F. Ezzet, G. Krishna, D. Wexler, P. Statkevich, T. Kosoglou, V. Batra
Schering-Plough Research Institute: Kenilworth, NJ United States
Purpose. To develop a population pharmacokinetic (PPK) model encompassing enterohepatic recirculation (EHC (1)).
Methods. Ezetimibe is an azetidinone inhibitor of intestinal absorption of cholesterol for the treatment of hypercholesterolemia. It is rapidly absorbed and glucuronidated in the intestine. The parent compound and the conjugated metabolite undergo EHC, resulting in multiple peaks in plasma concentration-time profiles. A population compartment model incorporating input from the gallbladder consistent with food intake was developed. The amount recycled was allowed to vary within 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 non-linear mixed effect function in Splus.
Results. The amount recycled into the central compartment was estimated to be about 18% of the total amount absorbed with an intra subject coefficient of variation (ISCV) of 73%. ISCV in apparent clearance and volume was 67% and 70%, respectively.
Conclusions. Standard PK models adapted for EHC allowed a formal assessment of the magnitude and frequency of this process. Using the population approach inter and intra subject variability was estimated. Further inference with this model was possible; e.g. correlation between observed Cmin and model based AUC. Confirming the appropriateness of Cmin as a surrogate measure of drug exposure for a possible correlation with pharmacodynamics in subsequent patient studies.
(1) Plusquellec Y., et.al. (1998), Enterohepatic recirculation of the new antihypertensive drug UP 269-6 in Humans, Arzneim.-Forsch./Drug Res. 48 (1), 138-144.
Reference: PAGE 10 (2001) Abstr 175 [www.page-meeting.org/?abstract=175]
Poster: poster