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Eur J Clin Pharmacol. 2020 Feb 4. doi: 10.1007/s00228-019-02814-x. [Epub ahead of print]

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.

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Department of Internal Medicine, Zuyderland Medical Centre, Dr. H. van der Hoffplein 1, 6162, BG, Sittard-Geleen, The Netherlands.
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.
Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Centre, Universiteitssingel 40, 6229, Maastricht, ER, Netherlands.
Department of Internal Medicine, Maastricht University Medical Centre, P. Debyelaan 25, 6229, HX, Maastricht, The Netherlands.



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.


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).


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.


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.


Kidney transplantation; Limited sampling strategy; Pharmacokinetics; Tacrolimus; Therapeutic drug monitoring


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