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A limited sampling strategy to estimate exposure of once-daily modified release tacrolimus in renal transplant recipients using linear regression analysis and comparison with Bayesian population pharmacokinetics in different cohorts

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

Abstract

Purpose

Tacrolimus has a narrow therapeutic window. Measuring trough level (C0) as surrogate for drug exposure (AUC) in renal transplant recipients has limitations. Therefore, limited sampling strategies (LSS’s) have been developed. For the newer modified release, once-daily formulation (Tac QD) LSS’s are based on either linear regression analysis (LRA) or population pharmacokinetics with maximum a posteriori Bayesian (MAPB) estimation. The predictive performances of both methods were compared, also to LSS’s as described in literature.

Methods

LSS’s (maximally three sampling time points) were developed for Tac QD from full 24-h sampling by LRA in 27 Caucasian, stable renal transplant recipients. Performance for accuracy (mean absolute prediction error < 10%) and precision (root mean squared error < 15%) was quantified also after MAPB estimation in two independent groups (early and late post-transplant, n = 12 each).

Results

LRA determined a single 8 hours post-dose measurement (C8) to fulfil predefined criteria for accuracy (MAPE 3.41%) and precision (RMSE 4.28%). The best LSS contained C2, C8 and C12 for the stable (MAPE 2.42%, RMSE 3.1%) and the early post-transplant group (MAPE 2.46%, RMSE 3.14%). LRA did not include C0 for any LSS, unless it was forced into the model. MAPB estimation showed similar performance.

Conclusions

In renal transplant patients, sampling in the elimination phase (C8) accurately predicted Tac QD exposure, contrary to C0. The 3-point sampling C2, C8 and C12 had the best performance and is also valid early post-transplant. These LSS’s were similarly predictive with MAPB estimation. Dried blood spot could facilitate late sampling in clinical practice.

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Acknowledgements

We would like to thank Dr. Nas Undre from Astellas Pharma for kindly providing us the raw data of the pharmacokinetic trial as published by Saint Marcoux et al. [14]. Dr. Undre nor Astellas was otherwise involved in our study. We would also like to thank our trial nurse, Mrs. Monique Mullens, and the nurse practitioners Mr. John Dackus and Mr. Philip Ulrichts for taking the blood samples during the trials that involved patients from our centre.

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Authors and Affiliations

  1. Department of Internal Medicine, Zuyderland Medical Centre, Dr. H. van der Hoffplein 1, 6162, BG, Sittard-Geleen, The Netherlands

    Frank Stifft

  2. Department of Clinical Pharmacy and Toxicology, CAPHRI, School for Public health and Primary Care, Maastricht University Medical Centre, P. Debyelaan 25, 6229, HX, Maastricht, The Netherlands

    Franciscus Vandermeer & Cees Neef

  3. Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Centre, Universiteitssingel 40, 6229, Maastricht, ER, Netherlands

    Sander van Kuijk

  4. Department of Internal Medicine, Maastricht University Medical Centre, P. Debyelaan 25, 6229, HX, Maastricht, The Netherlands

    Maarten H. L. Christiaans

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Contributions

FS collected and analysed the data, provided intellectual content of critical importance to the work, drafted and revised the manuscript. FV collected and analysed the data, provided intellectual content of critical importance to the work, drafted and revised the manuscript. CN conceived the study, provided intellectual content of critical importance to the work, revised and approved the version to be published. SvK provided intellectual content of critical importance to the work, revised and approved the version to be published. MC conceived the study, provided intellectual content of critical importance to the work, revised and approved the version to be published. Both authors FS and FV contributed equally to this manuscript.

Corresponding author

Correspondence to Frank Stifft.

Ethics declarations

Ethical approval

All main studies cited above were conducted in accordance with the Declaration of Helsinki. The protocols had been reviewed by the Ethics Committee at each study centre and each patient had given written informed consent prior to enrolment into the study. The main studies were conducted between 2003 and 2004 [19, 20], i.e. before the cut-off date for registration of new and ongoing clinical trials and, thus, were not registered in a public trials registry. Collection, storage, and use of patient data were performed in agreement with FEDERA (Federation of Dutch University Medical Centers) Code of Conduct (www.nfu.nl).

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The authors declare that they have no conflicts of interest.

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Stifft, F., Vandermeer, F., Neef, C. et al. A limited sampling strategy to estimate exposure of once-daily modified release tacrolimus in renal transplant recipients using linear regression analysis and comparison with Bayesian population pharmacokinetics in different cohorts. Eur J Clin Pharmacol 76, 685–693 (2020). https://doi.org/10.1007/s00228-019-02814-x

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