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

Abstract

AIMS A population pharmacokinetic (PK) analysis was performed to: (1) characterise the PK of unbound and total mycophenolic acid (MPA) and its 7-O-mycophenolic acid glucuronide (MPAG) metabolite, and (2) identify the clinically significant covariates that cause variability in the dose-exposure relationship to facilitate dose optimisation.METHODS A total of 740 unbound MPA (uMPA), 741 total MPA (tMPA) and 734 total MPAG (tMPAG) concentration-time data from 58 Chinese kidney transplant patients were analysed using a nonlinear mixed-effect model. The influence of covariates was tested using a stepwise procedure. RESULTSThe PK of unbound MPA and MPAG were characterised by a two-and one-compartment model with first-order elimination, respectively. Apparent clearance of uMPA (CL uMPA /F) was estimated to be 852 L/h with a relative standard error (RSE) of 7.1%. The tMPA and uMPA were connected using a linear protein binding model, in which the protein binding rate constant (k B ) increased non-linearly with the serum albumin (ALB) concentration. The estimated k B was 53.4 /h (RSE, 2.3%) for patients with ALB of 40 g/L. In addition, model-based simulation showed that changes in ALB substantially affected tMPA but not uMPA exposure. CONCLUSIONS The established model adequately described the population PK characteristics of the uMPA, tMPA, and MPAG. The estimated CL uMPA /F and unbound fraction of MPA (FU MPA ) in Chinese kidney transplant recipients were comparable to those published previously in Caucasians. We recommend monitoring uMPA instead of tMPA to optimise mycophenolate mofetil (MMF) dosing for patients with lower ALB levels. Keywordspopulation pharmacokinetics, unbound mycophenolic acid, linear protein binding, adult kidney transplant recipients tMPA population PK [17][18][19][20][21][22][23][24][25][26]. There are few investigations of the population PK characteristics of unbound MPA (uMPA) [27][28][29][30], the pharmacologically active component, due to the technical complexity of measurements. Furthermore, little is known in Chinese kidney transplant recipients.Therefore, the aims of this study were to develop a population PK model to: (1) characterise the PK of uMPA, tMPA, and the metabolite MPAG, and (2) identify the clinically significant covariates that cause variability in the dose-exposure relationship to facilitate dose optimisation. Methods Study design and patientsThe data were obtained from two clinical studies conducted in 58 Chinese adult kidney transplant recipients [31,32]. All recipients received triple immunosuppressive therapy comprising MMF (CellCept®, Roche Pharma Ltd., Shanghai, China), CsA, and corticosteroids. The first study was an evaluation of the PK of MPA and MPAG during the early post-transplantation period conducted at Huashan Hospital, Fudan University [31]. MMF was initiated at 1500 mg/day from the day of the surgery. The second study was an open-label, multi-centre, two-phase, sequential, bioequivalence study conducted in stable kidney transplantation patients [32]. MMF dose wa...

Genetic polymorphisms in metabolic enzymes and transporters have no impact on mycophenolic acid pharmacokinetics in adult kidney transplant patients co‐treated with tacrolimus: A population analysis

“…MPA PK has been extensively studied in kidney transplant recipients 22,31,41‐44 . CL MPA /F (9.05 L∙h −1 ) at more than 1 month post‐transplantation and CL MPAG /F (1.09 L∙h −1 ) were similar to previously reported values (9.3–13.6 and 0.96–1.7 L∙h −1 , respectively) 4,22,32,42,44‐46 . We found that CL MPA /F (10.9 L∙h −1 ) within 1 month post‐transplantation was markedly lower than that previously reported 32,47 (17–27 L∙h −1 ), possibly because of the different regimens (cyclosporine or tacrolimus), higher body weight of patients, relatively low serum ALB levels, and ethnic differences, among other factors.…”

“…MPA has a complex pharmacokinetic (PK) profile with great differences 2‐4 . After oral administration, MMF is quickly and completely converted into MPA.…”

“…Approximately 85% of MPA is metabolized by uridine diphosphate glucuronic acid‐base transferases (UGTs) 1A9 and 1A8 to form the abundant but inactive metabolite mycophenolic acid glucuronide (MPAG) 6 . The protein‐binding rate of MPAG is 82% 4,5 . Approximately 15% of MPA is converted into the active product acyl‐glucuronide MPA by UGT2B7.…”

Estimation of Mycophenolic Acid Exposure in Heart Transplant Recipients by Population Pharmacokinetic and Limited Sampling Strategies

“…In previous studies, a series of covariates, including low plasma albumin levels and accumulation of the inactive MPAG, decreased the binding of MPA to ALB. WT and ALB were found to significantly influence MPA clearance and distribution volume or the protein-binding rate in renal transplant recipients (de Winter et al, 2010;Sheng et al, 2020). The subsequent increase in unbound MPA produces an increase in MPA clearance, resulting in decreased MPA exposure (de Winter et al, 2010).…”

Effects of Corticosteroid Treatment on Mycophenolic Acid Exposure in Renal Transplant Patients—Results From the SAILOR Study

“…However, also other factors may be important, and our study does not provide information on the influence of gastro-intestinal absorption, proton pump inhibitor use, ethnicity, or UGT-enzyme polymorphisms that could possibly have contributed to this variation. MPA exposure is also shown to be affected by plasma albumin concentrations with a risk of increased MPA exposure in patients with low albumin levels ( Sheng et al, 2020 ). However, the limited number of plasma albumin measurements precluded us from including this factor in the regression analysis.…”