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

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 E_max 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.

Keywords: Body mass index; Model simulation; Morniflumate; Niflumic acid; Pharmacodynamics; Population pharmacokinetics modeling.