Following solid organ transplantation individualizing the immunosuppressive therapy to obtain an optimal balance between therapeutic efficacy and the occurrence of adverse events is the ultimately goal. This is complicated by the high intra- and interindividual pharmacokinetic variability and the narrow therapeutic index of the immunosuppressive drugs. Small variations in drug exposure may result in suboptimal immunosuppression or drug toxicity, with potentially adverse effects on patient outcomes. Therapeutic drug monitoring (TDM) is therefore mandatory in order to individualize the therapy. More knowledge and further improvements of drug treatment strategies and monitoring techniques are still desirable to further improve TDM and hence potentially both short- and long term outcomes after transplantation.
The primary objective of this thesis was to investigate some different pharmacological treatments and monitoring strategies to improve outcome in solid organ transplants. In this thesis results from three prospective clinical trials in solid organ transplants are presented. The lipid-lowering effect of rosuvastatin in comparison with fluvastatin, and the potential bilateral drug-drug interaction between rosuvastatin and everolimus (EVE) were assessed in renal transplant recipients at a stable phase following transplantation. Further, the relationship between both cyclosporine A (CsA) and EVE concentrations in different body compartments were evaluated as potential TDM tools in heart- and renal transplant recipients, respectively. Finally, the bioequivalence of an approved generic tacrolimus (TAC) was investigated with the original drug as reference in elderly stable renal transplant recipients.
In renal transplant recipients receiving EVE based immunosuppression and treated with fluvastatin, a switch to rosuvastatin induced a significant additional lipid lowering effect. The combination of EVE and rosuvastatin appears to be safe as EVE pharmacokinetics were unaffected following the switch to rosuvastatin. The systemic exposure of rosuvastatin was less than 3-fold higher compared to non-transplants reported in the literature when combined with EVE, and this is comparable to what is previously shown for fluvastatin in combination with CsA, a combination considered to be safe in renal transplant recipients. Safely achieving reduction in lipids could be of great importance in reducing cardiovascular risk in this high risk population.
No correlation between CsA concentrations in whole blood, T-lymphocytes or endomyocardial tissue was established in heart transplant recipients, potentially challenging traditional TDM based on whole blood CsA concentrations in these patients. In contrast, EVE concentrations in whole blood and PBMC correlated well and supports that TDM of EVE in whole blood is an appropriate choice.
The generic TAC formulation was not found to be bioequivalent to the original drug in elderly renal transplant recipients. Use of generic TAC resulted in a significantly higher systemic drug exposure. In the long run this may put the patients at higher risk of calcineurin inhibitor-related toxicity and impaired long-term outcomes. Importantly, the lack of bioequivalence would not have been detected by the standard monitoring parameter, TAC trough concentrations, as these concentrations were similar for both formulations Generic TAC should be used with caution in elderly renal transplant recipients and it should be recognized that bioequivalence studies performed in healthy volunteers do not necessarily reflect the average transplant recipient.
List of papers I. - IV. Papers I., III. and IV. is removed from the thesis due to publisher copyright restrictions.
I. Robertsen I, Åsberg A, Granseth T, Vethe NT, Akhlaghi F, Ghareeb M, Molden E, Reier-Nilsen M, Holdaas H and Midtvedt K. More potent lipid lowering effect by rosuvastatin in everolimus treated renal transplant recipients. Transplantation. 2014. 27;97(12): 1266-1271. doi:10.1097/01.TP.0000443225.66960.7e
II. Robertsen, Ida, Pål Falck, Arne K. Andreassen, Nina K. Næss, Niclas Lunder, Hege Christensen, Lars Gullestad, and Anders Åsberg. "Endomyocardial, intralymphocyte, and whole blood concentrations of ciclosporin A in heart transplant recipients." Transplantation research 2, no. 1 (2013): 5. doi:10.1186/2047-1440-2-5
III. Robertsen I, Vethe NT, Midtvedt K, Falck P, Christensen H and Åsberg A. Closer to the site of action; everolimus concentrations in peripheral blood mononuclear cells correlate well with whole blood concentrations. (Submitted to Therapeutic Drug Monitoring).
IV. Robertsen I, Åsberg A, Ingerø AO, Vethe NT, Bremer S, Bergan S and Midtvedt K. Use of generic tacrolimus in elderly renal transplant recipients – precaution is needed. (Accepted for publication in Transplantation, June 2014). doi:10.1097/TP.0000000000000384.