Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Fimasartan Following Single and Repeated Oral Administration in the Fasted and Fed States in Healthy Subjects

Ha, Yong; Lee, Howard; Paik, Soo Heui; Lee, Joo Han; Yoo, Byoung Wook; Kim, Ji Han; Tan, Hyun Kwang; Kim, Sang Lin

doi:10.2165/11593840-000000000-00000

Cited by 43 publications

(61 citation statements)

References 17 publications

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“…Multiple plasma concentration peaks were also present after oral administration of fimasartan in clinical trials (17)(18)(19)(20)(21)(22), indicating that EHC impacts on human PK and potentially pharmacodynamics (PD). It is therefore important to quantitatively understand how EHC affects the systemic fimasartan exposure to enable animal to human scaling and ultimately the prediction of first-in-human (FIH) PK.…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

“…The single dose PK of fimasartan was assessed in a randomized, double-blind study (21) following oral administration of a tablet formulation containing 20, 60, 120, 240, and 480 mg fimasartan to 30 healthy subjects (six subjects per dose group). Five of the six subjects in the 240-mg group also received 240 mg fimasartan in the fed state after a wash-out period of 7 days as described previously (21).…”

Section: Clinical Studiesmentioning

confidence: 99%

“…Five of the six subjects in the 240-mg group also received 240 mg fimasartan in the fed state after a wash-out period of 7 days as described previously (21). We additionally used data from a randomized, double-blind, multiple-dose PK study which included 12 subjects receiving oral doses of 120 or 360 mg fimasartan every 24 h for 7 days.…”

Section: Clinical Studiesmentioning

confidence: 99%

“…We additionally used data from a randomized, double-blind, multiple-dose PK study which included 12 subjects receiving oral doses of 120 or 360 mg fimasartan every 24 h for 7 days. Detailed PK profiles were obtained on days 1 and 7 (21).…”

Section: Clinical Studiesmentioning

confidence: 99%

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

Kim

Shin

Landersdorfer

et al. 2015

AAPS J

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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.

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Section: Electronic Supplementary Materialsmentioning

confidence: 99%

Section: Clinical Studiesmentioning

confidence: 99%

Section: Clinical Studiesmentioning

confidence: 99%

Section: Clinical Studiesmentioning

confidence: 99%

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

Kim

Shin

Landersdorfer

et al. 2015

AAPS J

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“…38) Additionally, AP-1 is able to regulate expression of a large number of genes. As a result, AP-1 has been implicated in a wide range of cellular processes, including proliferation, death, survival and differentiation, and participates in diverse biological and pathological processes, such as epidermal and neuronal development, immune and inflammatory responses, and tumorigenesis.…”

Section: )mentioning

confidence: 99%

Fimasartan, Anti-hypertension Drug, Suppressed Inducible Nitric Oxide Synthase Expressions <i>via</i> Nuclear Factor-Kappa B and Activator Protein-1 Inactivation

Ryu

Shin

Cho

et al. 2013

Biological & Pharmaceutical Bulletin

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Since inhibition of angiotensin II type 1 (AT1) receptor reduces chronic inflammation associated with hypertension, we evaluated the anti-inflammatory potential and the underlying mechanism of fimasartan, a Korean Food and Drug Administration approved anti-hypertension drug, in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Fimasartan suppressed the expressions of inducible nitric oxide synthase (iNOS) by down-regulating its transcription, and subsequently inhibited the productions of nitric oxide (NO). In addition, fimasartan attenuated LPS-induced transcriptional and DNA-binding activities of nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1). These reductions were accompanied by parallel reductions in the nuclear translocation of NF-κB and AP-1. Taken together, our data suggest that fimasartan down-regulates the expression of the iNOS in macrophages via NF-κB and AP-1 inactivation.Key words fimasartan; inflammation; nitric oxide; nuclear factor-kappa B; activator protein-1 Inflammatory processes are important participants in the pathophysiology of hypertension and cardiovascular disease. Hypertension patients have impaired functions of the endothelium, in which inflammation plays a key role.1) Angiotensin II is recognized as an important vascular pro-inflammatory factor in hypertension. Angiotensin II-driven vascular inflammation is considered the result of direct modulates on cytokine release and pro-inflammatory transcription factor including nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1), and angiotehsin II receptor blockers (ARBs) reduce the peripheral and cerebrovascular inflammation associated with this disease. 2,3)Anti-inflammatory effects of ARBs, first established in the peripheral vasculature, 4) were later demonstrated in the cerebral vasculature 5) and in stress-induced gastric ulcerations. 6)These observations suggest that ARBs may exert general antiinflammatory effects beyond those associated with cardiovascular and metabolic disease. 7) Thus, apart from being a major vasopressor effector of the renin-angiotensin system, ARBs are probably good candidate drugs for inflammation. 8)Since the important role of macrophages in inflammation, many investigations about ARBs (e.g., candesartan, losartan, telmisartan and valsartan) were performed in lipopolysaccharide (LPS)-induced macrophages.9-11) In fact, there are several physiological roles of angiotensin II type 1 (AT1) receptor in macrophages, such as positive regulation of peroxide production 12) and shift M1/M2 polarization balance. 13) However, in macrophages AT1a receptor expression level is reportedly low and AT1b receptor is not detected at all 14) and the most important feature of macrophages is that macrophages are widely distributed in the body and provide an immediate defense against foreign agents, such as lipopolysaccharide (LPS).15) Nitric oxide (NO), a potent pro-inflammatory mediator, is mainly produced by macrophages and acts as a cytotoxic agent during immune and inflammatory responses, which is...

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Visible‐Light‐Driven Multicomponent Reactions for the Versatile Synthesis of Thioamides by Radical Thiocarbamoylation

Guo,

Wang,

Xiong

et al. 2024

Angewandte Chemie

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Thioamides are widely used structures in pharmaceuticals and agrochemicals, as well as important synthons for the construction of sulfur‐containing heterocycles. This report presents a series of visible‐light‐driven multicomponent reactions of amines, carbon disulfide, and olefins for the mild and versatile synthesis of linear thioamides and cyclic thiolactams. The use of inexpensive and readily available carbon disulfide as the thiocarbonyl source in a radical pathway enables the facile assembly of structurally diverse amine moieties with non‐nucleophilic carbon‐based reaction partners. Radical thiocarbamoylative cyclization provides a practical protocol that complements traditional approaches to thiolactams relying on deoxythionation. Mechanistic studies reveal that direct photoexcitation of in situ formed dithiocarbamate anions as well as versatile photoinduced electron transfer with diverse electron acceptors are key to the reactions.

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Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Fimasartan Following Single and Repeated Oral Administration in the Fasted and Fed States in Healthy Subjects

Cited by 43 publications

References 17 publications

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

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

Fimasartan, Anti-hypertension Drug, Suppressed Inducible Nitric Oxide Synthase Expressions <i>via</i> Nuclear Factor-Kappa B and Activator Protein-1 Inactivation

Visible‐Light‐Driven Multicomponent Reactions for the Versatile Synthesis of Thioamides by Radical Thiocarbamoylation

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