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Population Pharmacokinetics and Bayesian Estimators for Refined Dose Adjustment of a New Tacrolimus Formulation in Kidney and Liver Transplant Patients

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Abstract

Background and Objectives

A new once-daily formulation of tacrolimus (Envarsus®) has recently been developed, with alleged different pharmacokinetics from previous tacrolimus formulations. The objectives of this study were to develop population pharmacokinetic models and Bayesian estimators based on limited sampling strategies for Envarsus® in kidney and liver transplant recipients.

Materials and Methods

Full tacrolimus concentration-time profiles (13 samples) were drawn from 57 liver (113 profiles) and 49 kidney (97 profiles) graft recipients transplanted for at least 6 months and switched from Prograf® to Envarsus®. The two databases were split into a development (75%) and a validation (25%) dataset. Pharmacokinetic models characterised by a single compartment with first-order elimination and absorption in two phases described by a sum of two gamma distributions were developed using non-parametric (Pmetrics) and parametric (ITSIM) approaches in parallel. The best limited sampling strategy for each patient group was determined using the multiple model optimal algorithm. The performance of the models and derived Bayesian estimators was evaluated in the validation set.

Results

The best limited sampling strategy was 0, 8 and 12 h post-dose, leading to a relative bias ± standard deviation (root-mean-square error) between observed and modelled inter-dose area under the curve in the validation dataset of: 0.32 ± 6.86% (6.87%) for ITSIM and 3.4 ± 13.4% (13.2%) for Pmetrics in kidney transplantation; and 0.89 ± 7.32% (7.38%) for ITSIM and −2.62 ± 8.65% (8.89%) for Pmetrics in liver transplantation.

Conclusion

Population pharmacokinetic models and Bayesian estimators for Envarsus® in kidney and liver transplantation were developed and are now available online for area under the curve-based tacrolimus dose adjustment.

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Acknowledgements

The authors gratefully thank Mrs. Karen Poole for manuscript editing, and Veloxis and Chiesi for providing the phase II pharmacokinetic data and for funding this pharmacokinetic analysis.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, CHU Limoges, Limoges University Hospital, Limoges Cedex, 87042, France

    Jean-Baptiste Woillard, Jean Debord, Caroline Monchaud, Franck Saint-Marcoux & Pierre Marquet

  2. INSERM UMR 850, Limoges, France

    Jean-Baptiste Woillard, Jean Debord, Caroline Monchaud, Franck Saint-Marcoux & Pierre Marquet

  3. University of Limoges, Limoges, France

    Jean-Baptiste Woillard, Jean Debord, Caroline Monchaud, Franck Saint-Marcoux & Pierre Marquet

Authors
  1. Jean-Baptiste Woillard
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  2. Jean Debord
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  3. Caroline Monchaud
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  4. Franck Saint-Marcoux
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  5. Pierre Marquet
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Corresponding author

Correspondence to Pierre Marquet.

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Conflict of interest

J.-B. Woillard have no conflict of interest. J. Debord have no conflict of interest. C. Monchaud have no conflict of interest. F. S. Marcoux have no conflict of interest. Pierre Marquet has been a member of scientific boards for, and received funding for this study from, Chiesi France.

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Woillard, JB., Debord, J., Monchaud, C. et al. Population Pharmacokinetics and Bayesian Estimators for Refined Dose Adjustment of a New Tacrolimus Formulation in Kidney and Liver Transplant Patients. Clin Pharmacokinet 56, 1491–1498 (2017). https://doi.org/10.1007/s40262-017-0533-5

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  • DOI: https://doi.org/10.1007/s40262-017-0533-5

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