Mycophenolic acid trough level monitoring in solid organ transplant recipients treated with mycophenolate mofetil: association with clinical outcome.

UIC Multiorgan Transplant Center, University of Illinois, Chicago, IL 60612, USA.
Current Medical Research and Opinion (Impact Factor: 2.37). 01/2007; 22(12):2355-64. DOI: 10.1185/030079906X148481
Source: PubMed

ABSTRACT Mycophenolate mofetil (MMF) is widely and successfully used in immunosuppressive regimens for the prophylaxis of organ rejection following transplantation. Conventionally, it is administered at a fixed dose without serial measurements of plasma concentrations of mycophenolic acid (MPA), the active metabolite. Recently, there has been an increased interest in therapeutic drug monitoring (TDM) of MMF therapy to optimize the benefit/risk index of the drug. Predose trough samples of MPA are considered most convenient and economic, thereby allowing an increased use of TDM in the transplant setting. However, the added value of TDM for MMF therapy is still under debate.
This paper reviews (based on a systematic PubMed and EMBASE search, 1995-June 2006) the current evidence of the usefulness and clinical relevance of MPA trough level monitoring during MMF therapy in solid organ transplantation.
Based on data available in the public domain, the contribution of MPA trough level monitoring during MMF therapy in solid organ transplant recipients remains unproven. Available studies have limitations and report conflicting results. There is a lack of prospective randomized trials, particularly in pediatric renal transplant recipients and in cardiac and liver transplantation. While there is a suggestion that there may be a relationship between efficacy and MPA trough levels, the majority of studies showed no correlation between MPA plasma concentrations and adverse effects. Based on current evidence, the adherence to presently recommended target ranges for MPA troughs in solid organ transplantation cannot assure an improved clinical outcome with MMF therapy. Whether MPA trough level monitoring leads to improved efficacy and less toxicity is currently subject to a large randomized trial; final results are eagerly awaited.

  • [Show abstract] [Hide abstract]
    ABSTRACT: The immunosuppressive drug mycophenolate mofetil (MMF), with mycophenolic acid (MPA) as active metabolite, is a nonnephrotoxic alternative to calcineurin inhibitors. Therapeutic drug monitoring (TDM) of MPA may improve clinical benefit from MMF therapy, especially in MMF monotherapy or with reduced dose of a calcineurin inhibitor. Limited data are available on TDM strategies for MPA in orthotopic liver transplantation (OLT). The authors here describe the pharmacokinetic (PK) behavior of MPA after OLT and developed a Bayesian limited sampling model for monitoring MMF after OLT. PK data were obtained from 57 stable patients, and trapezoidal area under the curve (AUC0-12h) was calculated. The effect of the covariates kidney function and serum albumin concentration was studied. A TDM strategy was developed based on individualized population PKs using Bayesian estimations and limited sampling models to predict the MPA AUC. A relationship between MMF dose and MPA AUC was found and a 8-fold apparent clearance range of MPA was observed at the same dose level. Significant relationships of albumin concentration and creatinine clearance with MPA plasma clearance were identified (respectively, r² = 0.12 and 0.24; P < 0.05). A model with limited sampling at 0, 0.5, 1, 2, and 3 hours after drug administration showed very good correlation with trapezoidal AUC0-12h with acceptable bias and precision (r² = 0.92, mean prediction error = 1, mean absolute prediction error = 13; P < 0.05). Remarkable variability of MPA clearance in stable OLT patients exists, which can be partially explained by the patients' albumin serum levels and creatinine clearance. Systemic exposure in these patients can be accurately assessed by the Bayesian limited sampling TDM strategy.
    Therapeutic drug monitoring 09/2013; · 2.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Abbreviations: ACR, acute cellular rejection; Alc., alcoholic; AUC 0-12 , area under the curve from 0 to 12 hours; BUN, blood urea nitrogen; BWT, body weight; C 0 MPA, plasma concentration of mycophenolic acid at
    Clinical and Molecular Hepatology. 08/2014; 20:291-299.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: There are wide individual differences in pharmacokinetic parameters of mycophenolate mofetil (MMF) among transplanted patients. Some studies have shown that single nucleotide polymorphisms (SNPs) of the Uridine Diphosphate Glucuronosyl Transferase1A9 (UGT1A9) are responsible for these differences in early days after transplantation. Therefore it was decided to evaluate the influence of UGT polymorphism on MMF pharmacokinetics among stable Iranian transplant patients. This was a cross sectional study from March 2008 through December 2008 in Imam Khomeini Hospital affiliated to the Tehran University of Medical Sciences in Iran. Blood samples were taken from 40 de novo stable Iranian renal transplant patients taking 2 g MMF daily with SrCr≤1.4 mg/dL with at least 3 months history of transplantation. Appropriate PCR and HPLC methods were used for the determination of SNPs and their impact on MPA pharmacokinetics. T-275A polymorphism occurred in 15% of patients, UGT1A9*3 occurred in 2.5% of patients. Carriers of T-275A polymorphism had significant lower MPA AUC 0-12 in comparison with non-carriers or wild type (73.3±17.8 g/h/mL vs. 110.8±31.1 μg/h/mL, p = 0.006). There was no significant difference in AUC 6-12 between the two groups although carriers of T-275A SNP had lower MPA AUC 6-12 (22.4±4.5 μg/h/mL vs. 26.8±10.2 μg/h/mL, p = 0.24). Cmax was lower in the carriers of (20.2±9.0 μg/mL vs. 37.2±12.5 μg/mL, p=0.004). There was no significant difference in C0 between two groups. (3.0±1.2 μg/mL vs. 3.9±1.6 μg/mL, p = 0.1). This study in Iranian stable transplanted patients shows that carriers of T-275A polymorphism had significantly lower MPA exposure compared to non-carriers.
    Iranian journal of pharmaceutical research (IJPR) 01/2013; 12(3):547-56. · 0.51 Impact Factor