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Pharmacokinetics of Mycophenolate Mofetil and Sirolimus in Children

Filler, Guido MD, PhD, FRCPC*; Bendrick-Peart, Jamie MS; Christians, Uwe MD, PhD

doi: 10.1097/FTD.0b013e31816ba73a
Proceedings Paper

This review summarizes the pharmacokinetics in children and youths of 2 commonly used immunosuppressive drugs, mycophenolate mofetil (MMF) and sirolimus (Sir), as presented at the IATDMCT 2007 conference. The review focuses on the developmental changes of drug disposition during childhood and adolescence. Regarding mycophenolate mofetil, the authors were unable to demonstrate age dependency of MMF in combination with cyclosporine. By contrast, there was an inverse relationship between age and the dose-normalized mycophenolate (MPA) area-under-the-time-concentration curve (AUC) in children who received concomitant tacrolimus (Tac). Dose-normalized MPA AUCs were higher than commonly observed in adult patients. It can be hypothesized that the age dependency is related to developmental changes in the expression of the UDP-glucuronosyltransferases. Sirolimus half-life and mean residence time (MRT) are shorter than in adults. Similar to that in adults, there is a profound drug-drug interaction between cyclosporine and Sir. In our own experience, Sir was started at 0.13 ± 0.05 mg/kg/day. The average Sir AUC was 64.9 ± 29.7 ng*h/mL. The median (range) AUC for each metabolite was as follows: 12-hydroxy-Sir, 7.6 (0.2-18.8); 46-hydroxy-Sir, 3.1 (0.0-12.4); 24-hydroxy-Sir, 4.3 (0.0-12.6); piperidine-hydroxy-Sir, 3.5 (0.0-8.3); 39-desmethyl-Sir, 3.6 (0.0-11.3); 16-desmethyl-Sir, 5.0 (0.1-9.9); and di-hydroxy-Sir, 4.3 (0.0-32.5) ng*h/mL. Of the total metabolite AUC, 77.5% was due to hydroxylated metabolites, while 39-O-desmethyl Sir (the main metabolite in adults) comprised only 8.4% of the metabolites. This is clinically relevant, as 39-O-desmethyl Sir shows 86% to 127% cross-reactivity with the Sir immunoassay. Metabolites reached a median AUC of 60% of that of Sir, but the range was 2.6% to 136%. The age dependency of Sir metabolite formation was confirmed in a human liver microsome model. On the basis of the age dependency of piperidine-hydroxy Sir, the authors postulate that the ontogeny of the drug disposition can be largely explained by developmental changes of the CYP2C8 expression. In conclusion, both Sir and MMF drug disposition vary in children and adolescents from adult patients, most likely because of developmental changes of biliary transporters and metabolic enzymes.

From the *Department of Paediatrics, Children's Hospital at London Health Science Centre, University of Western Ontario, London, Ontario, Canada; and †Department of Anesthesiology, University of Colorado Health Science Center, Denver, Colorado, USA.

Received for publication September 11, 2007; accepted November 5, 2007.

Financial support: The United States National Institutes of Health/NIDDK supported this work (grant P30 DK048520-10; Clinical Nutrition Research Unit, Mass Spectrometry Core).

The study was also supported by grants from the Research Institute of the Children's Hospital of Eastern Ontario and Fujisawa Canada, Inc.

Correspondence: Guido Filler, MD, PhD, FRCPC, Professor and Chair, Department of Paediatrics, Children's Hospital of Western Ontario, 800 Commissioners Road East, London, Ontario, Canada N6A 5W9 (e-mail: guido.filler@lhsc.on.ca).

© 2008 Lippincott Williams & Wilkins, Inc.