Background: Tacrolimus, an immunosuppressive drug widely used after transplantations, has a narrow therapeutic index and displays large inter-patient pharmacokinetic variability, partly explained by genetic variation in its main metabolizing enzyme, CYP3A5. Monitoring tacrolimus concentrations is required in order to avoid under-treatment (increasing the risk for transplant rejection) or over-treatment (increasing the risk of toxicity). Tacrolimus is routinely measured as total whole blood concentrations, although it is concentrated in erythrocytes (concentrations in whole blood are 50-fold higher than in plasma at a normal hematocrit) and only the unbound fraction (<1%) is pharmacologically active. Thus, in patients with anemia, whole blood concentrations decrease in proportion to the hematocrit; however, since tacrolimus is a low extraction-ratio drug, the unbound, therapeutically active concentration remains unchanged.
Aim: To improve the interpretation of tacrolimus blood concentrations by integrating hematocrit, and to assess the magnitude of error by using non-standardized (=measured) concentrations.
Methods: We measure whole blood tacrolimus levels by immunoassay and set up an assay for the only common low-activity CYP3A5 variant, *3, which is associated with reduced tacrolimus clearance. From our electronic medical record system, we retrospectively extracted patients with a first recorded tacrolimus measurement between 2000 -2018 who had an hematocrit value determined within the same week. We calculated hematocrit-standardized tacrolimus concentrations and compared them to whole blood concentrations. We then utilized these tools to investigate a patient after renal transplant with very high tacrolimus dose requirements.
Between 2000 and 2017, we identified 852 patients with first recorded quantifiable tacrolimus measurement and corresponding hematocrit (mean±SD, 32.5±6.4). Median measured (Tm) and standardized (Tstd) tacrolimus concentrations were 9.1 (IQR, 5.5-13.8 ) and 12.7 (7.5-19.5) ng/mL. The median Tstd/ Tm ratio was 1.41, and for 25% of patients Tstd exceeded Tm by ≥62%. 187 (21.9%) of Tm but only 128 (15.0%) of Tstd were below 5 ng/mL. In a patient with very high tacrolimus dose requirements (24 mg/d), CYP3A5 *1/*3 genotype and standardization of tacrolimus concentrations fully explained the high apparent oral clearance.
Conclusion: Measured tacrolimus concentrations greatly underestimate standardized tacrolimus levels in anemic patients. Target concentration intervention (TCI) integrating information on hematocrit and CYP3A5 genotype can greatly help in dose individualizion to achieve target exposure.