Hyun-moon Back (1), Byungjeong Song (1), Hwi-yeol Yun (1), Jung-woo Chae (1), Kwang-il Kwon (1)
(1) College of Pharmacy, Chungnam National University, Korea
Objectives: Fenofibrate is a prodrug of the active metabolite fenofibric acid and it is used for hypercholesterolemia and hypertriglyceridemia. Absorption of fenofibrate is significantly different after consumption of food [1]. The aim of this study was to develop a mechanistic population pharmacokinetic model of fenofibrate following food consumption in human.
Methods: A randomized, three-way crossover trial study was conducted in 24 healthy Korean subjects (13 male, 11 female). PK data collected after administration of fenofibrate 250mg and different food type on three occasions, with a 1-week wash out period between each drug administration. A mechanistic multicompartmental PK model was developed in NONMEM 7.3.0 [2]. Linear and nonlinear effect were evaluated for explaining impact of food intake measured by calorie on fenofibrate absorption. For explaining change of gastric emptying time of fenofibrate affected by food, MTIME option in ka was assessed. For evaluating the final PK model, visual predictive check was performed.
Results: Multi-compartment model with two physiological compartments for fenofibrate and two additional compartments for food consumption best described fenofibrate pharmacokinetics. Amount of calorie intake was used to explain food effect and in our final model. The absorption of fenofibrate was stimulated depending on the amound of calorie in duodenum compartment. The visual predictive check (VPC) was performed and the prediction power of final model was acceptable.
Conclusions: A mechanistic multicompartmental PK model was successfully developed and acceptable parameters were obtained for explaining fenofibrate absorption variation after food intake. Using this final model, we can simulate PK of fenofibrate following food intake and make a quantification of fenofibrate concentration depending on the amount of calorie.
References:
[1] Yun HY, Lee EJ, Chung SY, Choi SO, Kim HK, Kwon JT, Kang W, Kwon KI. The effects of food on the bioavailability of fenofibrate administered orally in healthy volunteers via sustained-release capsule. Clin Pharmacokinet, (2006) 45(4): 425-432.
[2] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. Icon Development Solutions, Ellicott City, Maryland, USA.
Reference: PAGE 24 () Abstr 3362 [www.page-meeting.org/?abstract=3362]
Poster: Drug/Disease modeling - Absorption & PBPK