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Population pharmacokinetics of mycophenolic acid during the first week after renal transplantation

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Abstract

Objective

To investigate the population pharmacokinetics of mycophenolic acid (MPA) in adult kidney transplant recipients during the crucial first week after transplantation.

Methods

Data were collected from 117 patients. MPA plasma concentrations were determined at t=0, 1, 2, 3 and 4 h after mycophenolate mofetil dosing on days 3, 5 and 7. Population analysis was performed using NONMEM. Covariates screened were sex, age, body weight, serum creatinine, creatinine clearance, serum albumin, days of therapy, diabetes mellitus, organ source (live or cadaveric) and co-therapy (tacrolimus or cyclosporine). Final model validity was evaluated using 200 bootstrapped samples from the original data. Bias and precision were determined through comparison of observed and predicted concentrations.

Results

Individual concentration–time profiles showed evidence of an absorption lag time and enterohepatic recirculation of MPA in some patients on some occasions. The best base model had bi-exponential elimination with a typical population (SE%) apparent clearance (CL/F) of 29 l/h (5%) and apparent volume of the central compartment of 65 l (7%). CL/F decreased significantly with increasing serum albumin (1.42 l/h reduction in total plasma CL/F with each 1 g/l increase in albumin) and was 27% greater in patients receiving cyclosporine than in those receiving tacrolimus. Evaluation of the final model showed close agreement between pairs of bootstrapped and final model parameter estimates (all differences <7%). Predictions were non-biased (0.11 mg/l) but imprecise (2.8 mg/l).

Conclusion

Population pharmacokinetic parameters for MPA were determined. These can be used to achieve specific target MPA concentrations or areas under the concentration–time curve.

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Acknowledgements

Mycophenolate (Roche no. RS-5797-00) and carboxy butoxy ether mycophenolate-internal standard (Roche no. RS-60461-000) were gifts of Hoffmann-LaRoche Limited, Mississauga, Ontario, Canada. This research was partially supported by a National Health and Medical Research Council (NHMRC) project grant (#210173) and partially by a NHMRC Neil Hamilton Fairley Fellowship, awarded to C. Staatz. The authors of this article had no conflict of interest that would influence its publication.

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Authors and Affiliations

  1. School of Pharmacy, University of Queensland, Brisbane, QLD, 4072, Australia

    Christine E. Staatz, Stephen B. Duffull & Susan E. Tett

  2. Departments of Medicine, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, Nova Scotia, Canada

    Bryce Kiberd

  3. Departments of Pathology, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, Nova Scotia, Canada

    Albert D. Fraser

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  1. Christine E. Staatz
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  2. Stephen B. Duffull
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  3. Bryce Kiberd
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  4. Albert D. Fraser
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  5. Susan E. Tett
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Correspondence to Christine E. Staatz.

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Staatz, C.E., Duffull, S.B., Kiberd, B. et al. Population pharmacokinetics of mycophenolic acid during the first week after renal transplantation. Eur J Clin Pharmacol 61, 507–516 (2005). https://doi.org/10.1007/s00228-005-0927-4

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  • DOI: https://doi.org/10.1007/s00228-005-0927-4

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