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

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Abstract

This study aimed to quantify and explain inter-subject variability in morniflumate pharmacokinetics and identify effective covariates through population pharmacokinetics modeling. Models were constructed using bioequivalence pharmacokinetics results from healthy Korean males and individual physiological and biochemical parameters. Additionally, we incorporated previously reported pharmacokinetics results of niflumic acid, a major active metabolite of morniflumate, to extend the established population pharmacokinetics model and predict niflumic acid pharmacokinetics. Moreover, we used quantitative reports of leukotriene B4 (LTB4) synthesis inhibition in response to niflumic acid exposure to predict drug efficacy using Sigmoid Emax model. Population pharmacokinetics profiles of morniflumate were described using a multi-absorption (5-sequential) two-compartment 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 morniflumate and niflumic acid, resulting in increased and sustained inhibition of LTB4 synthesis. Under steady-state conditions, average plasma concentrations of morniflumate and niflumic acid were 2.66–2.68 times higher in group with a BMI of 17.36 kg/m2 compared to the group with a BMI of 28.41 kg/m2. Additionally, inhibition of LTB4 synthesis was 1.02 times higher in group with a BMI of 17.36 kg/m2 compared to group with a BMI of 28.41 kg/m2, and the fluctuation was significantly reduced from 6.06 to 0.01%. These findings suggest that the concentration of active metabolite in plasma following morniflumate exposure was lower in the obese group compared to the normal group, thus potentially reducing the drug’s efficacy.

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Data availability

All data and related materials are accessible in this manuscript and supplementary materials.

Abbreviations

BMI:

Body mass index

LTB4 :

Leukotriene B4

NSAID:

Nonsteroidal anti-inflammatory drug

TXB2 :

Thromboxane B2

IIV:

Inter-individual variability

T lag :

Lag-time

NCA:

Noncompartment analysis

AIC:

Akaike’s information criterion

\(-\) 2LL:

Negative log likelihood

GOF:

Goodness of fit

VPC:

Visual predictive check

NPDE:

Normalized prediction distribution error

CWRES:

Conditional weighted residuals

QQ:

Quantile-quantile

WRES:

Weighted residuals

OFV:

Objective function value

BSA:

Body surface area

GFR:

Glomerular filtration rate

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Funding

This work was supported by the Medical Research Program of Handok Jeseok Foundation.

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Author notes

  1. Seung-Hyun Jeong and Ji-Hun Jang contributed equally to this manuscript.

Authors and Affiliations

  1. College of Pharmacy, Sunchon National University, 255 Jungang-Ro, Suncheon-Si, 57922, Republic of Korea

    Seung-Hyun Jeong

  2. College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Suncheon-Si, 57922, Republic of Korea

    Seung-Hyun Jeong

  3. College of Pharmacy, Chonnam National University, 77 Yongbong-Ro, Buk-Gu, Gwangju, 61186, Republic of Korea

    Ji-Hun Jang & Yong-Bok Lee

Authors
  1. Seung-Hyun Jeong
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  2. Ji-Hun Jang
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Contributions

Seung-Hyun Jeong: Conceptualization, investigation, methodology, writing-original draft, writing-review and editing, software, data analysis, and visualization; Ji-Hun Jang: Conceptualization, investigation, methodology, writing-review and editing, software, and data analysis; Yong-Bok Lee: Conceptualization, methodology, writing-review and editing, and supervision. All authors reviewed the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding author

Correspondence to Yong-Bok Lee.

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Ethical approval

Clinical studies were conducted in accordance with the Rules of Good Clinical Practice and the revised Declaration of Helsinki for Biomedical Research with Human Subjects. All subjects had no prior history of hypersensitivity or related reactions to steroid drugs and were physically normal. In addition, healthy adults aged 19–55 years have no history of digestive, liver, kidney, cardiovascular, central nervous system, endocrine, or blood diseases in the past and have not been taking any other drugs. All subjects underwent a physical examination, clinical screening, complete blood count, urinalysis, and blood chemistry analysis prior to participation in this clinical study to confirm their physical health. The clinical study protocol used in this study was thoroughly reviewed and approved by the Institutional Review Board of the Institute of Bioequivalence and Bridging Study, Chonnam National University, Gwangju, Republic of Korea (bioequivalence study permit numbers: 100329; 01.28.2010).

Consent to participate

All subjects provided written informed consent prior to their participation in the bioequivalence and pharmacokinetics studies.

Consent for publication

All data were anonymized and participants were informed that the results of this study may be subject to publication and presentation in meetings.

Competing interests

The authors declare no competing interests.

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Jeong, SH., Jang, JH. & Lee, YB. Modeling population pharmacokinetics of morniflumate in healthy Korean men: extending pharmacometrics analysis to niflumic acid, its major active metabolite. Naunyn-Schmiedeberg's Arch Pharmacol 397, 843–856 (2024). https://doi.org/10.1007/s00210-023-02640-0

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