Nephrology Dialysis Transplantation, Vol 12, Issue 8 1668-1671, Copyright © 1997 by Oxford University Press
G Filler, R Grygas, I Mai, H Stolpe, C Greiner, S Bauer and J Ehrich
Background: Only few data exist on pharmacokinetics of
tacrolimus in children. Patients: In 1995 and 1996, 14
children (mean age 13 years, range 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 for untreatable gingival hyperplasia on CsA, and
one child was treated primarily after transplantation because of severe
liver involvement in nephronophthisis. Pharmacokinetic investigations were
performed after establishing a stable maintenance dose with trough levels
in the desired window of 5-12 ng/ml. Results: Mean
follow-up time was 6 months (range 3-25 months). Eleven patients were still
on tacrolimus. Two were discontinued because of severe aggravation of
chronic persistent hepatitis C (one of them also developed diabetes
mellitus),and one patient was subsequently switched to conventional
immunosuppression because of tacrolimus-associated nephrotoxicity. All
tacrolimus levels were measured by a modified assay (MEIA, Tacrolimus,
Abbott) with improved sensitivity. At the time of switch, median serum
creatinine was 234±82 7mgr;mol;l and 6 months after switch
201±99 &mgr;mol/l. All grafts are still functioning. Mean
FK-506 dose was 0.16 mg/kg body weight/day (range 0.036-0.30 mg/kg). Mean
trough level was 7.1±2.6 ng/ml in the morning and
6.5±2.0 ng/ml in the evening. Median time of maximum
concentration (tmax) was 120 min after application, and the mean maximum
concentration (Cmax) was 15.2±6.7 ng/ml. Mean area under the
curve (AUC) was 104±33 ng * h/ml, with a range from 65 to 169 ng
* h/ml. No patient had unsatisfactorily low trough levels during the study.
There was only a weak but significant (P<0.05) correlation between
dose per kg body weight and AUC and, as expected, an excellent correlation
(r2=0.73, P<0.001) between AUC and trough
level. Conclusion: Because of interindividual
variation between patients, therapeutic 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 establishing stable FK 506 trough levels to ascertain a safe
profile. Keywords: renal transplantation; rescue
therapy; tacrolimus; tacrolimus pharmacokinetics
ORIGINAL ARTICLES
Pharmacokinetics of tacrolimus (FK 506) in children and adolescents with renal transplants
Department of Paediatric Nephrology, Charite Children's Hospital, Humboldt University Berlin, Schumannstrasse 20-21, D-10098 Berlin, Germany; Department of Clinical Pharmacology, Humboldt University, Berlin, Germany; Department of Paediatric Nephrology, Children's Hospital, University of Rostock, Germany; St George's Children's Hospital, Leipzig, Germany; Corresponding author
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