Tools to optimize the immunosuppressive treatment after renal transplantation
Appears in the following Collection
- Farmasøytisk institutt 
AbstractLivelong immunosuppressive treatment is needed after renal transplantation. Tacrolimus has been the cornerstone in most transplant centers. Its narrow therapeutic window and large inter- and intra-individual variability makes tacrolimus dosing challenging and therapeutic drug monitoring is mandatory. The short-term outcome after renal transplantation is good, however, there is room for further improvement in long-term outcomes. Individually optimized dosing of current available immunosuppressive regimen, with focus on finding new therapeutic drug monitoring strategies and ensuring good medication adherence, are potential strategies to further improve both long-term patient- and graft survival. Area under the concentration versus time curve (AUC) is the preferred measure for systemic drug exposure, and hence also in theory the best pharmacokinetic marker associated with effect. For practical reasons, trough concentrations are however used for tacrolimus dose individualization in most centers, and all efficacy studies have been done using trough therapeutic drug monitoring. Potentially AUC-targeted therapeutic drug monitoring of tacrolimus will provide better outcomes. This thesis presents novel tools that make such AUC-targeted therapeutic drug monitoring possible. In a prospective pharmacokinetic study accurate estimations of tacrolimus AUC for fasting morning dose was shown to be possible utilizing population pharmacokinetic model derived Bayesian estimators and three optimally timed blood samples using capillary microsampling. That patient themselves can obtain capillary microsamples at home, ease tacrolimus therapeutic drug monitoring in many ways. Most population pharmacokinetic models of tacrolimus are developed on data from clinical trials; obtained in selected patients under highly controlled fasting conditions and almost exclusively only the morning dose of twice-daily tacrolimus dosing is investigated. These models do therefore not reflect real-life, as both timing of dose administration (morning, evening) and food consumption can affect tacrolimus pharmacokinetics. This thesis present a prospective pharmacokinetic study of tacrolimus morning and evening dose performed in a real-life setting with regards to food. We found that circadian variation was present after fasting dose administration, but not in a real-life non-fasting setting. Non-fasting dose administration results in flatter pharmacokinetic profiles. Data on a patient’s actual behavior when it comes to dose administration are hence essential for accurately estimations of AUC with these kind of models. Irrespectively of how accurately individualized doses are calculated, nonadherence to the immunosuppressive treatment is a major risk factor for poor clinical outcome after renal transplantation. To overcome this problem, assessment of adherence data and identification of risk factors affecting the behavior are crucial. This thesis presents an open prospective randomized controlled trial evaluating adherence tools for annual assessment of immunosuppressive adherence in a clinical routine setting. In conclusion, the work presented in this thesis contributes with important knowledge and new tools for optimization of the immunosuppressive treatment that potentially can improve long-term outcome after renal transplantation.
List of papers
|Paper I. Gustavsen MT, Midtvedt K, Vethe NT, Robertsen I, Bergan S and Åsberg A. Tacrolimus area under the concentration versus time curve monitoring, using home-based volumetric absorptive capillary microsampling. Therapeutic Drug Monitoring. 2020; 43(3): 407-417. doi: 10.1097/FTD.0000000000000697. The article is not available in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1097/FTD.0000000000000697|
|Paper II. Gustavsen MT, Midtvedt K, Robertsen I, Woillard JB, Debord J, Klaasen RA, Vethe NT, Bergan S and Åsberg A. Fasting status and circadian variation must be considered when performing AUCbased therapeutic drug monitoring of tacrolimus in renal transplant recipients. Clinical and Translational Science. 2020; 0, 1-9; doi:10.1111/cts.12833 The article is included in the thesis. Also available at: https://doi.org/10.1111/cts.12833|
|Paper III. Gustavsen MT, Midtvedt K, Lønning K, Jacobsen T, Reisæter AV, De Geest S, Andersen MH, Hartmann A and Åsberg A. Evaluation of tools for annual capture of adherence to immunosuppressive medications after renal transplantation – a single-centre open prospective trial. Transplant International. 2019; 32(6): 614-625. doi:10.1111/tri.13412. The article is not available in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1111/tri.13412|