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Therapeutic Drug Monitoring Strategies for Envarsus in De Novo Kidney Transplant Patients Using Population Modelling and Simulations

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Abstract

Introduction

Tacrolimus, the cornerstone of transplantation immunosuppression, is a narrow therapeutic index drug with a low and highly variable bioavailability. Therapeutic drug monitoring based on trough level assessment is mandatory in order to target a personalised exposure and avoid both rejection and toxicity. Population pharmacokinetic (POPPK) models might be a useful tool for improving early attainment of target range by guiding initial doses until steady state is reached and trough levels can be reliably used as surrogate marker of exposure. Here we present the first POPPK for predicting the initial doses of the once-daily prolonged release tacrolimus Envarsus (LCPT) in adult kidney recipients.

Methods

The model was developed exploiting the data from a recent pharmacokinetic randomised clinical study, in which 69 de novo kidney recipients, 33 of whom treated with LCPT, underwent an intensive blood sampling strategy for tacrolimus including four complete pharmacokinetic profiles.

Results

The complex and prolonged absorption of LCPT is well described by the three-phase model that incorporates body weight and CYP3A5 genotype as significant covariates accounting for a great proportion of the inter-patient variability: in particular, CYP3A5*1/*3 expressors had a 66% higher LCPT clearance. We have then generated by simulation a personalised dosing strategy based on the model that could improve the early attainment of therapeutic trough levels by almost doubling the proportion of patients within target range (69.3% compared to 36.1% with the standard body weight-based approach) on post-transplantation day 4 and significantly reduce the proportion of overexposed patients at risk of toxicity.

Conclusions

A POPPK model was successfully developed for LCPT in de novo kidney recipients. The model could guide a personalised dosing strategy early after transplantation. For the model to be translated into clinical practice, its beneficial impact of earlier attainment of therapeutic trough levels should be demonstrated on hard clinical outcomes in further studies.

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Acknowledgements

Funding

This study was funded by Chiesi Farmaceutici S.p.A., Parma, Italy. Chiesi Farmaceutici S.p.A. is also funding the Rapid Service Fee.

Authorship

All named authors meet the International Committee of Medical Journal Editors criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Author Contributions

Mirco Govoni and Giovanni Piotti conceived the project. Emilie Henin performed the research with the inputs of all the authors. All authors contributed to the data analysis. Emilie Henin and Giovanni Piotti wrote the manuscript. All authors revised the manuscript.

Disclosure

Mirco Govoni, Massimo Cella and Giovanni Piotti are all employees of Chiesi Farmaceutici S.p.A.

Emilie Henin and Christian Laveille received a consultancy assignment from Chiesi Farmaceutici S.p.A.

Compliance with Ethics Guidelines

All procedures performed in the study were according to the clinical study protocol, the International Council for Harmonization Good Clinical Practice guidelines, local guidelines and the Declaration of Helsinki (1964 and amendments). The independent ethics committee for the study was the Committee for the Protection of Persons South Mediterranean V, CHU de Nice-Hôpital De Cimiez. Informed consent was obtained from all individual participants included in the study. A specific patient information sheet–informed consent form for genotyping tests was also obtained.

Data Availability

The data sets analysed and/or generated during the current study are available from the corresponding author on reasonable request.

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Authors and Affiliations

  1. Calvagone, Liergues, France

    Emilie Henin & Christian Laveille

  2. Global Clinical Development, Chiesi Farmaceutici S.p.A., Parma, Italy

    Mirco Govoni, Massimo Cella & Giovanni Piotti

Authors
  1. Emilie Henin
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Corresponding author

Correspondence to Giovanni Piotti.

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Henin, E., Govoni, M., Cella, M. et al. Therapeutic Drug Monitoring Strategies for Envarsus in De Novo Kidney Transplant Patients Using Population Modelling and Simulations. Adv Ther 38, 5317–5332 (2021). https://doi.org/10.1007/s12325-021-01905-5

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