Leiden University Scholarly Publications

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Press, R.R. (2011)

Individualized dosing of calcineurin inhibitors in renal transplantation

Doctoral Thesis
Calcineurin inhibitors are crucial in the prevention of acute rejection in the first year after renal transplantation. Unfortunately, these drugs (ciclosporin A, tacrolimus) are characterized by serious clinical toxicity and between patient variability in their effect. Therefore, the dose of these drugs should be individualized in order to reach a balance between rejection and toxicity. This thesis aimed to describe the variability between and within patients using mathematical models and subsequently to explain this variability. Genetic and non-genetic factors were used to explain variability and several factors were identified (polymorphism in metabolism enzyme CYP3A5, body weight, concomitant prednisolone dose). For this purpose drug concentrations in blood are measured as a concentration biomarker. Furthermore, another biomarker the activity ot the target enzyme calcineurin was determined in leukocytes, but was found to be more variable within patients than between patients....Show moreCalcineurin inhibitors are crucial in the prevention of acute rejection in the first year after renal transplantation. Unfortunately, these drugs (ciclosporin A, tacrolimus) are characterized by serious clinical toxicity and between patient variability in their effect. Therefore, the dose of these drugs should be individualized in order to reach a balance between rejection and toxicity. This thesis aimed to describe the variability between and within patients using mathematical models and subsequently to explain this variability. Genetic and non-genetic factors were used to explain variability and several factors were identified (polymorphism in metabolism enzyme CYP3A5, body weight, concomitant prednisolone dose). For this purpose drug concentrations in blood are measured as a concentration biomarker. Furthermore, another biomarker the activity ot the target enzyme calcineurin was determined in leukocytes, but was found to be more variable within patients than between patients. This response biomarker was not found to be clinically useful to individualize the drug dosage. Finally, pharmacological determinants for subclinical acute rejection at 6 months were determined in patients treated with ciclosporin. Although ciclosporin exposure and several genetic variants were not found to relate, a previous acute rejection period and a kidney from a deceased donor increased the risk of rejection 5-fold.Show less
Calcineurin inhibitors
Ciclosporin A
Kidney transplantation
Pharmacodynamics
Pharmacogenetics
Pharmacokinetics
Population approach
Tacrolimus
All authors
Press, R.R.
Supervisor
Guchelaar, H-J.; Fijter, J.W. de; Danhof, M.
Co-supervisor
Ploeger, B.A.
Qualification
Doctor (dr.)
Awarding Institution
Leiden University Medical Center (LUMC), Leiden University
Date
2011-04-13
ISBN (print)
9789090260372

Funding

Sponsorship
Only for the printing of the thesis: AZL Onderzoeks- en Ontwikkelingskrediet Apotheek, Afdeling Nierziekten LUMC, J.E. Jurriaanse Stichting, Nederlandse Transplantatievereniging, Stichting KNMP-fondsen and LAP&P Consultants BV.