Population pharmacokinetics of mycophenolic acid in children and young people undergoing blood or marrow and solid organ transplantation.
OBJECTIVE
To characterize the population pharmacokinetics of mycophenolic acid (MPA) and evaluate dose regimens using a simulation approach and accepted therapeutic drug monitoring targets in children and young people undergoing blood or marrow, kidney and liver transplantation.


METHODS
MPA concentration-time data were collected using an age specific sampling protocol over 12h. Some patients provided randomly timed but accurately recorded blood samples. Total and unbound MPA were measured by HPLC. NONMEM was employed to analyze MPA pharmacokinetic data. Simulations (n= 1000) were conducted to assess the suitability of the MPA dose regimens to maintain total MPA AUC(0,12h) within the range 30 and 60mg l(-1) h associated with optimal outcome.


RESULTS
A two-compartment pharmacokinetic model with first-order elimination best described MPA concentration-time data. Population mean estimates of MPA clearance, inter-compartmental clearance, volumes of distribution in the central and peripheral compartments, absorption rate constant and bioavailability were 6.42 l h(-1) , 3.74 l h(-1) , 7.24 l, 16.8l, 0.39h(-1) and 0.48, respectively. Inclusion of bodyweight and concomitant ciclosporin reduced the inter-individual variability in CL from 54.3% to 31.6%. Children with a bodyweight of 10kg receiving standard MPA dose regimens achieve an MPA AUC below the target range suggesting they may be at a greater risk of acute rejection.


CONCLUSIONS
The population pharmacokinetic model for MPA can be used to explore dosing guidelines for safe and effective immunotherapy in children and young people undergoing transplantation.
Zeng
Lihua
L
Faculty of Pharmacy Department of Paediatrics and Child Health, University of Sydney, Sydney.
Blair
Elaine Y L
EY
Nath
Christa E
CE
Shaw
Peter J
PJ
Earl
John W
JW
Stephen
Katherine
K
Montgomery
Kay
K
Coakley
John C
JC
Hodson
Elisabeth
E
Stormon
Michael
M
McLachlan
Andrew J
AJ
D000284:Administration, Oral; D000293:Adolescent; D001803:Blood Transfusion; D016026:Bone Marrow Transplantation; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007223:Infant; D007275:Injections, Intravenous; D008297:Male; D008954:Models, Biological; D009173:Mycophenolic Acid / Q000493:pharmacokinetics*; D016377:Organ Transplantation; D055815:Young Adult
D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid