title: Area under the plasma concentration-time curve for total, but not for free, mycophenolic acid increases in the stable phase after renal transplantation: a longitudinal study in pediatric patients. German Study Group on Mycophenolate Mofetil Therapy in Pediatric Renal Transplant Recipients.
abstract: Mycophenolate mofetil, an ester prodrug of the immunosuppressant mycophenolic acid (MPA), is widely used for maintenance immunosuppressive therapy in pediatric renal transplant recipients. However, little is known about the pharmacokinetics of MPA in this patient population in the stable transplant phase, and dosage guidelines are preliminary. The authors therefore compared the pharmacokinetics of MPA, free MPA, and the renal metabolite MPA glucuronide (MPAG) in the initial (sampling at 1 and 3 weeks) and stable phases (sampling at 3 and 6 months) posttransplant in 17 children (age, 12.0 +/- 0.77 years; range, 5.9 to 15.8 years), receiving the currently recommended dose of 600 mg MMF/m2 body surface area (BSA) twice a day. Plasma concentrations of MPA and MPAG were measured by reverse phase HPLC. Because MPA is extensively bound to serum albumin and only the free drug is presumed to be pharmacologically active, the authors also analyzed the MPA free fraction by HPLC after separation by ultrafiltration. The intraindividual variability of the area under the concentration-time curves (AUC0-12) of MPA throughout the 12-hour dosing interval was high in the immediate posttransplant period, but declined in the stable phase, whereas the interindividual variability remained unchanged. The median MPA-AUC0-12 values increased 2-fold from 32.4 (range, 13.9 to 57.0) mg x h/L at 3 weeks to 65.1 (range, 32.6 to 114) mg x h/L at 3 months after transplantation, whereas the median AUC0-12 values of free MPA did not significantly change over time. This discrepancy can be attributed to a 35% decline of the MPA free fraction from 1.4% in the initial phase posttransplant to 0.9% (p < 0.01) in the stable phase. In conclusion, pediatric renal transplant recipients given a fixed MMF dose exhibit a 2-fold increase of the AUC0-12 of total MPA in the stable phase posttransplant and a 35% decrease of the MPA free fraction, whereas the AUC0-12 of free MPA remains unchanged over time. Because the latter pharmacokinetic variable is theoretically best predictive of the clinical immunosuppressive efficacy of MMF, these findings may have consequences for the dosing recommendations of MMF in renal transplant recipients.
authors.affiliation: Division of Pediatric Nephrology, University Children's Hospital Heidelberg, Germany.
authors.forename: L T
authors.initials: LT
authors.lastname: Weber
authors.forename: T
authors.initials: T
authors.lastname: Lamersdorf
authors.forename: M
authors.initials: M
authors.lastname: Shipkova
authors.forename: P D
authors.initials: PD
authors.lastname: Niedmann
authors.forename: M
authors.initials: M
authors.lastname: Wiesel
authors.forename: L B
authors.initials: LB
authors.lastname: Zimmerhackl
authors.forename: A
authors.initials: A
authors.lastname: Staskewitz
authors.forename: E
authors.initials: E
authors.lastname: Schütz
authors.forename: O
authors.initials: O
authors.lastname: Mehls
authors.forename: M
authors.initials: M
authors.lastname: Oellerich
authors.forename: V W
authors.initials: VW
authors.lastname: Armstrong
authors.forename: B
authors.initials: B
authors.lastname: Tönshoff
mesh_terms: D000293:Adolescent; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D005260:Female; D020719:Glucuronides / Q000097:blood*; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism*; D016030:Kidney Transplantation / Q000502:physiology*; D008137:Longitudinal Studies; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood* / Q000378:metabolism; D010597:Pharmacogenetics; D011355:Prodrugs; D011485:Protein Binding; D013997:Time Factors
chemical_list: D020719:Glucuronides; D007166:Immunosuppressive Agents; D011355:Prodrugs; D009173:Mycophenolic Acid