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A genetic-based population PK/PD modeling of methadone in Chinese opiate dependence patients

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The full potential of methadone maintenance treatment (MMT) is often limited by the large inter-individual variability in both pharmacokinetics (PK) and pharmacodynamics (PD), and by the risk of torsade de pointes, a severe adverse effect caused by QTc prolongation. The current study aims to quantitate the contribution of genetic polymorphisms and other variables in PK/PD variability, and their contribution to the QTc interval prolongation in Chinese MMT patients.

Methods

Population PK models were developed to fit (R)- and (S)-methadone PK data. Hierarchical models were tested to characterize the PK profile, the concentration–QTc relationship, and concentration–urinalysis illicit drug testing relationship, with demographics and genetic variants being included as covariates. Simulation based on the developed PK/PD models was performed to assess the effect of methadone dose and genetic variants on QTc interval prolongation.

Results

The PK data were best-fit by a one-compartment, first-order absorption model. Clearance of (R)- and (S)-methadone was both affected by the weighted activity score derived from genetic variants. A linear model was used to describe both the methadone concentration–urinalysis illicit drug testing relationship and the methadone concentration–QTc relationship. Concentration of (R)- and (S)-methadone exhibits a comparable effect on QTc prolongation. Simulation showed that the percentage of QTc higher than 450 ms was almost doubled in the lowest clearance group as compared the highest when methadone dose was greater than 120 mg.

Conclusions

The large variability in PK/PD profiles can be partially explained by the genetic variants in an extent different from other population, which confirmed the necessity to conduct such a study in the specific Chinese patients.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was support in part by the National Natural Science Foundation of the People’s Republic of China (Grant 81202594) and the Guangxi University of Chinese Medicine PhD Research (Grant 2017BS045).

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China

    Dong Guo, Zhirong Tan, Xiaoya Lou, Yan Shu, Honghao Zhou & Hong Yang

  2. Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Baltimore, MD, USA

    Dong Guo, Yan Shu & Hong Yang

  3. Nanning Red Cross Hospital, Nanning, 530000, Guangxi, China

    Shan Shi

  4. Guangxi University of Chinese Medicine, Nanning, 530000, Guangxi, China

    Li Yu

  5. Department of Pharmacy, The First Hospital of Changsha, Changsha, 410008, Hunan, China

    Xiaoya Lou

Authors
  1. Dong Guo
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  2. Zhirong Tan
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  3. Xiaoya Lou
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  4. Shan Shi
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  5. Yan Shu
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  6. Honghao Zhou
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  7. Li Yu
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  8. Hong Yang
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Contributions

All authors contributed to the study conception and design. The population pharmacokinetic modeling and simulation analyses were performed by H.Y. and D.G.; the clinical trial was operated by H.Y., D.G., L.Y., and S.S.; DNA samples were prepared by H.Y. and X.L.; plasma samples for methadone quantification were prepared by H.Y. and Z.T.. All authors reviewed the manuscript for critical intellectual contents and approved the final manuscript.

Corresponding authors

Correspondence to Li Yu or Hong Yang.

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The authors declare no competing interest.

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Guo, D., Tan, Z., Lou, X. et al. A genetic-based population PK/PD modeling of methadone in Chinese opiate dependence patients. Eur J Clin Pharmacol 78, 565–578 (2022). https://doi.org/10.1007/s00228-021-03227-5

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  • DOI: https://doi.org/10.1007/s00228-021-03227-5

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