Population Pharmacokinetic Modeling of the Enterohepatic Recirculation of Fimasartan in Rats, Dogs, and Humans

Abstract

Abstract. Enterohepatic recirculation (EHC) can greatly enhance plasma drug exposures and therapeutic effects. This study aimed to develop a population pharmacokinetic model that can simultaneously characterize the extent and time-course of EHC in three species using fimasartan, a novel angiotensin II receptor blocker, as a model drug. All fimasartan plasma concentration profiles in 32 rats (intravenous doses, 0.3-3 mg/kg; oral doses, 1-10 mg/kg), 34 dogs (intravenous doses, 0.3-1 mg/kg; oral doses, 1-10 mg/kg), and 42 healthy volunteers (single or multiple oral doses, 20-480 mg) were determined via liquid chromatography-tandem mass spectrometry (LC-MS/MS) and simultaneously modeled in S-ADAPT. The proposed model quantitatively characterized EHC in three species after oral and intravenous dosing. The median (range) fraction of drug undergoing recirculation was 76.3% (64.9-88.7%) in rats, 33.3% (24.0-45.9%) in dogs, and 65.6% (56.5-72.0%) in humans. In the presence compared with the absence of EHC, the area under the curve in plasma was predicted to be 4.22-fold (2.85-8.85) as high in rats, 1.50-fold (1.32-1.85) in dogs, and 2.91-fold (2.30-3.57) in humans. The modeled oral bioavailability in rats (median (range), 38.7% (20.0-59.8%)) and dogs (median, 7.13% to 15.4%, depending on the formulation) matched the non-compartmental estimates well. In humans, the predicted oral bioavailability was 25.1% (15.1-43.9%) under fasting and 18.2% (12.2-31.0%) under fed conditions. The allometrically scaled area under the curve predicted from rats was 420 ng⋅h/mL for 60 mg fimasartan compared with 424±63 ng⋅h/mL observed in humans. The developed population pharmacokinetic model can be utilized to characterize the impact of EHC on plasma drug exposure in animals and humans.

Decreased potency of fimasartan in liver cirrhosis was quantified using mixed-effects analysis

“…The second peaks were also observed after intravenous administration in other clinical trials, suggesting the presence of enterohepatic recirculation. [3,7,12] The empirical model of two-compartment distribution and mixed zero-order absorption followed by firstorder absorption with a lag time best described PK characteristics of fimasartan in this study. This may have been the result of insufficient data to develop a physiological model incorporating the enterohepatic recirculation.…”

Liquid Chromatography-Tandem Mass Spectrometry of Desoxo-Narchinol a and Its Pharmacokinetics and Oral Bioavailability in Rats and Mice

“…Extensive enterohepatic recirculation typically leads to multiple peaks or shoulders in the plasma concentration-time profiles and a prolonged terminal half-life [22,23]. Alternatively, complex absorption processes, including the presence of different absorption sites in the gastrointestinal tract, may also be associated with the double peak phenomenon [24].…”

Pharmacokinetics and Anti-Gastric Ulceration Activity of Oral Administration of Aceclofenac and Esomeprazole in Rats

“…These results agree with those of previous studies in which multiple peaks were present [ 6 ]. The multiple-peak phenomenon may result from the presence of either enterohepatic recirculation or a complicated absorption process [ 33 , 34 ], which may be favorable in fasting conditions [ 6 ]. The pharmacokinetics of the metabolite diclofenac were not altered by the presence of food.…”