Abstract
ObjectivesThe 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.MethodsA 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.ResultsThe 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 (VC/F) of uMPA (CLuMPA/F and VCuMPA/F, respectively) and protein binding rate constant (kB) 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 (CLuMPAG) and VC/F (VCuMPAG/F) were 5.71 L/h (4.4%) and 29.9 L (7.7%), respectively. Between-subject variability (BSVs) on CLuMPA/F, VCuMPA/F, CLuMPAG/F, and VCuMPAG/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 kB and serum albumin (ALB) and between CLuMPAG/F and glomerular filtration rate (GFR). Additionally, model-based simulation showed that changes in ALB concentrations substantially affected tMPA but not uMPA exposure.ConclusionsThe established model adequately described the popPK characteristics of the uMPA, tMPA, and MPAG. The estimated CLuMPA/F and unbound fraction of MPA (FUMPA) 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.
Highlights
Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is the predominant antimetabolite immunosuppressant used as a cotherapy with tacrolimus (TAC) or cyclosporine (CsA) to prevent graft rejection after solid organ transplantation (Hart et al, 2018; Hart et al, 2019)
A total of 27 full concentration–time profiles containing unbound MPA (uMPA), total MPA (tMPA), and total MPAG (tMPAG) data were obtained from 20 patients in study 1, including 23 profiles collected within 3 months posttransplantation
The present study extensively investigated the population PK (popPK) characteristics of uMPA, tMPA, and MPAG in Chinese adult kidney transplant recipients cotreated with CsA during both the early and stable periods posttransplantation
Summary
Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is the predominant antimetabolite immunosuppressant used as a cotherapy with tacrolimus (TAC) or cyclosporine (CsA) to prevent graft rejection after solid organ transplantation (Hart et al, 2018; Hart et al, 2019). MMF is extensively absorbed and rapidly hydrolyzed to the active component MPA after oral administration. The majority of MPA is metabolized to the pharmacologically inactive 7-Omycophenolic acid glucuronide (MPAG), whereas a lower fraction is metabolized to the active acyl-glucuronide mycophenolic acid (AcMPAG) (Bullingham et al, 1998; Kiang and Ensom, 2016). MPAG undergoes enterohepatic circulation (EHC) through biliary excretion, followed by intestinal deglucuronidation and reabsorption as MPA in the colon. This process contributes to approximately 40% (range: 10–60%) of the area under the concentration–time curve (AUC) of MPA and causes multiple peaks in the concentration–time profile (Staatz and Tett, 2007). Most absorbed MMF is eliminated through the kidney as MPAG (Staatz and Tett, 2007)
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