Population Pharmacokinetics of Mycophenolic Acid and Metabolites in Patients with Glomerulonephritis

Mycophenolic acid (MPA) is an inosine monophosphate dehydrogenase inhibitor used for glomerulonephritis treatment. The objective of the current study was to develop a population pharmacokinetic model for MPA and metabolites in glomerulonephritis to enable appropriate design of MPA regimens in these patients with alterations in kidney structure and function. Thirty-nine patients with glomerulonephritis and receiving mycophenolate mofetil were recruited to participate in a 24-hour pharmacokinetic study. Blood was collected at times 0, 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours and urine was collected over the intervals of 0 to 6, 6 to 12, and 12 to 24 hours. Plasma and urine samples were assayed for MPA and MPA glucuronide (MPAG) by high-performance liquid chromatography and for acyl-MPA glucuronide (AcMPAG) by liquid chromatography/mass spectrometry. Population pharmacokinetic analysis and covariate model building were evaluated using Non-linear Mixed Effect Modeling software (NONMEM, Version 6.2.0; ICON Development Solutions, Ellicott City, MD). The final model for MPA and its metabolites consisted of nine discrete compartments; 1) depot gastrointestinal; 2) central MPA; 3) peripheral MPA; 4) gallbladder; 5) MPA urine; 6) MPAG central; 7) MPAG urine; 8) AcMPAG central; and 9) AcMPAG urine compartment. The MPA population mean estimates for apparent nonrenal clearance (ClNR/F) and apparent central volume of distribution were 14.3 L/hr and 21.1 L, respectively. The mean population estimate for apparent renal clearance (ClR/F) was dependent on estimated creatinine clearances (eClcr); 0.0975 L/hr for eClcr 80 mL/min or less and 0.157 L/hr for eClcr greater than 80 mL/min. Covariate analyses identified: eClcr on CLNR,MPA/F (P < 0.001), eClcr (with a cutoff value at 80 mL/min) on CLR,MPA/F (P < 0.025), serum albumin on CLNR,MPA/F (P < 0.01), eClcr on CLR,MPAG/F (P < 0.001), and eClcr on CLR,AcMPAG/F (P < 0.001). Evaluation of the final model by visual predictive check showed that most of the observed values were within the 95th percent prediction interval generated from 100 simulations of the final model. The current population pharmacokinetic model demonstrated eClcr and serum albumin influenced the renal and nonrenal components of Cl/F, suggesting patients with glomerulonephritis would have highly altered MPA exposures.