title: Population Pharmacokinetic Modeling of the Enterohepatic Recirculation of Fimasartan in Rats, Dogs, and Humans.
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.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Korea.
authors.forename: Tae Hwan
authors.initials: TH
authors.lastname: Kim
authors.forename: Soyoung
authors.initials: S
authors.lastname: Shin
authors.forename: Cornelia B
authors.initials: CB
authors.lastname: Landersdorfer
authors.forename: Yong Ha
authors.initials: YH
authors.lastname: Chi
authors.forename: Soo Heui
authors.initials: SH
authors.lastname: Paik
authors.forename: Jayhyuk
authors.initials: J
authors.lastname: Myung
authors.forename: Rajbharan
authors.initials: R
authors.lastname: Yadav
authors.forename: Stefan
authors.initials: S
authors.lastname: Horkovics-Kovats
authors.forename: Jürgen B
authors.initials: JB
authors.lastname: Bulitta
authors.forename: Beom Soo
authors.initials: BS
authors.lastname: Shin
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D057911:Angiotensin Receptor Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics; D000818:Animals; D019540:Area Under Curve; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004764:Enterohepatic Circulation; D005260:Female; D006801:Humans; D008297:Male; D008954:Models, Biological; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D053719:Tandem Mass Spectrometry; D013777:Tetrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D011743:Pyrimidines; D013777:Tetrazoles; C558933:fimasartan