PII-43Population pharmacokinetics of mycophenolic acid and its metabolites in renal transplant patients

AIMS To study the population pharmacokinetics (PK) of MPA and its phenolic (MPAG) and acyl (AcMPAG) glucuronide metabolites in patients taking oral doses of mycophenolate mofetil (MMF)(1–2 g day−1). METHODS An average of 12 plasma samples per patient were obtained from 24 renal transplant recipients during a 12-hour steady state dosing interval (305 samples in total) and were analyzed for MPA, MPAG and AcMPAG using HPLC. PK analysis was performed using nonlinear mixed effect modeling (NONMEM). Interindividual variability (IIV) and residual variability in the PK were estimated. RESULTS A 2-compartment PK model was found to best fit the MPA data while a 1-compartment model was most suitable for MPAG and AcMPAG. Population mean estimates for MPA were: apparent clearance (CL/F) 5.68 L/hr (IIV=55.2%) and apparent volume of distribution (V/F) 51.1 L (IIV=133%). Population mean fraction of MPA converted to AcMPAG and MPAG normalized by the volume of distribution of the respective metabolites were 0.0265 L−1 and 0.9735 L−1, respectively. Population mean elimination rate constants of AcMPAG and MPAG were 0.531hr−1(IIV=39.9%) and 0.664 hr−1(IIV=42.3%), respectively. CONCLUSIONS A model describing the population PK of MPA, MPAG and AcMPAG was developed, which may be useful for predicting the time course of MPA and its metabolites after the administration of MMF. Additionally, it may be used for studying potential covariates affecting PK of MPA and its metabolites. Clinical Pharmacology & Therapeutics (2005) 79, P47–P47; doi: 10.1016/j.clpt.2005.12.168