Volume 85, Issue 6, Pages 1434-1443 (June 2014) Pharmacokinetic modeling of enterohepatic circulation of mycophenolic acid in renal transplant recipients  Helena Colom, Núria Lloberas, Franc Andreu, Ana Caldés, Joan Torras, Federico Oppenheimer, Jaime Sanchez-Plumed, Miguel A. Gentil, Dirk R. Kuypers, Mercè Brunet, Henrik Ekberg, Josep M. Grinyó  Kidney International  Volume 85, Issue 6, Pages 1434-1443 (June 2014) DOI: 10.1038/ki.2013.517 Copyright © 2014 International Society of Nephrology Terms and Conditions

Figure 1 Plasma concentration–time (post-dosing time) profiles of mycophenolic acid (MPA) (left panel), 7-O-MPA-glucuronide (MPAG) (middle panel), and acyl-glucuronide (AcMPAG) (right panel) after mycophenolate mofetil (MMF) oral administration to the target population. Open circles, observed data. Solid line, smooth line indicating the general trend of the data. A high variability was observed in all the cases. Plasma MPAG concentrations >250mg/l corresponded to two patients treated with sirolimus and tacrolimus, with CLCR values of 8.43 and 26.82ml/min, on day 7 of the study, respectively. Approximately 21 out of 56 patients showed a slight second rise in MPA concentration either at 8 or 12h post dosing, on at least one occasion. Kidney International 2014 85, 1434-1443DOI: (10.1038/ki.2013.517) Copyright © 2014 International Society of Nephrology Terms and Conditions

Figure 2 Schematic representation of the final pharmacokinetic model to simultaneously describe the pharmacokinetics of mycophenolic acid (MPA), and its conversion to the 7-O-glucuronide (MPAG) and acyl-glucuronide (AcMPAG) conjugates after oral administration of mycophenolate mofetil (MMF), by first-order processes. Enterohepatic circulation (EHC) of MPAG is also implemented. CL, clearance; CLD, distributional clearance between central and peripheral compartments; fm, fraction of MPA converted to MPAG; ka, first-order absorption rate constant; KT, first-order transfer rate constant from the central compartment of MPAG to the absorption site; VC and VP, volumes of distribution for central and peripheral compartments. Kidney International 2014 85, 1434-1443DOI: (10.1038/ki.2013.517) Copyright © 2014 International Society of Nephrology Terms and Conditions

Figure 3 Goodness-of-fit plots for the population pharmacokinetic model. OBS, observed concentrations; PRED, population predictions; dashed line, identity line; solid line, smooth line indicating the general data trend. CWRES, conditional population-weighted residuals; dashed line, represents the line y= 0; solid line, smooth line indicating the general data trend. Concentrations expressed as μmol/l, given as ln values. Time given in hours from the start of the treatment. Kidney International 2014 85, 1434-1443DOI: (10.1038/ki.2013.517) Copyright © 2014 International Society of Nephrology Terms and Conditions

Figure 4 Boxplots of the distributions of predicted and observed area under the curve (AUC)0–12h ((mg/l)·h) values of mycophenolic acid (MPA), 7-O-glucuronide (MPAG), and acyl-glucuronide (AcMPAG) from 50 simulations from the final population model. The bold horizontal bars in the middle show the median values, whereas the outer boundaries of the boxes represent the ranges of the 25th and 75th percentiles (interquartile ranges). The whiskers indicate the maximum and the minimum values of AUC0–12h. Outliers are not shown in these plots. Kidney International 2014 85, 1434-1443DOI: (10.1038/ki.2013.517) Copyright © 2014 International Society of Nephrology Terms and Conditions

Figure 5 Median simulated area under the curve (AUC)0–12h ((mg/l)·h) values of mycophenolic acid (MPA), 7-O-glucuronide (MPAG), and acyl-glucuronide (AcMPAG), after oral administration of 1g of mycophenolate mofetil (MMF), in the following scenarios. MPA and MPAG: Macrolide patients with CLCR values from 10 to 120ml/min, cyclosporine (CsA) patients with mean trough concentrations of 100ng/ml and CLCR values from 10 to 120ml/min, CsA patients with mean trough concentrations of 300ng/ml and CLCR values from 10 to 120ml/min. AcMPAG: Macrolide patients with CLCR values from 10 to 120ml/min, CsA patients with CLCR values from 10 to 120ml/min. The effect of changes in CLCR (10, 25, 60, 90, and 120ml/min) and co-medication on MPA, MPAG, and AcMPAG AUC0–12h are displayed. Kidney International 2014 85, 1434-1443DOI: (10.1038/ki.2013.517) Copyright © 2014 International Society of Nephrology Terms and Conditions