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Title: Population Pharmacokinetics of Mycophenolic Acid A Comparison between Enteric-Coated Mycophenolate Sodium and Mycophenolate Mofetil in Renal Transplant Recipients
Authors: Winter, Brenda C. M. de
van Gelder, Teun
Glander, Petra
Cattaneo, Dario
Tedesco-Silva Junior, Hélio [UNIFESP]
Neumann, Irmgard
Hilbrands, Luuk
van Hest, Reinier M.
Pescovitz, Mark D.
Budde, Klemens
Mathot, Ron A. A.
Erasmus Univ
Humboldt Univ
Mario Negri Inst Pharmacol Res
Universidade Federal de São Paulo (UNIFESP)
Wilhelminenspital Stadt Wien
Radboud Univ Nijmegen
Indiana Univ
Issue Date: 1-Jan-2008
Publisher: Adis Int Ltd
Citation: Clinical Pharmacokinetics. Auckland: Adis Int Ltd, v. 47, n. 12, p. 827-838, 2008.
Abstract: Objective: the pharmacokinetics of mycophenolic acid (MPA) were compared in renal transplant patients receiving either mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS).Methods: MPA concentration-time profiles were included from EC-MPS- (n = 208) and MMF-treated (n = 184) patients 4-257 months after renal transplantation. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modelling (NONMEM (R)). A two-compartment model with first-order absorption and elimination was used to describe the data.Results: No differences were detected in MPA clearance, intercompartmental clearance, or the central or peripheral volume of distribution. Respective values and interindividual variability (IIV) were 16 L/h (39%), 22 L/h (78%), 40 L (100%) and 518 L (490%). EC-MPS was absorbed more slowly than MMF with respective absorption rate constant values of 3.0 h(-1) and 4.1 h(-1) (p < 0.001) [IIV 187%]. A mixture model was used for the change-point parameter lag-time (t(lag)) in order to describe IIV in this parameter adequately for EC-MPS. Following the morning dose of EC-MPS, the t(lag) values were 0.95, 1.88 and 4.83 h for 51%, 32% and 17% of the population (IIV 8%), respectively. the morning t(lag) following EC-MPS administration was significantly different from both the t(lag) following MMF administration (0.30 h; p < 0.001 [IIV 11%]) and the t(lag) following the evening dose of EC-MPS (9.04 h; p < 0.001 [IIV 40%]). Post hoc analysis showed that the tlag was longer and more variable following EC-MPS administration (morning median 2.0 h [0.9-5.5 h], evening median 8.9 h [5.4-12.3 h]) than following MMF administration (median 0.30 h [0.26-0.34 h]; p < 0.001). the morning MPA predose concentrations were higher and more variable following EC-MPS administration than following MMF administration, with respective values of 2.6 mg/L (0.4-24.4 mg/L) and 1.6 mg/L (0.2-7.6 mg/L). the correlation between predose concentrations and the area under the plasma concentration-time curve (AUC) was lower in EC-MPS-treated patients (r(2) = 0.02) than in MMF-treated patients (r(2) = 0.48).Conclusion: Absorption of MPA was delayed and also slower following EC-MPS administration than following MMF administration. Furthermore, the t(lag) varied more in EC-MPS-treated patients. MPA predose concentrations were poorly correlated with the MPA AUC in both MMF- and EC-MPS-treated patients.
ISSN: 0312-5963
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