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Prediction of Free from Total Mycophenolic Acid Concentrations in Stable Renal Transplant Patients: A Population-Based Approach

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Abstract

Background

A population pharmacokinetic (PK) protein-binding model was developed to (1) predict free mycophenolic acid (fMPA) based on total MPA (tMPA) concentrations in renal transplant patients, to establish the therapeutic range of fMPA through pharmacokinetic-pharmacodynamic studies; and (2) provide a guideline for dosing mycophenolate mofetil (MMF).

Methods

Full PK profiles of 56 patients (from five different occasions) during the first year after transplantation who were treated with oral MMF and cyclosporine, or macrolides (either tacrolimus or sirolimus), were analysed. fMPA protein-binding was modelled using nonlinear mixed effects modelling (NONMEM). The influence of physiological factors and coadministered immunosupressant was studied.

Results

A two-compartment model with first-order absorption and elimination, linear protein binding and enterohepatic circulation (EHC) best described the PK of MPA. Different recycling rate constants were considered depending on the coadministered immunosuppressant. The protein-binding rate constant (KB [relative standard error, RSE%]) increased nonlinearly with renal function according to K B = 43.1 (3.13)·(CLCR/59.51)0.394(10.66) h−1. Furthermore, fMPA plasma clearance, given by clearance of the free mycophenolic acid (CLfMPA), CLfMPA = 410 (RSE%3.00)·(1+CsA·0.594 (22.39)) L/h, was 59.4% greater in cyclosporine-treated patients than in macrolide-treated patients, leading to lower MPA exposures. External evaluation proved acceptable area under the plasma concentration-time curve and trough concentration predictions.

Conclusions

A reliable protein-binding population PK model was developed for prediction of fMPA or tMPA from each other and for dose guiding in stable renal transplant recipients.

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Acknowledgments

Nuria Lloberas is a researcher from ISCIII Miguel Servet (CP06/00067) and REDinREN RD12/0021/003. This study was supported by grants from the Instituto de Salud Carlos III and Ministerio de Sanidad y Consumo (PI12/01564 and PI15/00871), and co-funded by the European Regional Development Fund (ERDF).

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Authors and Affiliations

  1. Department of Pharmacy and Pharmaceutical Technology and Physical-Chemistry, Biopharmaceutics and Pharmacokinetics Unit, School of Pharmacy, University of Barcelona, Barcelona, Spain

    Helena Colom & Franc Andreu

  2. Nephrology Department, Bellvitge University Hospital (IDIBELL), Barcelona, Spain

    Franc Andreu, Oriol Bestard, Joan Torras, Josep M. Cruzado, Josep M. Grinyó & Núria Lloberas

  3. Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    Teun van Gelder & Dennis A Hesselink

  4. Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    Teun van Gelder & Brenda C. M. de Winter

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  1. Helena Colom
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  4. Brenda C. M. de Winter
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Correspondence to Núria Lloberas.

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Helena Colom, Franc Andreu, Teun van Gelder, Dennis A. Hesselink, Brenda C.M. de Winter, Oriol Bestard, Joan Torras, Josep M. Cruzado, Josep M. Grinyó, and Núria Lloberas have no conflicts of interest to declare.

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Colom, H., Andreu, F., van Gelder, T. et al. Prediction of Free from Total Mycophenolic Acid Concentrations in Stable Renal Transplant Patients: A Population-Based Approach. Clin Pharmacokinet 57, 877–893 (2018). https://doi.org/10.1007/s40262-017-0603-8

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