MO999: Intra-Patient Variability of Tacrolimus in Kidney Transplant Patients: An Experience of a Kidney Disease Specialist Hospital
Authors: Sukkha Sayamon , Watanyutangkul Pitiyathorn , Jiamrattanapitak Sakrapol , Kitrungpaiboon Thidarat , Jiamjariyapon Teerayuth 
Published: May 2022

Abstract

BACKGROUND AND AIMS
The complexity of tacrolimus pharmacokinetics results in a unique tacrolimus recommendation in transplant centers and global level [1]. Intra-patient variability (IPV) of tacrolimus has become a simple and interesting marker to predict transplant outcomes in addition to minimum concentration (Cmin) monitoring [2–4]. As differences in ethnic affecting tacrolimus pharmacokinetics and patient response, we investigated a pilot study of tacrolimus IPV in our institution.

METHOD
The cohort study was conducted in all new kidney transplant patients receiving twice-daily tacrolimus as a standard immunosuppressive therapy. Patients were switched from twice-daily tacrolimus to other immunosuppressive agents were excluded from the study. All patients were followed-up at an outpatient clinic with routine monitoring. A one-year follow-up period was evaluated in the study. The primary outcome was the IPV of tacrolimus during the 3–12 months after transplantation. IPV of tacrolimus Cmin was calculated by [SD/(mean tacrolimus dose-normalized Cmin)] × 100.5 We categorized the IPV of tacrolimus into three levels: low (0%–10%), intermediate (11%–30%) and high IPV (&gt;30%). The secondary outcomes were to assess renal function by eGFR and pre-defined factors associated with the IPV of tacrolimus. The study protocol was reviewed and approved by the Thai Clinical Trial Registry (TCTR20210519005).

RESULTS
There were 56 patients who underwent kidney transplantation during the study period. Of these 56 patients, 12 patients experienced late conversion from twice-daily to once-daily tacrolimus or were combined with sirolimus, and 4 patients became lost to follow-up. A total of 40 patients completed the one-year study period and were included in the analysis. The mean age of patients was 50.85 ± 11.07 years. A total of 39 patients received basiliximab, and one patient received anti-thymoglobulin as an induction therapy. Baseline characteristics are shown in Table 1.
At 3–12 months after transplantation, the mean IPV of tacrolimus was 23.77% ± 11.23%. When categorized patients according to %IPV of tacrolimus, we found that most patients were in the intermediate IPV. The percentage of patients in each category was 7.5%, 65% and 27.5% of patients in low, intermediate and high IPV of tacrolimus, respectively (Fig. 1). The eGFR at discharge of patients with high IPV was significantly lower than that with low to intermediate IPV (P = .0282). For pre-defined factors associated with IPV of tacrolimus, the hemoglobin level at 3 months of patients with high IPV (11.23 ± 1.72 g/dL) was significantly lower than that of patients with low to intermediate IPV (12.54 ± 1.77, P = .0425). All patients were compliant as measured by pill counts and no difference in drug interaction between groups. Renal function remained stable and was similar between groups at one year of follow-up (52.03 ± 14.74 and 57.93 ± 16.40 mL/min/1.73 m2P = .3254 for high IPV and low to intermediate IPV, respectively).

CONCLUSION
Our findings showed that most patients were in low to intermediate IPV of tacrolimus. A low level of eGFR at discharge and a low level of hemoglobin in the early-post transplant period were associated with high IPV of tacrolimus. Therefore, clinicians should be cautious to monitor levels and adjust the dose of tacrolimus, especially if patients at risk of tacrolimus variability. A practical calculation of IPV provides a tremendous benefit for clinicians to individualized tacrolimus therapeutic drug monitoring. This study was a starting point and would expand for our large patient population. Clinical correlation with IPV of tacrolimus and IPV-directed interventions for Asian population are needed to improve tacrolimus using for achieving transplant outcomes.