in the plasma concentration-time profile.
  
  
  OBJECTIVE
  The purpose of this study was to develop a population pharmacokinetic (PPK) model for ezetimibe that incorporates enterohepatic recirculation.
  
  
  METHODS
  A population compartment model incorporating input from the gallbladder, consistent with food intake, was developed to account for enterohepatic recirculation. The amount recycled was allowed to vary within a subject and between subjects, accommodating variability in bile secretion. The data used consisted of 90 profiles from healthy subjects who received single or multiple doses of ezetimibe 10 or 20 mg. Modeling was carried out using a nonlinear mixed-effect function in the S-PLUS statistical program.
  
  
  RESULTS
  The amount of ezetimibe recycled into the central compartment was estimated to be approximately 17% to 20% of the total amount absorbed, independent of the volume of distribution. The intersubject coefficient of variation was 46% to 80% in the absorption rate constant, 27% in the distribution phase, and approximately 50% in the volume of distribution.
  
  
  CONCLUSIONS
  PPK models adapted for enterohepatic recirculation allowed a formal assessment of the magnitude and frequency of the enterohepatic recirculation process, and the associated intersubject and intrasubject variability in healthy subjects. The PPK approach also helped to assess the correlation between the observed maximum or minimum (24 hours postdose) concentration with the model-based area under the curve, confirming the appropriateness of the former measures as a surrogate of drug exposure for a possible correlation with pharmacodynamics.
authors: Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. farkad.ezzet@spcorp.com
authors: F
authors: F
authors: Ezzet
authors: G
authors: G
authors: Krishna
authors: D B
authors: DB
authors: Wexler
authors: P
authors: P
authors: Statkevich
authors: T
authors: T
authors: Kosoglou
authors: V K
authors: VK
authors: Batra
mesh_terms: D000328:Adult; D000465:Algorithms; D000924:Anticholesteremic Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001384:Azetidines / Q000097:blood / Q000493:pharmacokinetics*; D004764:Enterohepatic Circulation; D000069438:Ezetimibe; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008954:Models, Biological
chemical_list: D000924:Anticholesteremic Agents; D001384:Azetidines; D000069438:Ezetimibe