Population pharmacokinetics and Bayesian estimation of mycophenolic acid concentrations in Chinese adult renal transplant recipients

Abstract

Mycophenolate mofetil (MMF) is an important immunosuppressant used in renal transplantation, and mycophenolic acid (MPA) is the active component released from the ester prodrug MMF. The objective of this study was to investigate the population pharmacokinetics of mycophenolic acid (MPA) following oral administration of MMF in Chinese adult renal transplant recipients and to identify factors that explain MPA pharmacokinetic variability. Pharmacokinetic data for MPA and covariate information were retrospectively collected from 118 patients (79 patients were assigned to the group for building the population pharmacokinetic model, while 39 patients were assigned to the validation group). Population pharmacokinetic data analysis was performed using the NONMEM software. The pharmacokinetics of MPA was best described by a two-compartment model with a first-order absorption rate with no lag time. Body weight and serum creatinine level were positively correlated with apparent clearance (CL/F). The polymorphism in uridine diphosphate glucuronosyltransferase gene, UGT2B7, significantly explained the interindividual variability in the initial volume of distribution (V/F). The estimated population parameters (and interindividual variability) were CL/F 18.3 L/h (34.2%) and V/F 27.9 L (21.3%). The interoccasion variability was 13.7%. These population pharmacokinetic data have significant clinical value for the individualization of MMF therapy in Chinese adult renal transplant patients.

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

“…Table 3, the population estimate of CL uMPA /F (852 L/h) was comparable to most of previously reported values in Caucasians (654-866 L/h) [27][28][29]. Moreover, the calculated typical value of apparent clearance of tMPA (CL tMPA /F, 15.68 L/h) was also comparable to most of previously reported values (12.3-20.8 L/h) [17][18][19][20][21][22][23][24][25][26]. The population estimate of FU MPA in our study (1.84%) was similar to values reported by van Hest et al [28] and Colom et al [29] (2.03% and 1.93%, respectively).…”

“…population 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.…”

Systematic external evaluation of published population pharmacokinetic models of mycophenolate mofetil in adult kidney transplant recipients co‐administered with tacrolimus

“…A total of 11 popPK models of MMF co‐administered with TAC were included for external evaluation after the literature retrieval. The details of the literature search process are provided in Appendix S1.…”

“…The details of the literature search process are provided in Appendix S1. Among them, seven were multicentre studies and four were single‐centre studies . Although >60% of the included models were conducted in multicentres, the sample size of kidney transplant recipients co‐administered with TAC was >100 in only one study , and 50–100 in two .…”

“…Although >60% of the included models were conducted in multicentres, the sample size of kidney transplant recipients co‐administered with TAC was >100 in only one study , and 50–100 in two . In addition, only one study was conducted in Chinese individuals while the remaining 10 were mainly conducted in Caucasians. Liquid chromatography methods were used to detect the MPA concentrations in all studies (Table ).…”