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

Ji-Hun Jang; Seung-Hyun Jeong; Yong-Bok Lee

doi:10.1016/j.jpha.2023.04.001

Volume 13 Issue 6

Jun. 2023

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Ji-Hun Jang, Seung-Hyun Jeong, Yong-Bok Lee. Quantitative assessment of the relevance of organic-anion-transporting-polypeptide 1B1 and 2B1 polymorphisms in fexofenadine pharmacokinetic variants via pharmacometrics[J]. Journal of Pharmaceutical Analysis, 2023, 13(6): 660-672. doi: 10.1016/j.jpha.2023.04.001

Citation:

Ji-Hun Jang, Seung-Hyun Jeong, Yong-Bok Lee. Quantitative assessment of the relevance of organic-anion-transporting-polypeptide 1B1 and 2B1 polymorphisms in fexofenadine pharmacokinetic variants via pharmacometrics[J]. Journal of Pharmaceutical Analysis, 2023, 13(6): 660-672. doi: 10.1016/j.jpha.2023.04.001

Citation:

Ji-Hun Jang, Seung-Hyun Jeong, Yong-Bok Lee. Quantitative assessment of the relevance of organic-anion-transporting-polypeptide 1B1 and 2B1 polymorphisms in fexofenadine pharmacokinetic variants via pharmacometrics[J]. Journal of Pharmaceutical Analysis, 2023, 13(6): 660-672. doi: 10.1016/j.jpha.2023.04.001

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

doi: 10.1016/j.jpha.2023.04.001

a. Department of Pharmacy, College of Pharmacy, Chonnam National University, Gwangju, 61186, Republic of Korea;
b. Department of Pharmacy, College of Pharmacy, Sunchon National University, Suncheon-si, 57922, Republic of Korea

Received Date: Jan. 14, 2023
Accepted Date: Apr. 02, 2023
Rev Recd Date: Mar. 06, 2023
Publish Date: Apr. 06, 2023

Abstract

Abstract

Fexofenadine is useful in various allergic disease treatment. However, the pharmacokinetic variability information and quantitative factor identification of fexofenadine are very lacking. This study aimed to verify the validity of previously proposed genetic factors through fexofenadine population pharmacokinetic modeling and to explore the quantitative correlations affecting the pharmacokinetic variability. Polymorphisms of the organic-anion-transporting-polypeptide (OATP) 1B1 and 2B1 have been proposed to be closely related to fexofenadine pharmacokinetic diversity. Therefore, modeling was performed using fexofenadine oral exposure data according to the OATP1B1- and 2B1-polymorphisms. OATP1B1 and 2B1 were identified as effective covariates of clearance (CL/F) and distribution volume (V/F)-CL/F, respectively, in fexofenadine pharmacokinetic variability. CL/F and average steady-state plasma concentration of fexofenadine differed by up to 2.17- and 2.20-folds, respectively, depending on the OATP1B1 polymorphism. Among the individuals with different OATP2B1 polymorphisms, the CL/F and V/F differed by up to 1.73- and 2.00-folds, respectively. Ratio of the areas under the curves following single- and multiple-administrations, and the cumulative ratio were significantly different between OATP1B1- and 2B1-polymorphism groups. Based on quantitative prediction comparison through a model-based approach, OATP1B1 was confirmed to be relatively more important than 2B1 regarding the degree of effect on fexofenadine pharmacokinetic variability. Based on the established pharmacokinetic-pharmacodynamic relationship, the difference in fexofenadine efficacy according to genetic polymorphisms of OATP1B1 and 2B1 was 1.25- and 0.87-times, respectively, and genetic consideration of OATP1B1 was expected to be important in the pharmacodynamics area as well. This population pharmacometrics study will be a very useful starting point for fexofenadine precision medicine.
- OATP1B1,
- OATP2B1,
- Fexofenadine,
- Population pharmacometrics,
- Genetic polymorphism

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References(24)

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