Effect of Protein Binding on Exposure of Unbound and Total Mycophenolic Acid: A Population Pharmacokinetic Analysis in Chinese Adult Kidney Transplant Recipients

Abstract

Objectives: The population pharmacokinetic (popPK) characteristics of total mycophenolic acid (tMPA) have been investigated in various ethnic populations. However, investigations of popPK of unbound MPA (uMPA) are few. Thus, a popPK analysis was performed to: (1) characterize the PK of uMPA and tMPA and its 7-O-mycophenolic acid glucuronide (MPAG) metabolite in kidney transplant patients cotreated with cyclosporine (CsA), and (2) identify the clinically significant covariates that explain variability in the dose-exposure relationship.

Methods: A total of 740 uMPA, 741 tMPA, and 734 total MPAG (tMPAG) concentration-time data from 58 Chinese kidney transplant patients receiving MPA in combination with CsA were analyzed using NONMEM^® software with the stochastic approximation expectation maximization (SAEM) followed by the important sampling (IMP) method. The influence of covariates was tested using a stepwise procedure.

Results: The PK of uMPA and unbound MPAG (uMPAG) were characterized by a two- and one-compartment model with first-order elimination, respectively. A linear protein binding model was used to link uMPA and tMPA. Apparent clearance (CL/F) and central volume of distribution (V_C/F) of uMPA (CL_uMPA/F and V_CuMPA/F, respectively) and protein binding rate constant (k _B) were estimated to be 851 L/h [relative standard error (RSE), 7.1%], 718 L (18.5%) and 53.4/h (2.3%), respectively. For uMPAG, the population values (RSE) of CL/F (CL_uMPAG) and V_C/F (V_CuMPAG/F) were 5.71 L/h (4.4%) and 29.9 L (7.7%), respectively. Between-subject variability (BSVs) on CL_uMPA/F, V_CuMPA/F, CL_uMPAG/F, and V_CuMPAG/F were 51.0, 80.0, 31.8 and 48.4%, respectively, whereas residual unexplained variability (RUVs) for uMPA, tMPA, and uMPAG were 47.0, 45.9, and 22.0%, respectively. Significant relationships were found between k _B and serum albumin (ALB) and between CL_uMPAG/F and glomerular filtration rate (GFR). Additionally, model-based simulation showed that changes in ALB concentrations substantially affected tMPA but not uMPA exposure.

Conclusions: The established model adequately described the popPK characteristics of the uMPA, tMPA, and MPAG. The estimated CL_uMPA/F and unbound fraction of MPA (FU_MPA) in Chinese kidney transplant recipients cotreated with CsA were comparable to those published previously in Caucasians. We recommend monitoring uMPA instead of tMPA to optimize mycophenolate mofetil (MMF) dosing for patients with lower ALB levels.

Keywords: adult kidney transplant recipients; linear protein binding; nonlinear mixed-effect modeling; population pharmacokinetics; unbound mycophenolic acid.

Figure 1

Schematic representation of the final structural model characterizing the linear protein binding and intermittent EHC processes. In this model, mealtimes are used as an index of gallbladder emptying. This process is assumed to occur at specific time points (mealtimes) with a first-order rate constant and a certain duration. The fraction of MPA metabolized to MPAG is fixed at 87%. MMF, mycophenolate mofetil; MPA, mycophenolic acid; MPAG, 7-O-mycophenolic acid glucuronide; tMPA, total MPA; tMPAG, total MPAG; uMPA, unbound MPA; uMPAG, unbound MPAG; ALB, serum albumin; BW, body weight; CL_uMPA/F, apparent clearance of uMPA; D_GB, duration of gallbladder emptying; EHC, enterohepatic circulation; %EHC, percentage of MPAG recycled into the systemic circulation; FU_MPA, unbound fraction of MPA; FU_MPAG, unbound fraction of MPAG; GFR, glomerular filtration rate; k₂₀, elimination rate constant of uMPA; k₂₃, transfer rate constant from uMPA central compartment to peripheral compartment; k₂₄, rate constant of uMPA transformed to uMPAG; k₃₂, transfer rate constant from uMPA peripheral compartment to central compartment; k_a, absorption rate constant; k_B, protein binding rate constant; k_e0, elimination rate constant of uMPAG; k_GB, gallbladder emptying rate constant; k_GG, transfer rate constant from uMPAG central compartment to gallbladder; Tlag, lagged absorption time; V_CuMPA/F and V_CuMPAG/F, apparent central volume of distribution of uMPA and uMPAG, respectively; V_PuMPA/F, apparent peripheral volume of distribution of uMPA.

Figure 2

Goodness-of-fit plots of final model for uMPA, tMPA and tMPAG. (A) Population predictions versus observations; (B) individual predictions versus observations; (C) population predictions versus conditional weighted residuals; (D) time after previous dose versus conditional weighted residuals. Red dashed lines and gray-shaded areas represent the locally weighted regression line and 95% confidence interval, respectively. In plots A and B, black solid lines represent the line of unity. In plots C and D, black solid and dashed lines represent the y = 0 and y = ± 1.96 reference lines, respectively. tMPA, total mycophenolic acid (MPA); tMPAG, total 7-O-mycophenolic acid glucuronide; uMPA, unbound MPA.

Figure 3

Prediction-corrected visual predictive check plots of final model for uMPA, tMPA and tMPAG. Blue dots represent the observed concentrations. Red solid lines represent the median of observations, and the semitransparent red fields represent the simulation-based 95% CIs for the median. The observed 5th and 95th percentiles are presented with red dashed lines, and the simulation-based 95% CIs for corresponding percentiles are shown as semitransparent blue fields. In general, the median, and 5th and 95th percentile lines of observations fall inside the area of the corresponding 95% CIs. Additionally, the majority of observed concentrations fall within the 90% prediction interval, which demonstrates that the predicted variability does not exceed the observed variability. CIs, confidence intervals; tMPA, total mycophenolic acid (MPA); tMPAG, total 7-O-mycophenolic acid glucuronide; uMPA, unbound MPA.

Figure 4

Posterior predictive check graphics of final model for uMPA, tMPA, and tMPAG. The histograms represent the distribution of simulations. Black and blue solid lines represent the medians of observations and simulations, respectively. The observed 5th and 95th percentiles are presented by black dashed lines, and the simulated 5th and 95th percentiles are presented by blue dashed lines. The simulated AUC_0–12h values present good consistency with observations. In particular, the 5th percentiles of simulations and observations for uMPA, as well as the medians of simulations and observations for tMPAG, are completely overlapped in the graphics. AUC_0–12h, area under the concentration–time curve within 12-h dose-interval; tMPA, total mycophenolic acid (MPA); tMPAG, total 7-O-mycophenolic acid glucuronide; uMPA, unbound MPA.

Figure 5

Model-predicted covariate effects on AUC_0–12h of uMPA, tMPA, and tMPAG. Black squares represent median values and error bars represent 95% confidence intervals of the normalized exposure ratios relative to the typical reference subject (ALB 40 g/L, GFR 90 mL/min) across 2,000 simulation replicates. The vertical red dashed lines show an exposure ratio of 1 relative to the reference subject. ALB, serum albumin; AUC_0–12h, area under the concentration–time curve within 12-h dose-interval; GFR, glomerular filtration rate; tMPA, total mycophenolic acid (MPA); tMPAG, total 7-O-mycophenolic acid glucuronide; uMPA, unbound MPA.