Pharmacokinetic modeling of enterohepatic circulation of mycophenolic acid in renal transplant recipients

Abstract

Several factors contribute to mycophenolic acid (MPA) between-patient variability. Here we characterize the metabolic pathways of MPA and quantify the effect of combining genetic polymorphism of multidrug-resistant-associated protein-2, demographics, biochemical covariates, co-medication (cyclosporine (CsA) vs. macrolides), and renal function on MPA, 7-O-MPA-glucuronide (MPAG), and acyl-glucuronide (AcMPAG) disposition, in renal transplant recipients, after mycophenolate mofetil. Complete pharmacokinetic profiles from 56 patients (five occasions) were analyzed. Enterohepatic circulation was modeled by transport of MPAG to the absorption site. This transport significantly decreased with increasing CsA trough concentrations (CtroughCsA). MPAG and AcMPAG plasma clearances significantly decreased with renal function. No significant influence of multidrug-resistant-associated protein-2 C24T single-nucleotide polymorphism was found. The model adequately predicted the increase in MPAG/AcMPAG exposures in CsA and macrolide patients with decreased renal function. This resulted in higher MPA exposures in macrolide patients versus CsA patients, and increased MPA exposures with renal function from 25 to 10 ml/min, in macrolide patients, owing to enhanced MPAG enterohepatic circulation. Lower-percentage enterohepatic circulation occurred with higher CtroughCsA and renal function values. The lack of MPA protein-binding modeling did not permit evaluation of the impact of renal function and CtroughCsA on MPA exposures in CsA patients. Thus, dose tailoring of covariates is recommended for target MPA exposure.

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.…”

Impact of immunosuppressive drugs on the therapeutic efficacy of ex vivo expanded human regulatory T cells

“…20,21 Other data showed that renal function, serum albumin concentrations, hemoglobin levels and immunosuppressive co-medication, such as TAC, are factors contributing to the variability and time-dependent pharmacokinetics of drug treatments. 22,23 In this study, in which we aimed to translate in vitro the doses of ISDs used in clinical protocols, we tested a range of concentrations (TAC: 0.08-20 ng/mL; MPA: 0.08-2.5 µg/mL; mPr: 0.015-4 mg/mL) including both maximum and minimum therapeutic levels of ISDs, described in transplanted patients. [24][25][26] The doses leading to 50% of Treg viability (LD50) (2 ng/mL, 1 mg/mL and 0.5 mg/mL for TAC, MPA and mPr, respectively) were selected and used for the in vitro analysis ( Figure 1A-C).…”

Nonlinear relationship between enteric-coated mycophenolate sodium dose and mycophenolic acid exposure in Han kidney transplantation recipients

“…In our study, at day 7 post-transplantation, mean MPA CL increased from 7.80 to 54.30 L/h for tacrolimus-cotreated patients. This may be caused by a combination of improving renal function during the first weeks post-transplantation 25 .…”