PHARMACOKINETICS OF TACROLIMUS (FK-506) IN CHILDREN AND ADOLESCENTS WITH RENAL-TRANSPLANTS

Background. Only few data exist on pharmacokinetics of tacrolimus in c hildren.Patients. In 1995 and 1996, 14 children (mean age 13 years, ra nge 5-23 years) received tacrolimus after renal transplantation 10 of these after biopsy-proven steroid-resistant rejection (2 with vascular rejection), two for cyclosporin A (CsA)-induced severe nephrotoxicity , one ibr untreatable gingival hyperplasia on CsA, and one child was t reated primarily after transplantation because of severe liver involve ment in nephronophthisis. Pharmacokinetic investigations were performe d after establishing a stable maintenance dose with trough levels in t he desired window of 5-12 ng/ml. Results. Mean follow-up time was 6 mo nths (range 3-25 months). Eleven patients are still on tacrolimus. Two were discontinued because of severe aggravation of chronic persistent hepatitis C (one of them also developed diabetes mellitus), and one p atient was subsequently switched to conventional immunosuppression bec ause of tacrolimus-associated nephrotoxicity, All tacrolimus levels we re measured by a modified assay (MEIA, Tacrolimus, Abbott) with improv ed sensitivity. At the time of switch, median serum creatinine was 234 +/- 82 mu mol/l and 6 months after switch 201 +/- 99 mu mol/l. All gr afts are still functioning. Mean FK-506 dose was 0.16 mg/kg body weigh t/day (range 0.036-0.30 mg/kg). Mean trough level was 7.1 +/- 2.6 ng/m l in the morning and 6.5 +/- 2.0 ng/ml in the evening. Median time of maximum concentration (t(max)) was 120 min after application, and the mean maximum concentration (C-max) was 15.2 +/- 6.7 ng/ml. Mean area u nder the curve (AUG) was 104 +/- 33 ng h/ml, with a range from 65 yo 169 ng h/ml. No patient had unsatisfactorily low trough levels duri ng the study. There was only a weak but significant (P<0.05) correlati on between dose per kg body weight and AUC and, as expected, an excell ent correlation (r(2) = 0.73, P <0.001) between AUC and trough level. Conclusion, Because of interindividual variation between patients, the rapeutic drug monitoring of tacrolimus is mandatory. In this study, a daily dose of 0.15 mg/kg was sufficient in most patients. We recommend the performance of at least one pharmacokinetic study after establish ing stable FK 506 trough levels to ascertain a safe profile.