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

摘要

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.