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External validation of population pharmacokinetic models of tacrolimus in Thai adult liver transplant recipients

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Abstract

Objective

Several population pharmacokinetic models of tacrolimus in liver transplant patients were built, and their predictability was evaluated in their settings. However, the extrapolation in the prediction was unclear. This study aimed to evaluate the predictive performance of published tacrolimus models in adult liver transplant recipients using data from the Thai population as an external dataset.

Methods

The selected published models were systematically searched and evaluated for their quality. The external dataset of patients who underwent the first liver transplant and received immediate-release tacrolimus was used to assess the predictive performance of each selected model. Trough concentrations between 3 and 6 months were retrospectively collected to evaluate the predictability of each model using prediction-based diagnostics, simulation-based diagnostics, and Bayesian forecasting.

Results

Sixty-seven patients with 360 trough concentrations and eight selected published models were included in this study. None of the models met the predictive precision criteria in prediction-based diagnostics. Meanwhile, four published population pharmacokinetic models showed a normal distribution in NPDE testing. Regarding Bayesian forecasting, all models improved their forecasts with at least one prior information data point.

Conclusion

Bayesian forecasting is more accurate and precise than other testing methods for predicting drug concentrations. However, none of the evaluated models provides satisfactory predictive performance for generalization to Thai liver transplant patients. This underscores the need for future research to develop population PK models tailored to the Thai population. Such efforts should consider the inclusion of nonlinear pharmacokinetics and region-specific factors, including genetic variability, to improve model accuracy and applicability.

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Data availability

All datasets collected and analyzed are available at reasonable request from the corresponding author.

Code availability

Not applicable.

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Funding

This work received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand

    Virunya Komenkul & Thitima Wattanavijitkul

  2. Department of Pharmaceutical Care, College of Pharmacy, Rangsit University, Pathum Thani, Thailand

    Waroonrat Sukarnjanaset

  3. Division of Gastro-enterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

    Piyawat Komolmit

  4. Center of Excellence in Liver Diseases, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand

    Piyawat Komolmit

Authors
  1. Virunya Komenkul
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  2. Waroonrat Sukarnjanaset
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  3. Piyawat Komolmit
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  4. Thitima Wattanavijitkul
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Contributions

Virunya Komenkul, Piyawat Komolmit, and Thitima Wattanavijitkul conducted the study design. Piyawat Komolmit supported the acquisition of the external dataset. Virunya Komenkul and Waroonrat Sukarnjanaset collected and analyzed the data. All authors revised the manuscript independently.

Corresponding author

Correspondence to Thitima Wattanavijitkul.

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Ethics approval and consent to participate

The study protocol was conducted according to an ethical standard and approved by the Institutional Review Board of the Faculty of Medicine of Chulalongkorn University, Bangkok (IRB No. 0382/65). This study did not involve direct patient contact as it was conducted retrospectively. All data were collected exclusively from medical records.

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The authors declare no competing interests.

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Virunya Komenkul is the principal investigator.

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Komenkul, V., Sukarnjanaset, W., Komolmit, P. et al. External validation of population pharmacokinetic models of tacrolimus in Thai adult liver transplant recipients. Eur J Clin Pharmacol (2024). https://doi.org/10.1007/s00228-024-03692-8

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