Quantitative assessment of the relevance of organic-anion-transporting-polypeptide 1B1 and 2B1 polymorphisms in fexofenadine pharmacokinetic variants via pharmacometrics

This study aimed to quantify and explain inter-subject variability in morni umate pharmacokinetics and identify effective covariates through population pharmacokinetic modeling. Models were constructed using bioequivalence pharmacokinetic results from healthy Korean males and individual physiological and biochemical parameters. Additionally, we incorporated previously reported pharmacokinetic results of ni umic acid, a major active metabolite of morni umate, to extend the established population pharmacokinetic model and predict ni umic acid pharmacokinetics. Moreover, we used quantitative reports of leukotriene B 4 (LTB 4 ) synthesis inhibition in response to ni umic acid exposure to predict drug e cacy using Sigmoid E max model.Population pharmacokinetic pro les of morni umate were described using a multi-absorption (5-sequential) twocompartment model, and analysis of inter-individual variability suggested that volume of distribution in peripheral compartment was correlated with body mass index (BMI). Model simulation results showed that individuals with lower BMI had higher plasma concentrations of morni umate and ni umic acid, resulting in increased and sustained inhibition of LTB 4 synthesis. Under steady-state conditions, average plasma concentrations of morni umate and ni umic acid were 2.66-2.68 times higher in group with a BMI of 17.36 kg/m 2 compared to group with a BMI of 28.41 kg/m 2 . Additionally, inhibition of LTB 4 synthesis was 1.02 times higher in group with a BMI of 17.36 kg/m 2 compared to group with a BMI of 28.41 kg/m 2 , and the uctuation was signi cantly reduced from 6.06-0.01%. These ndings suggest that the concentration of active metabolite in plasma following morni umate exposure was lower in the obese group compared to normal group, thus potentially reducing the drug's e cacy.

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Modeling population pharmacokinetics of morniflumate in healthy Korean men: extending pharmacometrics analysis to niflumic acid, its major active metabolite

Jeong

Jang

Lee

2023

Naunyn-Schmiedeberg's Arch Pharmacol

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P-glycoprotein mechanical functional analysis using in silico molecular modeling: Pharmacokinetic variability according to ABCB1 c.2677G > T/A genetic polymorphisms

Jeong,

Jang,

Lee

2023

International Journal of Biological Macromolecules

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Quantitative assessment of the relevance of organic-anion-transporting-polypeptide 1B1 and 2B1 polymorphisms in fexofenadine pharmacokinetic variants via pharmacometrics

Cited by 2 publications

References 24 publications

Modeling population pharmacokinetics of morniflumate in healthy Korean men: extending pharmacometrics analysis to niflumic acid, its major active metabolite

Modeling population pharmacokinetics of morniflumate in healthy Korean men: extending pharmacometrics analysis to niflumic acid, its major active metabolite

P-glycoprotein mechanical functional analysis using in silico molecular modeling: Pharmacokinetic variability according to ABCB1 c.2677G > T/A genetic polymorphisms

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