Intra- and interindividual variation in the pharmacokinetics of tacrolimus (FK506) in kidney transplant recipients--importance of trough level as a practical indicator.

Background: Tacrolimus (FK506) is currently used as the primary immunosuppressant in clinical kidney transplantation in some centers. The purpose of this study was to evaluate the pharmacokinetics of this drug and to see if trough level, which has been used widely in therapeutic drug monitoring, can be used as an appropriate substitute for other pharmacokinetic measurement tests.

Methods: The blood concentration-time curve was studied in 10 kidney transplant recipients on 26 occasions after oral dosage of 2 to 18 mg every 12 hours. Whole blood concentration was measured by two-step immunoabsorption assay. Methylprednisolone was used as a concomitant immunosuppressive drug.

Results: The blood concentration-time curves showed remarkable interindividual variation. Intraindividual variation was also found, but the degree of variation was slight compared with interindividual variation. On 17 occasions of measurement in one patient, the dose was significantly correlated with trough (r = 0.684), Cmax (r = 0.838) and AUC0-12 (r = 0.817). In nine patients on nine occasions, however, the dose was not significantly correlated with trough (r = 0.351), Cmax (r = 0.270) or AUC0-12 (r = 0.355). tmax ranged from one to four hours (mean + SD; 2.8 + 1.3) and fluctuated in both intra- and interindividual measurements. In spite of a wide variation in the blood concentration-time-curve patterns, a highly significant linear relationship between trough and Cmax or AUC0-12 was observed in both intraindividual (Cmax, r = 0.876; AUC0-12, r = 0.926) and interindividual (Cmax, r = 0.943; AUC0-12, r = 0.984) measurements.

Conclusions: We conclude that trough level is a practical acceptable indicator of the blood levels of tacrolimus, and can be used to monitor blood concentration.