Fasting Status and Circadian Variation Must be Considered When Performing AUC-based Therapeutic Drug Monitoring of Tacrolimus in Renal Transplant Recipients.

Therapeutic drug monitoring (TDM) is mandatory for the immunosuppressive drug tacrolimus (Tac). For clinical applicability, TDM is performed using morning trough concentrations. With recent developments making tacrolimus concentration determination possible in capillary microsamples and Bayesian estimator predicted area under the concentration curve (AUC), AUC-guided TDM may now be clinically applicable. Tac circadian variation has, however, been reported, with lower systemic exposure following the evening dose. The aim of the present study was to investigate tacrolimus pharmacokinetic (PK) after morning and evening administrations of twice-daily tacrolimus in a real-life setting without restrictions regarding food and concomitant drug timing. Two 12 hour tacrolimus investigations were performed; after the morning dose and the following evening dose, respectively, in 31 renal transplant recipients early after transplantation both in a fasting-state and under real-life nonfasting conditions (14 patients repeated the investigation). We observed circadian variation under fasting-conditions: 45% higher peak-concentration and 20% higher AUC following the morning dose. In the real-life nonfasting setting, the PK-profiles were flat but comparable after the morning and evening doses, showing slower absorption rate and lower AUC compared with the fasting-state. Limited sampling strategies using concentrations at 0, 1, and 3 hours predicted AUC after fasting morning administration, and samples obtained at 1, 3, and 6 hours predicted AUC for the other conditions (evening and real-life nonfasting). In conclusion, circadian variation of tacrolimus is present when performed in patients who are in the fasting-state, whereas flatter PK-profiles and no circadian variation was present in a real-life, nonfasting setting.

Evaluation of tools for annual capture of adherence to immunosuppressive medications after renal transplantation - a single-centre open prospective trial.

Annual assessment of adherence would strengthen long-term outcome assessments from registry data. The objective of this study was to evaluate tools suitable for annual routine capture of adherence data in renal transplant recipients. A single-centre open prospective trial included 295 renal transplant recipients on tacrolimus. Two-thirds of the patients were included 4 weeks post-transplant, randomized 1:1 to intensive or single-point adherence assessment in the early phase and 1-year post-transplant. One-third were included 1-year post-transplant during a cross-sectional investigation. Adherence was assessed using multiple methods: The "Basel Assessment of Adherence to Immunosuppressive Medication Scale" (BAASIS© ) questionnaire was used to assess self-reported adherence. The treating clinician scored patient's adherence and tacrolimus trough-concentration variability was calculated. In the analyses, the data from the different tools were dichotomized (adherent/nonadherent). The BAASIS© overall response rate was over 80%. Intensive BAASIS© assessment early after transplantation increased the chance of capturing a nonadherence event, but did not influence the 1-year adherence prevalence. The adherence tools generally captured different populations. Combining the tools, the nonadherence prevalence at 1 year was 38%. The different tools identified to a large degree different patients as nonadherent. Combining these tools is feasible for annual capture of adherence status.

High Tacrolimus Clearance Is a Risk Factor for Acute Rejection in the Early Phase After Renal Transplantation.

BACKGROUND: Patients with high tacrolimus clearance eliminate more drug within a dose interval compared with those with low clearance. Delays in dosing time will result in transient periods of lower concentrations in high versus low clearance patients. Transient subtherapeutic tacrolimus concentrations may induce acute rejection episodes. METHODS: A retrospective study in all renal transplant patients treated with tacrolimus at our center from 2009 to 2013 was conducted. The association between individually estimated tacrolimus clearance (daily tacrolimus dose [mg]/trough concentration [µg/L]) and biopsy-proven acute rejection (BPAR) the first 90 days posttransplantation was investigated. RESULTS: In total, 638 patients treated with oral tacrolimus were included in the analysis. Eighty-five (13.3%) patients experienced BPAR. Patients were stratified into 4 groups per their estimated clearance. The patients in the high clearance group had significantly higher incidence of BPAR (20.6%) with a hazard ratio of 2.39 (95% confidence interval, 1.30-4.40) compared with the low clearance group. Clearance estimate (as a continuous variable) showed a hazard ratio of 2.25 (95% confidence interval, 1.70-2.99) after adjusting for other risk factors. There were no significant differences in neither trough concentrations the first week after transplantation nor time to target trough concentration between patients later experiencing BPAR or not. CONCLUSIONS: High estimated clearance is significantly associated with increased risk of BPAR the first 90 days posttransplantation and may predict an increased risk of rejection in the early phase after renal transplantation.