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 ofezetimibe 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.
RCT Entities:
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: Teddy Kosoglou; Ingo Meyer; Enrico P Veltri; Paul Statkevich; Bo Yang; Yali Zhu; Lillian Mellars; Stephen E Maxwell; James E Patrick; David L Cutler; Vijay K Batra; Melton B Affrime Journal: Br J Clin Pharmacol Date: 2002-09 Impact factor: 4.335
Authors: D R H Huntjens; A Strougo; A Chain; A Metcalf; S Summerfield; D J M Spalding; M Danhof; O Della Pasqua Journal: Br J Pharmacol Date: 2008-01-14 Impact factor: 8.739
Authors: Tae Hwan Kim; Soyoung Shin; Cornelia B Landersdorfer; Yong Ha Chi; Soo Heui Paik; Jayhyuk Myung; Rajbharan Yadav; Stefan Horkovics-Kovats; Jürgen B Bulitta; Beom Soo Shin Journal: AAPS J Date: 2015-05-20 Impact factor: 4.009