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Bayesian Estimation of Mycophenolate Mofetil in Lung Transplantation, Using a Population Pharmacokinetic Model Developed in Kidney and Lung Transplant Recipients

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Abstract

Background and Objectives

The immunosuppressive drug mycophenolate mofetil is used to prevent rejection after organ transplantation. In kidney transplant recipients, it has been demonstrated that adjustment of the mycophenolate mofetil dose on the basis of the area under the concentration-time curve (AUC) of mycophenolic acid (MPA), the active moiety of mycophenolate mofetil, improves the clinical outcome. Because of the high risks of rejections and infections in lung transplant recipients, therapeutic drug monitoring of the MPA AUC might be even more useful in these patients. The aims of this study were to characterize the pharmacokinetics of MPA in lung and kidney transplant recipients, describe the differences between the two populations and develop a Bayesian estimator of the MPA AUC in lung transplant recipients.

Methods

In total, 460 MPA concentration-time profiles from 41 lung transplant recipients and 116 kidney transplant recipients were included. Nonlinear mixed-effects modelling was used to develop a population pharmacokinetic model. Patients were divided into an index dataset and a validation dataset. The pharmacokinetic model derived from the index dataset was used to develop a Bayesian estimator, which was validated using the 35 lung transplant recipients’ profiles from the validation dataset.

Results

MPA pharmacokinetics were described using a two-compartment model with lag time, first-order absorption and first-order elimination. The influence of ciclosporin co-treatment and the changes over time post-transplantation were included in the model. Lung transplant recipients had, on average, a 53% slower absorption rate and 50% faster MPA apparent oral clearance than kidney transplant recipients (p<0.001). In lung transplant recipients, the bioavailability was, on average, 31% lower in patients with cystic fibrosis than in patients without cystic fibrosis (p<0.001). The Bayesian estimator developed using the population pharmacokinetic model — and taking into account ciclosporin co-treatment, cystic fibrosis and time post-transplantation, with concentrations measured at 0, 1 and 4 hours after mycophenolate mofetil dose administration — resulted in a non-significant bias and mean imprecision of 5.8 mg • h/L. This higher imprecision compared with those of similar estimators that have previously been developed in kidney transplantation might have been caused by the high MPA pharmacokinetic variability seen in the lung transplant recipients and by the fact that a large proportion of the patients did not receive ciclosporin, which reduces variability in the elimination phase of MPA by blocking its enterohepatic cycling.

Conclusion

Lung transplant recipients have a slower MPA absorption rate and faster apparent oral clearance than kidney transplant recipients, while cystic fibrosis results in lower MPA bioavailability. A Bayesian estimator using MPA concentration-time samples at 0, 1 and 4 hours post-dose had the best predictive performance.

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Acknowledgements

Caroline Monchaud and Aurélie Prémaud contributed equally to this work.

We thank Professors Yannick Le Meur and Yvon Lebranchu for their coordination and Roche for the sponsoring or funding of the different trials in kidney transplant recipients whose databases were used in the present study. We thank Mrs Hélène Roussel, Mr Fabrice Béavogui, Mr François-Ludovic Sauvage and Mr Jérome Lacouture for their excellent technical assistance, as well as Karen Poole for reading and correcting the manuscript.

The STIMMUGREP trial was sponsored by the Direction de la Recherche Clinique et de l’Innovation, Limoges University Hospital, and co-funded by the Programme Hospitalier de Recherche Clinique (PHRC) Régional, Vaincre la Mucoviscidose and Agence de la Biomédecine (France).

Pierre Marquet is a consultant for Roche Pharma, France, and has received honoraria and research grants from Roche Pharma and Novartis. Romain Kessler is a consultant for Roche Pharma, France, and Novartis, and has received honoraria and research grants from Roche Pharma and Novartis. All other authors have no conflicts of interest that are directly relevant to the content of this study.

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Authors and Affiliations

  1. INSERM Unit 850, CHU Limoges, University of Limoges, Limoges, France

    Brenda C. M. de Winter, Caroline Monchaud, Aurélie Prémaud, Pierre Marquet &  Annick Rousseau

  2. Clinique de Pneumologie, INSERM Unit 884, CHU de Grenoble, Université Joseph Fourier, Grenoble, France

    Christophe Pison

  3. Service de Pneumologie, Nouvel Hôpital Civil, Strasbourg, France

    Romain Kessler

  4. Service de Chirurgie Thoracique, CHU Nord, Marseille, France

    Martine Reynaud-Gaubert

  5. Service de Chirurgie Thoracique, Hôpital du Haut-Lévêque, Bordeaux, France

    Claire Dromer

  6. Service de Pneumologie, Hôpital Foch, Suresnes, France

    Marc Stern

  7. Service de Chirurgie Cardiovasculaire, Hôpital Européen Georges Pompidou (HEGP), Paris, France

    Romain Guillemain

  8. Service de Pneumologie, Hôpital Erasme, Bruxelles, Belgium

    Christiane Knoop & Marc Estenne

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  1. Brenda C. M. de Winter
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Correspondence to Annick Rousseau.

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de Winter, B.C.M., Monchaud, C., Prémaud, A. et al. Bayesian Estimation of Mycophenolate Mofetil in Lung Transplantation, Using a Population Pharmacokinetic Model Developed in Kidney and Lung Transplant Recipients. Clin Pharmacokinet 51, 29–39 (2012). https://doi.org/10.2165/11594050-000000000-00000

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