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

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

doi:10.1007/s00210-023-02640-0

Cited by 2 publications

(1 citation statement)

References 22 publications

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“…Nevertheless, this study had great significance in that it was able to quantitatively explore the pharmacokinetic and pharmacodynamic characteristics of levocetirizine and their effects across genders, which had not been clearly identified previously. In addition, it is important to accelerate precision medicine and present information related to drug efficacy and safety by discovering new covariates that can effectively explain the diversity of levocetirizine pharmacometrics within the population [ 14 , 21 ]. In particular, the fact that the gender factor was an effective covariate in the distribution of levocetirizine to peripheral tissues was a new and progressive discovery.…”

Section: Discussionmentioning

confidence: 99%

Is Gender an Important Factor in the Precision Medicine Approach to Levocetirizine?

Jeong,

Jang,

Lee

2024

Pharmaceutics

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Currently, there is insufficient information on the variability in levocetirizine pharmacometrics among individuals, a crucial aspect for establishing its clinical use. The gender differences in pharmacokinetics and the extent of variation in pharmacodynamics have not been definitively identified. The primary goal of this study was to investigate gender differences in levocetirizine pharmacokinetics and quantitatively predict and compare how these gender-related pharmacokinetic differences impact pharmacodynamics, using population pharmacokinetic–pharmacodynamic modeling. Bioequivalence results for levocetirizine (only from the control formulation) were obtained from both healthy Korean men and women. Physiological and biochemical parameters for each individual were utilized as pharmacokinetic comparison and modeling data between genders. Pharmacodynamic modeling was performed using reported data on antihistamine responses following levocetirizine exposure. Gender, weight, body surface area, peripheral distribution volume, albumin, central–peripheral inter-compartmental clearance, and the fifth sequential absorption rate constant were explored as effective covariates. A comparison of the model simulation results showed a higher maximum concentration and faster plasma loss in females than in males, resulting in a faster recovery to baseline of the antihistamine effect; however, the absolute differences between genders in the mean values were not large within 10 ng/mL (for plasma concentrations) or % (wheal and flare size changes). Regarding the pharmacokinetics and pharmacodynamics of levocetirizine, the gender effect may not be significant when applying the usual dosage (5 mg/day). This study will be useful for bridging the knowledge gap in scientific precision medicine by introducing previously unconfirmed information regarding gender differences in levocetirizine pharmacometrics.

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Section: Discussionmentioning

confidence: 99%

Is Gender an Important Factor in the Precision Medicine Approach to Levocetirizine?

Jeong,

Jang,

Lee

2024

Pharmaceutics

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Exploring Differences in Pharmacometrics of Rabeprazole between Genders via Population Pharmacokinetic–Pharmacodynamic Modeling

Jeong,

Jang,

Lee

2023

Biomedicines

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Rabeprazole is a proton pump inhibitor that inhibits gastric acid production and increases gastric pH; it is widely used clinically as a treatment option for gastritis and gastric ulcers. However, information on the inter-individual variability of rabeprazole pharmacometrics, which is a key element in establishing its scientific clinical use, is still lacking. Particularly, the differences in pharmacokinetics between genders and the degree of variation in pharmacodynamics have not been clearly identified. Thus, the main purpose of this study was to explore any differences in rabeprazole pharmacokinetics between genders and to quantitatively predict and compare the effects of any differences in pharmacokinetics between genders on known pharmacodynamics using population pharmacokinetic–pharmacodynamic modeling. To compare pharmacokinetics and modeling data between genders, bioequivalence results were used simultaneously on healthy Korean men and women using the physiological and biochemical parameters derived from each individual. Pharmacodynamic modeling was performed based on the data of previously reported gastric pH changes in response to rabeprazole plasma concentrations, which was co-linked to the central compartmental bioavailable concentration in the population pharmacokinetic model. There was no significant difference in the level of rabeprazole exposure and elimination of plasma between genders following oral administration of 10 mg enteric-coated rabeprazole tablets; however, there was a clear delay in absorption in women compared to men. Additionally, a comparison of pharmacokinetic parameters normalized to body weight between genders showed that the maximum plasma concentrations were significantly higher in women than in men, again suggesting gender differences in rabeprazole absorption. The population pharmacokinetic profiles for rabeprazole were described using a three-sequential multi-absorption with lag time (Tlag) two-compartment model, whereas body surface area and gender were explored as effective covariates for absorption rate constant and Tlag, respectively. The effect of increased gastric pH due to plasma exposure to rabeprazole was explained using the Sigmoid Emax model, with the baseline as a direct response. The significantly longer rabeprazole Tlag in females delayed the onset of an effect by an average of 1.58 times (2.02–3.20 h), yet the overall and maximum effects did not cause a significant difference within 15%. In the relative comparison of the overall efficacy of rabeprazole enteric-coated tablet administration between genders, it was predicted based on the model that males would have higher efficacy. This study will be very useful in broadening the perspective of interpreting drug diversity between individuals and narrowing the gap in knowledge related to scientific precision medicine by presenting new information on gender differences in rabeprazole pharmacometrics that had not been previously identified.

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

Cited by 2 publications

References 22 publications

Is Gender an Important Factor in the Precision Medicine Approach to Levocetirizine?

Is Gender an Important Factor in the Precision Medicine Approach to Levocetirizine?

Exploring Differences in Pharmacometrics of Rabeprazole between Genders via Population Pharmacokinetic–Pharmacodynamic Modeling

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