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Population pharmacokinetic modeling of levodropropizine: extended application to comparative analysis between commercial formulations and exploration of pharmacokinetic effects of diet

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Abstract

Levodropropizine, a nonopioid antitussive agent, is being increasingly used in clinical practice with the development of several formulations for symptomatic relief of acute and chronic bronchitis. However, scientific and quantitative population pharmacokinetic analyses of levodropropizine are lacking. Moreover, no integrated quantitative comparison has been performed between formulations. This study quantitatively evaluated and predicted pharmacokinetic properties of formulations through population pharmacokinetic model–based comparisons of commercially available formulations. Plasma concentration profile results from bioequivalence studies of 60-mg immediate release (IR) levodropropizine tablets in 40 healthy Korean males were used as population pharmacokinetic modeling data. For interindividual variability in levodropropizine pharmacokinetics, body surface area was identified as an effective covariate that was positively correlated with peripheral compartment distribution volume. Population pharmacokinetic model for IR tablets well-described the levodropropizine syrup and capsule datasets, suggesting no significant differences in pharmacokinetics among IR tablets, syrups, and capsules of levodropropizine. In contrast, pharmacokinetic profiles differed between 90-mg controlled release (CR) and IR levodropropizine tablets; however, separate parameter estimation was possible by applying the same model structure. In terms of pharmacokinetics, twice-daily regimen of 90-mg CR tablets was equivalent to thrice-daily regimen of 60-mg IR tablets. However, at steady-state, interindividual plasma concentration variability within population was reduced by approximately 36.71–83.18%. For levodropropizine CR tablets, a high-fat diet significantly delayed gastrointestinal absorption but maintained overall plasma exposure equivalent. This study provides useful quantitative judgment data for precision medicine of levodropropizine and can be helpful in predicting the pharmacokinetics of levodropropizine based on commercialized formulation switching.

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Data availability

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

Abbreviations

IR:

Immediate release

CR:

Controlled release

BSA:

Body surface area

NCA:

Noncompartmental analysis

IIV:

Interindividual variability

AIC:

Akaike’s information criterion

 − 2LL:

Twice the negative log-likelihood

GOF:

Goodness-of-fit

OFV:

Objective function value

VPC:

Visual predictive check

NPDE:

Normalized prediction distribution error

ANOVA:

Analysis of variance

CI:

Confidence interval

CWRES:

Conditional weighted residuals

QQ:

Quantile–quantile

IWRES:

Individual weighted residuals

T lag :

Lag time

BMI:

Body mass index

ALT:

Alanine transaminase

RSE:

Relative standard error

MRT:

Mean residence time

ALP:

Alkaline phosphatase

AST:

Aspartate transaminase

CrCL:

Creatinine clearance

GFR:

Glomerular filtration rate

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Acknowledgements

The authors are deeply grateful to the Korea Prime Pharm. Co. (Gwangju, Republic of Korea) for providing clinical trial data and related information in conducting this study.

Funding

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (RS-2023–00245453). This research was also supported by 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 work.

Authors and Affiliations

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

    Seung-Hyun Jeong & Ji-Hun Jang

  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

    Yong-Bok Lee

Authors
  1. Seung-Hyun Jeong
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Contributions

Seung-Hyun Jeong: conceptualization, data curation, formal analysis, investigation, methodology, software, validation, visualization, writing—original draft preparation, reviewing and editing; Ji-Hun Jang: conceptualization, data curation, formal analysis, investigation, methodology, software, validation, visualization, writing—original draft preparation, reviewing and editing; Yong-Bok Lee: project administration, resources, writing—reviewing and editing, supervision. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding author

Correspondence to Yong-Bok Lee.

Ethics declarations

Ethical approval

Clinical studies were conducted in accordance with the Rules of Good Clinical Practice and the revised Declaration of Helsinki for biomedical research involving human subjects.

Consent to participate

All participants provided written informed consent before participating in the bioequivalence and pharmacokinetic 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.

Clinical trial registration

The clinical trial protocol was thoroughly reviewed and officially approved by the Ministry of Food and Drug Safety (Cheongju-si, Republic of Korea). The approval number of the trial was 100744, and the approval date was November 1, 2022. The clinical trial was conducted at the Bumin Clinical Trial Center (Seoul, Republic of Korea), and the total duration was from November 30, 2022, to December 9, 2022.

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Jeong, SH., Jang, JH. & Lee, YB. Population pharmacokinetic modeling of levodropropizine: extended application to comparative analysis between commercial formulations and exploration of pharmacokinetic effects of diet. Naunyn-Schmiedeberg's Arch Pharmacol 397, 4403–4418 (2024). https://doi.org/10.1007/s00210-023-02889-5

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