Pharmacokinetics And Clinical Study Of FK506 After Oral Administration In Patients After Renal Transplantation

Objective: FK506 is a macrolide with potent immunosuppressive effects. It has been successfully used as a prophylactic and rescued imnlunosuppressant for solid organ transplantation. FK506 was approved in China in 1997. But the data of pharmacokinetics in Chinese patients after renal transplantation and the long term observation of Chinese transplanted patients had not yet been reported. This study is to perform the pharmacokinetic evaluations in ten patients after renal transplant. And to observe the long term efficacy and side effect(or toxicity) in these patients who received FK506-based immunosuppressive regimen, and to explore the relationship of FK506 whole blood concentrations and efficacy and toxicity after renal transplantation. Materials and Methods: Ten patients after renal transplantation were given FK506-based immunosuppressive regimen 24 hours postoperative. Blood samples to determine FK506 levels were drawn in heparinized tube at 0, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, l0hoursafterthefirstoraldosingme whole blood concentrations were measured by MEJA and the pharmacokinetic parameters were calculated by 3P87 program. Then, blood concentrations were monitored on day 2 or 3 after starting the administration, on average twice a week during the first month, and twice a month during the first to third month, and once a month during the third to twelve month. Special circumstances may warrant more frequent monitoring. The FK506 dose, the episodes of AR and toxicity were recorded in detail. Results: The mean Cmax was l3.2775?.4983ng/ml, the mean T(peak) wasl.4797?1. 2174h, the mean tl/2 alpha was 0. 7999?. 8651h, the mean tl/2 beta was 10.8065?2.0799h, the mean AUC was 94. 9869 ?7. 5871(ng/ml)*h, and the mean MRT was 8.0535?. 4750h. AUC was negative correlated with FK506 dose in the first month posttransplant (r?. 67, P0. 024). Two patients experienced AR and were reversed by MI? Two patients developed diabetes which needed insulin therapy. Patient 4 experience AR while developed diabetes. The blood concentrations were not significantly different between ?? AR group and non-R group (oneay ANOVA-, P0. 509). But the blood concentrations were significantly different between DM group and nonM group (oneay ANOVA, P0. 027). There was no other rejections and complications until the end of followp. Conclusions: l.The absorption of oral administration of FK506 was rapidly in patients after renal transplantation, and can achieve Cmax in 1. 5?. 2hr, the mean half-ife time is 10. 8hr. 2. The pharmacokinetic parameters can be guideline for FK506 application. 3. FK506 is a good prophylactic immunosuppressant for renal transplantation. 4. The whole blood concentrations are not corresponding to the episode of AR in a certain range. 5. There was a significant linear trend towards increasing rates of side effects rates with increasing trough concentrations. 6. Low trough FK506 concentrations can achieve good effect and lower its toxicity. 7. The ideal range of FK506 whole blood concentration is 5-lSng/ml.