Monitoring whole blood tacrolimus concentration during therapy, particularly in individuals coadministered CYP3A4 substrates, inhibitors, or inducers
Adjusting dose to optimize immunosuppression while minimizing toxicity
Evaluating patient compliance
Tacrolimus is a macrolide antibiotic derived from the fungus Streptomyces tsukubaensis. Like cyclosporine, tacrolimus inhibits calcineurin to suppress T cells. Tacrolimus is metabolized by CYP3A4, thus its concentrations are affected by drugs that inhibit (calcium channel blockers, antifungal agents, some antibiotics, grapefruit juice) or induce (anticonvulsants, rifampin) this enzyme. Tacrolimus has a narrow therapeutic range, and adverse effects are common, particularly at high dose and concentrations, making therapeutic drug monitoring essential.
Since 90% of tacrolimus is in the cellular components of blood, especially erythrocytes, whole blood is the preferred specimen for analysis of trough concentrations. Target steady-state concentrations vary depending on clinical protocol, the presence or risk of rejection, time from transplant, type of allograft, concomitant immunosuppression, and side effects (mainly nephrotoxicity). Optimal trough blood concentrations are generally between 5.0 and 15.0 ng/mL. Higher levels are often sought immediately after transplant, but as organ function stabilizes at about 4 weeks from transplant, doses are generally reduced in stable patients for most solid organ transplants. Trough concentrations should be maintained below 20 ng/mL.
Most individuals display optimal response to tacrolimus with trough whole blood levels of 5.0 to 15.0 ng/mL. Preferred therapeutic ranges may vary by transplant type, protocol, and comedications.
Therapeutic ranges are based on samples drawn at trough (ie, immediately before a scheduled dose). Blood drawn at other times will yield higher results.
The assay is specific for tacrolimus; it does not cross-react with cyclosporine, cyclosporine metabolites, sirolimus, sirolimus metabolites, or tacrolimus metabolites. Results by liquid chromatography with detection by tandem mass spectrometry are approximately 30% less than by immunoassay.
The recommended therapeutic range applies to trough specimens drawn immediately before a dose. Blood drawn at other times will yield higher results.
Clinical Reference Provides recommendations for further in-depth reading of a clinical nature
1. Kahan BD, Keown P, Levy GA, et al: Therapeutic drug monitoring of immunosuppressant drugs in clinical practice. Clin Ther 2002 March;24(3):330-350
2. Scott LJ, McKeage K, Keam SJ, et al: Tacrolimus: a further update of its use in the management of organ transplantation. Drugs 2003;63(12):1247-1297