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FK506 (Tacrolimus)

Tacrolimus, previously known as FK506, is an immunosuppressive drug derived from Streptomyces tsulenbaensis. Tacrolimus inhibits T-lymphocyte activation by inhibition of the phosphatase activity of calcineurin. It is approximately 100 times more potent than cyclosporine. Tacrolimus is used clinically for primary and rescue therapy of solid organ transplants.

Tacrolimus may be administered IV or orally. Absorption from the GI tract is variable and irregular. Peak blood concentrations are achieved at 1.5 to 3.5 hours. The elimination half-life from whole blood is 11.7 hours in liver transplant patients.

FK506 has a narrow therapeutic window. The most frequent side effect is nephrotoxicity, followed by hyperkalemia, hyperglycemia, GI upset, and neurotoxicity. Trough blood levels are useful in guiding dosage adjustments to achieve optimal immunosuppression while minimizing toxicity.

Preferred therapeutic ranges may vary by transplant type, transplant protocol, and concomitant medications.During the first four weeks following transplant an optimal response is obtained when the trough blood level is in the range of 15 to 20 ng/mL. Metabolism increases as renal and hepatic functions normalize and a steady state is reached two weeks or more after transplant.  At that time, optimal trough blood concentrations are generally between 3.0 and 8.0 ng/mL.

Drugs found to increase tacrolimus levels include diltiazem, verapamil, clotrimazole, fluconazole, ketoconazole, voriconazole, clarithromycin, erythromycin, nelfinavir, ritonavir, as well as grapefruit juice. Decreased tacrolimus levels have been found with coadministration of rifampicin, phenytoin, carbamazepine, phenobarbital, octreotide, and St John's wort.1

Since 90% of tacrolimus is in the cellular components of blood, especially erythrocytes, whole blood is the preferred specimen for analysis of trough concentrations. Specimen requirement is one lavender top (EDTA) tube of blood.

References

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.

Alak AM. Measurement of tacrolimus (FK506) and Its metabolites: A review of assay development and application in therapeutic drug monitoring and pharmacokinetic studies. Ther Drug Monit. 1997; 19(3):338-351. 

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