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Population Pharmacokinetics of Mycophenolic Acid and Its 2 Glucuronidated Metabolites in Kidney Transplant Recipients
Author(s) -
Sam WaiJohnn,
Akhlaghi Fatemeh,
Rosenbaum Sara E.
Publication year - 2009
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270008329558
Subject(s) - pharmacokinetics , mycophenolic acid , nonmem , population , volume of distribution , renal function , mycophenolate , population pharmacokinetics , chemistry , glucuronide , elimination rate constant , pharmacology , urology , probenecid , clearance , chromatography , metabolite , medicine , transplantation , biochemistry , environmental health
The population pharmacokinetics of mycophenolic acid (MPA) and its phenolic (MPAG) and acyl (AcMPAG) glucuronide metabolites were studied in patients taking enteric‐coated mycophenolate sodium. Plasma samples (n = 232), obtained from 18 renal transplant recipients, were analyzed for MPA, MPAG, and AcMPAG using a validated high‐performance liquid chromatography/ultraviolet assay. Population pharmacokinetic analysis was performed using NONMEM. The pharmacokinetics of MPA were best described by a 2‐compartment model, with MPAG and AcMPAG produced from the central compartment and with enterohepatic recirculation of MPA via these 2 metabolites. Population mean estimates for MPA were apparent clearance (CL/F) of 10.6 L/h (interindividual variability [IIV] = 21.4%) and apparent volume of distribution of the central compartment (V 1 /F) of 25.9 L (IIV = 87.8%). Mean elimination rate constants of MPAG and AcMPAG were 0.323 h −1 (IIV = 29.1%) and 0.206 h −1 (IIV = 48.8%), respectively. The mean fraction of MPA converted to MPAG and AcMPAG, normalized by their volumes of distribution (FM AG and FM AC , respectively), was also estimated. The elimination rate constant for MPAG and FM AC was influenced by glomerular filtration rate in patients with renal impairment. The visual predictive check, based on 100 simulated data sets each for MPA, MPAG, and AcMPAG, found that the final pharmacokinetic model adequately predicts the observed concentrations of all 3 species.