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Population Pharmacokinetics of Mycophenolic Acid and Its 2 Glucuronidated Metabolites in Kidney Transplant Recipients

From the Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston.

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 (V₁/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.

Key Words: acyl MPAG • enterohepatic recirculation • GFR • renal transplant • MPAG • mycophenolic acid • NONMEM • population pharmacokinetics

Address for reprints: Sara E. Rosenbaum, PhD, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, 41 Lower College Road, Kingston, RI 02881; e-mail: sarar{at}uri.edu.

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