A population pharmacokinetic model that describes multiple peaks due to enterohepatic recirculation of ezetimibe

Background: Ezetimibe, a selective inhibitor of intestinal cholesterol abso rption, is in clinical development for the treatment of hypercholesterolemi a. It is rapidly absorbed and glucuronidated in the intestine. The parent c ompound 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 pharmacoki netic (PPK) model for ezetimibe that incorporates enterohepatic recirculati on. Methods: A population compartment model incorporating input from the gallbl adder, consistent with food intake, was developed to account for enterohepa tic recirculation. The amount recycled was allowed to vary within a subject and between subjects, accommodating variability in bile secretion. The dat a used consisted of 90 profiles from healthy subjects who received single o r multiple doses of ezetimibe 10 or 20 mg. Modeling was carried out using a nonlinear mixed-effect function in the S-PLUS (R) statistical program. Results: The amount of ezetimibe recycled into the central compartment was estimated to be similar to 17% to 20% of the total amount absorbed, indepen dent of the volume of distribution. The intersubject coefficient of variati on was 46% to 80% in the absorption rate constant, 27% in the distribution phase, and similar to 50% in the volume of distribution. Conclusions: PPK models adapted for enterohepatic recirculation allowed a f ormal assessment of the magnitude and frequency of the enterohepatic recirc ulation process, and the associated intersubject and intrasubject variabili ty in healthy subjects. The PPK approach also helped to assess the correlat ion between the observed maximum or minimum (24 hours postdose) concentrati on with the model-based area under the curve, confirming the appropriatenes s of the former measures as a surrogate of drug exposure for a possible cor relation with pharmacodynamics.