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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.

SUBMITTER: Kim TH

PROVIDER: S-EPMC4540730 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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

Kim Tae Hwan TH Shin Soyoung S Landersdorfer Cornelia B CB Chi Yong Ha YH Paik Soo Heui SH Myung Jayhyuk J Yadav Rajbharan R Horkovics-Kovats Stefan S Bulitta Jürgen B JB Shin Beom Soo BS

The AAPS journal 20150520 5

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 ...[more]

PMID: 25990964

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Project description:ObjectiveFimasartan, an angiotensin II type 1 receptor blocker, and linagliptin, a dipeptidyl-peptidase-4 inhibitor, are frequently coadministered to treat patients with hypertension and diabetes, respectively. This study sought to evaluate the pharmacokinetic interactions between fimasartan and linagliptin after co-administration in healthy Korean subjects.MethodsThe overall study was divided into two separate parts, with each part designed as an open-label, multiple-dose, two-period, and single-sequence study. In Part A, to investigate the effect of linagliptin on fimasartan, 25 subjects received 120 mg fimasartan alone once daily for seven days during Period I, and 120 mg fimasartan with 20 mg linagliptin for seven days during Period II. In Part B, to examine the effect of fimasartan on linagliptin, 12 subjects received only linagliptin once daily for seven days during Period I, followed by concomitant administration of fimasartan for seven days during Period II, at the same doses used in Part A. Serial blood samples were collected at scheduled intervals for up to 24 h after the last dose to determine the steady-state pharmacokinetics of both drugs.ResultsThirty-six subjects completed the study. The geometric mean ratio and 90% confidence intervals for maximum plasma concentration at steady state (Cmax,ss) and area under the concentration-time curve at steady state (AUCτ,ss) of fimasartan with or without linagliptin were 1.2633 (0.9175-1.7396) and 1.1740 (1.0499-1.3126), respectively. The corresponding values for Cmax,ss and AUCτ,ss of linagliptin with or without fimasartan were 0.9804 (0.8480-1.1336) and 0.9950 (0.9322-1.0619), respectively. A total of eight adverse events (AEs) were reported and the incidence of AEs did not increase significantly with co-administration of the drugs.ConclusionOur results suggest that there are no clinically significant pharmacokinetic interactions between fimasartan and linagliptin when co-administered. Treatments were well tolerated during the study, with no serious adverse effects.Clinical trial registryhttp://clinicaltrials.gov, NCT03250052.

Dataset Information

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

Publications

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

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