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Mycophenolic Acid (mycophenolic + acid)

Distribution by Scientific Domains

Medical Sciences	76%
Chemistry	17%

Selected Abstracts

Preparative Enzymatic Synthesis of the Acylglucuronide of Mycophenolic Acid

ADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 6-7 2003
Matthias Kittelmann
Abstract The acylglucuronide (3) of mycophenolic acid (1) was enzymatically synthesised on a preparative scale (450,mg substrate) under optimised reaction conditions with 51% conversion. By screening 9 liver homogenates from 8 vertebrate species, it was shown that only with liver homogenate from horse as the catalyst were the acyl- (3) and the O -glucuronide (2) were formed in a ca. 1,:,1 ratio. With homogenates from other sources, the O -glucuronide (2) was produced in high excess. By optimising the concentration of the co-substrate UDP-glucuronic acid and the reaction temperature, the conversion to the acylglucuronide (3) was increased from initially 34 to 55% and the ratio of acyl- (3) to O -glucuronide (2) from 1.5,:,1 to 3.9,:,1. The reaction was also performed continuously in an enzyme membrane reactor, however, with lower conversion yield and therefore, higher specific UDP-glucuronic acid consumption. [source]

Therapeutic Monitoring of Mycophenolic Acid: Is There Clinical Utility?

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 11 2007
P. West-Thielke
Several studies have been done with mycophenolic acid drug monitoring. However, the critical utility still remains unclear. See also article by Le Meur et al in this issue on page 2496. [source]

Equivalent Pharmacokinetics of Mycophenolate Mofetil in African-American and Caucasian Male and Female Stable Renal Allograft Recipients

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 12 2003
Mark D. Pescovitz
African-American (AA) renal transplant recipients require higher doses of mycophenolate mofetil (MMF) than Caucasians. A hypothesized pharmacokinetic (PK) difference was tested in stable renal transplant recipients. Whole blood was collected before, and 20, 40 and 75 min, and 2, 3, 4, 6, 8 and 12 h after the MMF dose. Mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) were analyzed using HPLC. Analysis of variance was performed for the primary end-points of dose-adjusted PK parameters AUC0,12 and Cmax of MPA using log-transformed values. Differences between races and genders were estimated: 90% confidence intervals (CI) were calculated. Back-transformation gave estimates of the race and gender ratio and their CI. Equivalence of the groups was determined if the 90% confidence limits were included in the interval (0.80, 1.25). The calculated PK parameters were comparable among the four subgroups (Caucasian, AA, Male, Female). The 90% CIs for the ratio of dose-adjusted AUC0,12 of MPA between races were between 89.7 and 112.9%. There were no race, gender or race-by-gender effects (p-values = 0.196) nor differences between diabetics and nondiabetics. This study demonstrates that dosing requirement for MMF in AA and Caucasians is unlikely to be related to different exposures to MPA. [source]

Mycophenolic acid area under the curve correlates with disease activity in lupus patients treated with mycophenolate mofetil

ARTHRITIS & RHEUMATISM, Issue 7 2010
Noël Zahr
Objective Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil (MMF), which is widely used to treat systemic lupus erythematosus (SLE). In transplantation, MPA area under the plasma concentration,time curve from 0 to 12 hours (MPA AUC0,12) is correlated with clinical outcome. We undertook the present study to assess possible relationships between SLE activity and MPA AUC0,12. Methods Using a Bayesian estimator, MPA AUC0,12 was determined in 71 consecutive SLE patients (61 women and 10 men; mean ± SD age 34 ± 10 years) receiving a stable MMF dose. On the same day, SLE activity was assessed using the SLE Disease Activity Index (SLEDAI; active disease defined as a SLEDAI score ,6) and the British Isles Lupus Assessment Group (BILAG) index (active disease defined as BILAG A or B). Results Two groups were studied: patients with active SLE (mean ± SD SLEDAI score 11.6 ± 4.4; n = 26) and patients with inactive SLE (mean ± SD SLEDAI score 1.9 ± 1.6; n = 45). MPA AUC0,12 correlated weakly with the dose of MMF (r = 0.33, P = 0.005). Mean ± SD MPA AUC0,12 in the group with active SLE was significantly lower than that in the group with inactive SLE (26.8 ± 13.6 ,g.hour/ml versus 46.5 ± 16.3 ,g.hour/ml; P < 0.0001). MPA AUC0,12 was negatively correlated with the SLEDAI (r = ,0.64, P < 0.0001). In multivariate analysis, MPA AUC0,12 was the sole parameter associated with SLE activity (odds ratio 0.89 [95% confidence interval 0.83,0.96], P = 0.002). The MPA AUC0,12 threshold value of 35 ,g.hour/ml was associated with the lowest risk of active SLE. Conclusion Our data show that SLE activity is strongly correlated with MPA AUC0,12. An individualized dosing regimen of MMF, with a target AUC0,12 of 35 ,g.hour/ml, should be considered for SLE patients. [source]

Population pharmacokinetics of mycophenolic acid in children and young people undergoing blood or marrow and solid organ transplantation

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 4 2010
Lihua Zeng
WHAT IS ALREADY KNOWN ABOUT THIS PROJECT? , Mycophenolate mofetil (MMF) is an immunosuppressant drug used for the treatment and prevention of graft vs. host disease in blood or marrow transplantation and acute graft rejection in solid organ transplantation. , Mycophenolic acid (MPA) pharmacokinetics have not been thoroughly studied in paediatric blood or marrow transplant recipients and guidance for optimal dosing of mycophenolic acid in children is lacking. , Mycophenolic acid exhibits considerable inter- and intra-patient pharmacokinetic variability in adults and paediatric transplant recipients. , The AUC of mycophenolic acid over a 12 h dose interval at steady-state is generally agreed to be the most reliable metric associated with the risk of acute rejection. , Population pharmacokinetic analysis can utilize concentration information from both intensive sampling and sparse sampling to provide pharmacokinetic parameter estimates, estimates of inter- individual and intra-individual variability in these parameters and allows patient characteristics explaining inter-individual variability to be quantified. WHAT THIS STUDY ADDS , This study is one of the first investigations in which a population pharmacokinetic modelling approach was applied to assess the pharmacokinetics of both intravenous and oral MMF in children and young people undergoing blood or marrow and solid organ transplantation. , Bodyweight and concomitant ciclosporin were found to influence MPA pharmacokinetics. , This study evaluated current dosing strategies and found that they may be suboptimal for children weighing less than 10 kg. AIMS To characterize the population pharmacokinetics of mycophenolic acid (MPA) and evaluate dose regimens using a simulation approach and accepted therapeutic drug monitoring targets in children and young people undergoing blood or marrow, kidney and liver transplantation. METHODS MPA concentration,time data were collected using an age specific sampling protocol over 12 h. Some patients provided randomly timed but accurately recorded blood samples. Total and unbound MPA were measured by HPLC. NONMEM was employed to analyze MPA pharmacokinetic data. Simulations (n= 1000) were conducted to assess the suitability of the MPA dose regimens to maintain total MPA AUC(0,12 h) within the range 30 and 60 mg l,1 h associated with optimal outcome. RESULTS A two-compartment pharmacokinetic model with first-order elimination best described MPA concentration,time data. Population mean estimates of MPA clearance, inter-compartmental clearance, volumes of distribution in the central and peripheral compartments, absorption rate constant and bioavailability were 6.42 l h,1, 3.74 l h,1, 7.24 l, 16.8 l, 0.39 h,1 and 0.48, respectively. Inclusion of bodyweight and concomitant ciclosporin reduced the inter-individual variability in CL from 54.3% to 31.6%. Children with a bodyweight of 10 kg receiving standard MPA dose regimens achieve an MPA AUC below the target range suggesting they may be at a greater risk of acute rejection. CONCLUSIONS The population pharmacokinetic model for MPA can be used to explore dosing guidelines for safe and effective immunotherapy in children and young people undergoing transplantation. [source]

A simple and rapid CZE method for the analysis of mycophenolic acid and its phenol glucuronide metabolite in human serum,

ELECTROPHORESIS, Issue 17 2008
Kaname Ohyama
Abstract A simple and rapid capillary electrophoretic method was developed for simultaneous determination of mycophenolic acid and its metabolite, phenol glucuronide, in human serum. The sample preparation in the proposed method required only the precipitation by acetonitrile. Separation was performed by capillary zone electrophoresis using 75,mM phosphate buffer (pH 7.5) as running buffer, an applied voltage of 10,kV, and UV detection at 217,nm. Each serum sample analysis was completed within 15,min. The optimized method demonstrated good performance concerning specificity, linearity (r>0.9955), accuracy (95.9,113%), precision (<6.4%) and enough sensitivity for therapeutic drug monitoring. This method was successfully applied to measurements of mycophenolic acid and mycophenolic acid glucuronide in renal transplant patient samples and was a useful alternative to high-performance liquid chromatography-based methods. [source]

Preparative Enzymatic Synthesis of the Acylglucuronide of Mycophenolic Acid

Validation of limited sampling strategy for the estimation of mycophenolic acid exposure in Chinese adult liver transplant recipients

LIVER TRANSPLANTATION, Issue 12 2007
Chen Hao
Mycophenolate mofetil (MMF) is indicated as immunosuppressive therapy in liver transplantation. The abbreviated models for the estimation of mycophenolic acid (MPA) area under the concentration-time curve (AUC) have been established by limited sampling strategies (LSSs) in adult liver transplant recipients. In the current study, the performance of the abbreviated models to predict MPA exposure was validated in an independent group of patients. A total of 30 MPA pharmacokinetic profiles from 30 liver transplant recipients receiving MMF in combination with tacrolimus were used to compare 8 models' performance with a full 10 time-point MPA-AUC. Linear regression analysis and Bland-Altman analysis were used to compare the estimated MPA-AUC0-12h from each model against the measured MPA-AUC0-12h. A wide range of agreement was shown when estimated MPA-AUC0-12h was compared with measured MPA-AUC0-12h, and the range of coefficient of determination (r2) was from 0.479 to 0.936. The model based on MPA pharmacokinetic parameters C1h, C2h, C6h, and C8h had the best ability to predict measured MPA-AUC0-12h, with the best coefficient of determination (r2 = 0.936), the excellent prediction bias (2.18%), the best prediction precision (5.11%), and the best prediction variation (2SD = ±7.88 mg · h/L). However, the model based on MPA pharmacokinetic sampling time points C1h, C2h, and C4h was more suitable when concerned with clinical convenience, which had shorter sampling interval, an excellent coefficient of determination (r2 = 0.795), an excellent prediction bias (3.48%), an acceptable prediction precision (14.37%), and a good prediction variation (2SD = ±13.23 mg · h/L). Measured MPA-AUC0-12h could be best predicted by using MPA pharmacokinetic parameters C1h, C2h, C6h, and C8h. The model based on MPA pharmacokinetic parameters C1h, C2h, and C4h was more feasible in clinical application. Liver Transpl 13:1684,1693, 2007. © 2007 AASLD. [source]

Conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in liver transplant patients presenting gastrointestinal disorders: A pilot study

LIVER TRANSPLANTATION, Issue 9 2006
Jérôme Dumortier
Gastrointestinal (GI) disorders are one of the main adverse events in patients treated by mycophenolic acid (MPA). The aim of this prospective study was to evaluate the effect of conversion from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS) in liver transplant patients presenting GI side-effects Since January 2003, stable liver transplant patients receiving MMF and presenting GI disorders, without evidence of other origin than MMF were enrolled. Conversion was performed without a washout period at an equimolar daily dosage. Thirty-six patients were included after a median delay of 45 months after liver transplantation (LT) (16 women and 20 men, median age of 47 years). Diarrhoea was the main clinical symptom (n = 28, 77.7%). At the time of inclusion, patients were treated with MMF since 18 months (range 3-28) and GI disorders were known for 9 months (range 3-12). After a median follow-up of 12 months after conversion, GI disorders were resolved in 20 patients (55%), improved in 6 patients (17%) and not modified or worsened in 10 patients (28%). Our results strongly suggest that conversion from MMF to EC-MPS in liver transplant patients can improve gastrointestinal disorders in a majority of the patients, and therefore might be considered as the best therapeutic option. Liver Transpl 12:1342-1346, 2006. © 2006 AASLD. [source]

Rapamycin and MPA, But Not CsA, Impair Human NK Cell Cytotoxicity Due to Differential Effects on NK Cell Phenotype

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2010
D. N. Eissens
Cyclosporin A (CsA), rapamycin (Rapa) and mycophenolic acid (MPA) are frequently used for GVHD prophylaxis and treatment after allogeneic stem cell transplantation (SCT). As NK cells have received great interest for immunotherapeutic applications in SCT, we analyzed the effects of these drugs on human cytokine-stimulated NK cells in vitro. Growth-kinetics of CsA-treated cultures were marginally affected, whereas MPA and Rapa severely prevented the outgrowth of CD56bright NK cells. Single-cell analysis of NK cell receptors using 10-color flow cytometry, revealed that CsA-treated NK cells gained a similar expression profile as cytokine-stimulated control NK cells, mostly representing NKG2A+KIR,NCR+ cells. In contrast, MPA and Rapa inhibited the acquisition of NKG2A and NCR expression and NK cells maintained an overall NKG2A,KIR+NCR+/, phenotype. This was reflected in the cytolytic activity, as MPA- and Rapa-treated NK cells, in contrast to CsA-treated NK cells, lost their cytotoxicity against K562 target cells. Upon target encounter, IFN-, production was not only impaired by MPA and Rapa, but also by CsA. Overall, these results demonstrate that CsA, MPA and Rapa each have distinct effects on NK cell phenotype and function, which may have important implications for NK cell function in vivo after transplantation. [source]

Everolimus Plus Reduced-Exposure CsA versus Mycophenolic Acid Plus Standard-Exposure CsA in Renal-Transplant Recipients

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 6 2010
H. Tedesco Silva Jr.
Everolimus allows calcineurin-inhibitor reduction without loss of efficacy and may improve renal-transplant outcomes. In a 24-month, open-label study, 833 de novo renal-transplant recipients were randomized to everolimus 1.5 or 3.0 mg/day (target troughs 3,8 and 6,12 ng/mL, respectively) with reduced-exposure CsA, or mycophenolic acid (MPA) 1.44 g/day plus standard-exposure CsA. Patients received basiliximab ± corticosteroids. The primary endpoint was composite efficacy failure (treated biopsy-proven acute rejection, graft loss, death or loss to follow-up) and the main safety endpoint was renal function (estimated glomerular filtration rate [eGFR], by Modification of Diet in Renal Disease [MDRD]) at Month 12 (last-observation-carried-forward analyses). Month 12 efficacy failure rates were noninferior in the everolimus 1.5 mg (25.3%) and 3.0 mg (21.9%) versus MPA (24.2%) groups. Mean eGFR at Month 12 was noninferior in the everolimus groups versus the MPA group (54.6 and 51.3 vs 52.2 mL/min/1.73 m2 in the everolimus 1.5 mg, 3.0 mg and MPA groups, respectively; 95% confidence intervals for everolimus 1.5 mg and 3.0 mg vs MPA: ,1.7, 6.4 and ,5.0, 3.2, respectively). The overall incidence of adverse events was comparable between groups. The use of everolimus with progressive reduction in CsA exposure, up to 60% at 1 year, resulted in similar efficacy and renal function compared with standard-exposure CsA plus MPA. [source]

Sotrastaurin, a Novel Small Molecule Inhibiting Protein Kinase C: First Clinical Results in Renal-Transplant Recipients

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2010
K. Budde
Sotrastaurin, a novel protein-kinase-C inhibitor, blocks early T-cell activation. In this 12-month, Phase II study, de novo renal-transplant patients were randomized to sotrastaurin (200 mg b.i.d.) + standard-exposure tacrolimus (SET) or reduced-exposure tacrolimus (RET) (SET: n = 76; RET: n = 66), or control (SET + mycophenolic acid [MPA, 720 mg b.i.d.]; n = 74). In both sotrastaurin groups, patients were converted from tacrolimus to MPA after Month 3, achieving calcineurin inhibitor-free immunosuppression. The primary endpoint was composite efficacy failure (treated biopsy-proven acute rejection, graft loss, death or loss to follow-up). The key secondary endpoint was glomerular filtration rate (GFR). Composite efficacy failure rates were: 4.1%, 5.4% and 1.5% at Month 3 (preconversion) and 7.8%, 44.8% and 34.1% at study end in the control, sotrastaurin + SET and sotrastaurin + RET groups, respectively; these results led to premature study discontinuation. Median GFR at Month 6 was: 57.0, 53.0 and 60.0 mL/min/1.73 m2, respectively. Study-drug discontinuations due to adverse events occurred in 16.2%, 18.4% and 12.1%, respectively. Leukopenia and neutropenia occurred more frequently preconversion in control versus sotrastaurin groups: 13.7%, 5.6%, and 4.6%; and 11.1%, 4.3% and 3.1%, respectively. The initial sotrastaurin + tacrolimus regimen was efficacious and well tolerated but the postconversion sotrastaurin + MPA regimen showed inadequate efficacy. Longer-term evaluation of sotrastaurin + tacrolimus is warranted. [source]

Incidence, Risk Factors and Clinical Consequences of Neutropenia Following Kidney Transplantation: A Retrospective Study

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2009
L. Zafrani
Neutropenic episodes in kidney transplant patients are poorly characterized. In this retrospective study, neutropenia was experienced by 112/395 patients (28%) during the first year posttransplant. The only factor found to be significantly associated with the occurrence of neutropenia was combined tacrolimus-mycophenolate therapy (p < 0.001). Neutropenic patients experienced more bacterial infections (43% vs. 32%, p = 0.04). Grade of neutropenia correlated with the global risk of infection. Discontinuation of mycophenolic acid (MPA) due to neutropenia was associated with an increased incidence of acute rejection (odds ratios per day 1.11, 95% confidence intervals 1.02,1.22) but not with reduced renal function at 1 year. The time from onset of neutropenia to MPA discontinuation correlated with the duration of neutropenia. Granulocyte colony-stimulating factor (G-CSF) administration was safe and effective in severely neutropenic kidney graft recipients, with absolute neutrophil count >1000/,L achieved in a mean of 1.5±0.5 days. Neutropenia is an important and frequent laboratory finding that may exert a significant influence on outcomes in kidney transplantation. As well as leading to an increased incidence of infection, it is associated with a higher rate of allograft rejection if MPA is discontinued for >6 days (p = 0.02). G-CSF accelerates recovery of neutropenia and may be a good therapeutic alternative for severely neutropenic patients. [source]

Mycophenolate Blood Level Monitoring: Recent Progress

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 7 2009
T. Van Gelder
The concentration,effect relationship for mycophenolic acid (MPA), and the high variability in MPA concentrations in patients on standard dose mycophenolate mofetil (MMF) therapy, for some centers has provided enough evidence to implement therapeutic drug monitoring (TDM) for MMF in daily practice. Two randomized trials Adaption de Posologie du MMF en Greffe Renale (APOMYGRE) and fixed-dose versus concentration controlled (FDCC) investigated the added benefit of TDM for MMF in renal transplant recipients. The APOMYGRE study showed a significant reduction in the incidence of acute rejection in concentration-controlled patients, while the FDCC study had a negative outcome, despite a similar study design. Although it was expected that these prospective trials would give the final answer to the question of whether or not TDM for MMF would be of benefit, it seems that the studies have not had much impact on patient management. Several trials have shown the importance of early adequate exposure to MPA in the first week after transplantation. As it will be hard to improve MPA exposure with TDM, this early, ongoing study now investigates the use of an increased starting dose. The increased starting dose will avoid underexposure to MPA in higher proportions of patients shortly after transplantation but may result in more toxicity in patients with MPA exposures exceeding the upper threshold of the therapeutic window. [source]

Fixed- or Controlled-Dose Mycophenolate Mofetil with Standard- or Reduced-Dose Calcineurin Inhibitors: The Opticept Trial

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 7 2009
R. S. Gaston
Mycophenolate mofetil (MMF) was developed with cyclosporine as a fixed-dose immunosuppressant. More recent data indicate a relationship between mycophenolic acid (MPA) exposure in individuals and clinical endpoints of rejection and toxicity. This 2-year, open-label, randomized, multicenter trial compared the efficacy and safety of concentration-controlled MMF (MMFCC) dosing with a fixed-dose regimen in 720 kidney recipients. Patients received either (A) MMFCC and reduced-level calcineurin inhibitor (MMFCC/CNIRL); (B) MMFCC and standard-level CNI (MMFCC/CNISL); or (C) fixed-dose MMF and CNISL (MMFFD/CNISL). Antibody induction and steroid use were according to center practice. The primary endpoint was noninferiority (,= 0.05) of group A versus group C for treatment failure (including biopsy-proven acute rejection [BPAR], graft loss and death) at 1 year. Although mean CNI trough levels in group A did not reach the prespecified targets, they were statistically lower than those in groups B and C (p , 0.01 for each comparison). BPAR rates (8.5%) were low across groups. Group A had 19% fewer treatment failures (23% vs. 28%, p = 0.18). MMF doses were highest (p < 0.05), with withdrawals for adverse events the fewest (p = 0.02), in group A. Of the 80% of subjects taking tacrolimus (Tac), those with higher MPA exposure had significantly less rejection (p < 0.001) and diarrhea correlated with Tac, but not with MPA levels. Thus, MMFCC with low-dose CNI resulted in outcomes not inferior to those with standard CNI exposure and MMFFD, indicating potential utility of MMFCC in CNI-sparing regimens. [source]

Proton Pump Inhibitors Reduce Mycophenolate Exposure in Heart Transplant Recipients,A Prospective Case-Controlled Study

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 7 2009
S. Kofler
This prospective study investigates the impact of proton pump inhibitors (PPI) on mycophenolic acid (MPA) pharmacokinetics in heart transplant recipients receiving mycophenolate mofetil (MMF) and tacrolimus. MPA plasma concentrations at baseline (C0 h), 30 min (C0.5 h), 1(C1 h) and 2 h (C2 h) were obtained by high-performance liquid chromatography (HPLC) in 22 patients treated with pantoprazole 40 mg and MMF 2000 mg. Measurements were repeated 1 month after pantoprazole withdrawal. A four-point limited-sampling strategy was applied to calculate the MPA area under the curve (MPA-AUC). Predose MPA concentrations with PPI were 2.6 ± 1.6 mg/L versus 3.4 ± 2.7 mg/L without PPI (p = ns). Postdose MPA concentrations were lower with PPI at C0.5 h (8.3 ± 5.7 mg/L vs. 18.3 ± 11.3 mg/L, p = 0.001) and C1 h (10.0 ± 5.6 mg/L vs. 15.8 ± 8.4 mg/L, p = 0.004), without significant differences at C2 h (8.3 ± 6.5 mg/L vs. 7.6 ± 3.9 mg/L). The MPA-AUC was significantly lower with PPI medication (51.2 ± 26.6 mg × h/L vs. 68.7 ± 30.3 mg × h/L; p = 0.003). The maximum concentration of MPA (MPA-Cmax) was lower (12.2 ± 7.5 mg/L vs. 20.6 ± 9.3 mg/L; p = 0.001) and the time to reach MPA-Cmax (tmax) was longer with PPI (60.0 ± 27.8 min vs. 46.4 ± 22.2 min; p = 0.05). This is the first study to document an important drug interaction between a widely used immunosuppressive agent and a class of drugs frequently used in transplant patients. This interaction results in a decreased MMF drug exposure which may lead to patients having a higher risk for acute rejection and transplant vasculopathy. [source]

Prolonged Insulin Independence After Islet Allotransplants in Recipients with Type 1 Diabetes

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 11 2008
M. D. Bellin
We sought to determine the long-term outcomes in type 1 diabetic recipients of intraportal alloislet transplants on a modified immunosuppressive protocol. Six recipients with hypoglycemia unawareness received one to two islet infusions. Induction therapy was with antithymocyte globulin (ATG) plus etanercept for tumor necrosis factor-, blockade. Recipients received cyclosporine and everolimus for maintenance immunosuppression for the first year posttransplant, with mycophenolic acid or mycophenolate mofetil subsequently substituted for everolimus. Recipients have been followed for 1173 ± 270 days since their last infusion for islet graft function (insulin independence, hemoglobin A1c levels and C-peptide production) and for adverse events associated with the study protocol. Of the six recipients, five were insulin-independent at 1 year, and four continue to be insulin-independent at a mean of 3.4 ± 0.4 years posttransplant. None of the six recipients experienced recurrence of severe hypoglycemia. Measured glomerular filtration rate decreased from 110.5 ± 21.2 mL/min/1.73 m2 pretransplant to 82.6 ±19.1 mL/min/1.73 m2 at 1 year posttransplant. In conclusion, islet transplants restored insulin independence for a mean of >3 years in four of six recipients treated with ATG and etanercept induction therapy and with cyclosporine and, initially, everolimus for maintenance. Our results suggest this immunosuppressive protocol may allow long-term graft survival. [source]

Plasma Concentrations of Mycophenolic Acid Acyl Glucuronide Are Not Associated with Diarrhea in Renal Transplant Recipients

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 7 2007
T. Heller
The aim of this study was to determine whether plasma concentrations of the acyl (AcMPAG) and phenolic (MPAG) glucuronide metabolites of mycophenolic acid (MPA) were related to diarrhoea in renal transplant patients on mycophenolate mofetil (MMF) with cyclosporine (CsA) or tacrolimus (TCL). Blood samples (0, 30, 120 min) were taken at days 3, 10, week 4, months 3, 6 and 12 for determination of MPA, MPAG and AcMPAG. MPA-AUC was estimated using validated algorithms. Two hour AUCs were calculated for MPAG and AcMPAG. Immunosuppressive therapy consisted of CsA/MMF (n= 110) and of TCL/MMF (n= 180). In 70/290 (24%) patients 86 episodes of diarrhoea were recorded during 12 months. Significantly more patients on TCL (31.1%) suffered from diarrhea compared to CsA (12.7%). MMF dose, MPA-AUC and the 2 h AUCs of MPAG and AcMPAG did not differ between patients with and without diarrhoea. Plasma AcMPAG and MPAG concentrations were substantially higher in patients on CsA compared with TCL, while MPA-AUC was lower in the former group. These data support the concept that CsA inhibits the biliary excretion of MPAG and AcMPAG, thereby potentially reducing the risk of intestinal injury through enterohepatic recycling of MPA and its metabolites. [source]

Pharmacokinetic and Pharmacodynamic Comparison of Enteric-Coated Mycophenolate Sodium and Mycophenolate Mofetil in Maintenance Renal Transplant Patients

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 4 2007
K. Budde
The aim of this single-center crossover substudy was to assess pharmacokinetics and pharmacodynamics [inosine 5,-monophosphate dehydrogenase (IMPDH) activity] of enteric-coated mycophenolate sodium (EC-MPS) and mycophenolate mofetil (MMF) at steady-state conditions. Stable maintenance renal transplant patients on 1 g MMF b.i.d. participating in a double-blind, multicenter study, were randomized to receive EC-MPS (720 mg b.i.d.) or continue receiving MMF (1000 mg b.i.d.) for 12 months. Thereafter, all patients (n = 18) received 720 mg EC-MPS b.i.d. Area under the plasma mycophenolic acid (MPA) concentration,time curve with EC-MPS (57.4 ± 15.0 ,g h/mL) fulfilled bioequivalence criteria (geometric mean 0.98 (90% CI: 0.87,1.11) compared to MMF (58.4 ± 14.1 ,g h/mL). Consistent with the delayed release characteristics of EC-MPS, peak MPA concentration (geometric mean 0.89; 90% CI: 0.70,1.13) occurred approximately 0.5 h later (p < 0.05) and predose MPA levels (geometric mean 2.10; 90% CI: 1.51,2.91) were higher and more variable, not fulfilling bioequivalence criteria. IMPDH activity inversely followed MPA concentrations and was inhibited to a similar degree (approximately 85%) by both formulations. The calculated value for 50% IMPDH inhibition was identical for both drugs. In conclusion, equimolar doses of EC-MPS and MMF produce equivalent MPA exposure, while the delayed release formulation of EC-MPS exhibits more variable predose levels and Tmax. Overall, IMPDH activity reflected MPA pharmacokinetics. [source]

Influence of Co-Medication with Sirolimus or Cyclosporine on Mycophenolic Acid Pharmacokinetics in Kidney Transplantation

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 12 2005
D. Cattaneo
The pharmacokinetics of mycophenolic acid (MPA),the active metabolite of mycophenolate mofetil (MMF),is significantly influenced by co-medications. The impact of sirolimus on daily MPA exposure, however, has not been investigated so far. As a part of the study aimed at investigating the efficacy of Campath-1H induction therapy in a steroid-free regimen in kidney transplantation, MPA plasma levels were serially measured in 21 patients treated with low-dose sirolimus (SRL) or low-dose CsA both in addition to low-dose MMF over 12 months post-operatively. Full pharmacokinetic profiles were compared at month 6 and 12 post-surgery. Mean dose-adjusted MPA trough levels were 4.4-fold higher in patients on combined SRL and MMF than in those given CsA and MMF. Pharmacokinetic studies demonstrated that mean MPA Cmax and Tmax were comparable in the two groups, while mean MPA AUC0-12 was higher in SRL than CsA treated patients. The pharmacokinetic profile of SRL- but not of CsA-group showed a second peak consistent with the enterohepatic recirculation of MPA. These findings suggest that SRL and CsA have different effects on MPA metabolism and/or excretion eventually affecting its immunosuppressive property and/or toxicity. CsA, but not SRL, inhibits MPA enterohepatic recirculation, reducing MPA daily exposure. [source]

Anti-DNA antibody induction of protein kinase C phosphorylation and fibronectin synthesis in human and murine lupus and the effect of mycophenolic acid

ARTHRITIS & RHEUMATISM, Issue 7 2009
Susan Yung
Objective To examine fibronectin (FN) expression in human lupus nephritis and the effect of anti-DNA antibodies on transforming growth factor ,1 (TGF,1) and FN synthesis in cultured human mesangial cells. The effects of mycophenolic acid (MPA) on this pathway, and the effects of mycophenolate mofetil (MMF) treatment in (NZB × NZW)F1/J mice were also studied. Methods Immunohistochemical analyses of renal biopsy samples from patients with active diffuse proliferative lupus nephritis were performed. Cultured human mesangial cells were incubated with human polyclonal anti-DNA antibodies, with or without MPA. (NZB × NZW)F1/J mice with active nephritis were randomized to receive either MMF (100 mg/kg/day) or vehicle treatment for 12 weeks. Results Glomerular FN expression was increased in patients with lupus nephritis, and it colocalized with IgG deposition. Anti-DNA antibodies induced protein kinase C, (PKC,), PKC,I, and PKC,II activation, increased levels of bioactive TGF,1, and increased FN synthesis in human mesangial cells (P < 0.001 for each comparison versus control conditions). Pretreatment of anti-DNA antibodies with exogenous DNA reduced their cellular binding and abrogated their induction of TGF,1 and FN synthesis. Inhibition of PKC activation in human mesangial cells prior to anti-DNA antibody stimulation had no effect on cell proliferation, but resulted in significantly reduced antibody-mediated TGF,1 secretion and FN synthesis. MPA treatment down-regulated PKC,, PKC,I, and PKC,II phosphorylation, reduced levels of TGF,1 bioactivation, and decreased FN synthesis and deposition into the extracellular matrix. MMF treatment in (NZB × NZW)F1/J mice resulted in a reduction in glomerular IgG deposition, PKC activation, and FN expression, as well as an amelioration of proteinuria. Conclusion Human polyclonal anti-DNA antibodies induce TGF,1 and FN synthesis in human mesangial cells through PKC activation, which is inhibited by MPA. [source]

Crystallization and preliminary X-ray analysis of mycophenolic acid-resistant and mycophenolic acid-sensitive forms of IMP dehydrogenase from the human fungal pathogen Cryptococcus

ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 9 2010
Carl A. Morrow
Fungal human pathogens such as Cryptococcus neoformans are becoming an increasingly prevalent cause of human morbidity and mortality owing to the increasing numbers of susceptible individuals. The few antimycotics available to combat these pathogens usually target fungal-specific cell-wall or membrane-related components; however, the number of these targets is limited. In the search for new targets and lead compounds, C. neoformans has been found to be susceptible to mycophenolic acid through its target inosine monophosphate dehydrogenase (IMPDH); in contrast, a rare subtype of the related C. gattii is naturally resistant. Here, the expression, purification, crystallization and preliminary crystallographic analysis of IMPDH complexed with IMP and NAD+ is reported for both of these Cryptococcus species. The crystals of IMPDH from both sources had the symmetry of the tetragonal space group I422 and diffracted to a resolution of 2.5,Å for C. neoformans and 2.6,Å for C. gattii. [source]

HPLC-UV assay for monitoring total and unbound mycophenolic acid concentrations in children

BIOMEDICAL CHROMATOGRAPHY, Issue 1 2009
L. Zeng
Abstract A simple, accurate and sensitive HPLC method was developed for measuring total and unbound mycophenolic acid (MPA) in human plasma. Total MPA was extracted by protein precipitation and ultrafiltration was used to assess unbound MPA concentrations. The supernatant (20 µL) or ultrafiltrate (100 µL) was injected onto a C18 HPLC column with a mobile phase of 0.05 m sodium phosphate buffer (pH 2.31),acetonitrile (55:45, v/v for total MPA; 50:50 for unbound MPA) with UV detection at 254 nm. The extraction recovery was over 93% and reproducible. The assay was linear over the concentration range of 0.07,50 mg/L for total MPA and 4,1500 µg/L for unbound MPA. Intra- and inter-day assay reproducibility was less than 10%. Detection limits were 0.04 mg/L and 2 µg/L for total and unbound MPA, respectively. The assay utility was established in samples collected from five paediatric bone marrow transplant recipients who were receiving intravenous doses of mycophenolate mofetil. In these patients MPA concentrations ranged from 0.07 to 7.83 mg/L and unbound drug concentrations ranged from 2.1 to 107.5 µg/L. This method can be effectively applied to MPA pharmacokinetics in paediatric patients. Copyright © 2008 John Wiley & Sons, Ltd. [source]

Simultaneous determination of mycophenolic acid and valproic acid based on derivatization by high-performance liquid chromatography with fluorescence detection

BIOMEDICAL CHROMATOGRAPHY, Issue 4 2006
Yan Zhong
Abstract A reliable and validated reversed-phase high-performance liquid chromatography (HPLC) method using fluorescence detection is reported for the simultaneous quantitation of mycophenolic acid (MPA) and valproic acid (VPA) in human plasma. The method is based on the pre-column derivatization of valproic acid with 4-bromomethyl-6, 7-dimethoxycoumarin (BrMMC) and online solvatochromism of MPA by pH adjustment. The linear calibration range was 0.50,30 µg/mL for MPA and 5.00,150 µg/mL for VPA. The relative standard deviations of the method of intra- and inter-day analyses (n = 6) were below 6.5 and 6.7% for MPA, and 5.8 and 6.3% for VPA, respectively. Dichloromethane was used for the simultaneous extraction of MPA and VPA from acidified plasma. This reliable method can be applied in the analysis of MPA and VPA in human plasma using only a small volume (100 µL). Copyright © 2005 John Wiley & Sons, Ltd. [source]

Population pharmacokinetics of mycophenolic acid in children and young people undergoing blood or marrow and solid organ transplantation

Risk of diarrhoea in a long-term cohort of renal transplant patients given mycophenolate mofetil: the significant role of the UGT1A8*2 variant allele

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2010
Jean-Baptiste Woillard
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Mycophenolate mofetil (MMF), the most widely used drug in allograft transplantation, is subject to hepatic and intestinal glucuronidation and entero-hepatic cycling. , Diarrhoea is its most frequent adverse event leading to non-compliance, treatment interruption and ultimately to an increased rate of acute rejection. , Cyclosporin reduces the biliary excretion of mycophenolate metabolites, presumably by inhibiting the efflux transporter MRP2. , When combined with MMF, cyclosporin reduces the incidence of diarrhoea, suggesting the role played by biliary excretion of mycophenolate glucuronides in this adverse event. WHAT THIS STUDY ADDS , In a long-term cohort of renal transplant patients on MMF, the two factors significantly associated with a reduced incidence of diarrhoea were the co-medication with cyclosporin (as opposed to tacrolimus or sirolimus) and the *2 variant allele of the intestinal UGT1A8. , Polymorphisms in the other UDP-glucuronosyl-transferases and MRP2 were not significant. AIM In renal transplant patients given mycophenolate mofetil (MMF), we investigated the relationship between the digestive adverse events and polymorphisms in the UGT genes involved in mycophenolic acid (MPA) intestinal metabolism and biliary excretion of its phase II metabolites. METHODS Clinical data and DNA from 256 patients transplanted between 1996 and 2006 and given MMF with cyclosporin (CsA, n = 185), tacrolimus (TAC, n = 49) or sirolimus (SIR, n = 22), were retrospectively analysed. The relationships between diarrhoea and polymorphisms in UGT1A8 (*2; 518C>G, *3; 830G>A), UGT1A7 (622C>T), UGT1A9 (,275T>A), UGT2B7 (,840G>A) and ABCC2 (,24C>T, 3972C>T) or the co-administered immunosuppressant were investigated using the Cox proportional hazard model. RESULTS Multivariate analysis showed that patients on TAC or SIR had a 2.8 higher risk of diarrhoea than patients on CsA (HR = 2.809; 95%CI (1.730, 4.545); P < 0.0001) and that non-carriers of the UGT1A8*2 allele (CC518 genotype) had a higher risk of diarrhoea than carriers (C518G and 518GG genotypes) (HR = 1.876; 95%CI (1.109, 3.175); P = 0.0192). When patients were divided according to the immunosuppressive co-treatment, a significant effect of UGT1A8*2 was found in those co-treated with CsA (HR = 2.414; 95%CI (1.089, 5.354); P = 0.0301) but not TAC or SIR (P = 0.4331). CONCLUSION These results suggest that a possible inhibition of biliary excretion of MPA metabolites by CsA and a decreased intestinal production of these metabolites in UGT1A8*2 carriers may be protective factors against MMF-induced diarrhoea. [source]

Pharmacokinetics, safety, and efficacy of mycophenolate mofetil in combination with sirolimus or ciclosporin in renal transplant patients

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2007
Mark D. Pescovitz
Aims To compare the pharmacokinetics of mycophenolic acid (MPA) and its metabolite (MPAG) when mycophenolate mofetil (MMF) is administered in combination with sirolimus or ciclosporin (CsA) in renal allograft recipients. Safety and efficacy (biopsy-proven acute rejection (BPAR)) were also assessed. Methods Patients (n = 45) were randomized 2 : 1 to receive treatment with sirolimus (n = 30; dosed to maintain trough concentrations of 10,25 ng ml,1 until week 8, and then 8,15 ng ml,1 thereafter) or CsA (n = 15; administered as per centre practice) both in combination with daclizumab, oral MMF and corticosteroids. Pharmacokinetic assessments were performed at day 7, week 4, and months 3 and 6 post-transplant. The primary endpoint was the AUC(0,12 h) for MPA and MPAG. The pharmacokinetics of sirolimus were also assessed. Results MPA exposure was 39,50% lower (month 6 mean AUC(0,12 h) (95%CI): 40.4 (33.8, 47.0) vs. 68.5 (54.9, 82.0) µg ml,1 h) and MPAG exposure was 25,52% higher (722 (607, 838) vs. 485 (402, 569) µg ml,1 h at month 6) in the presence of CsA compared with sirolimus across visits. BPAR was 40.0% with sirolimus and 13.3% with CsA. The incidence of hypertension, tremors and hirsutism was higher with CsA than with sirolimus, while the incidence of diarrhoea, hyperlipidaemia and impaired wound closure was higher with sirolimus. No deaths, malignancies or graft losses were reported. Conclusions Co-administration of sirolimus with MMF led to greater MPA exposure, but lower MPAG exposure, than co-administration with CsA. As rejection rates were higher in the absence of CsA, further study of calcineurin inhibitor-free regimens is required before general recommendations can be made. [source]

Mycophenolate mofetil in uveitis

ACTA OPHTHALMOLOGICA, Issue 2009
P NERI
Purpose To review the current Literature and to describe the experience of a tertiary referral centre on the use of mycophenolate mofetil (MMF) treatment in uveitis. Methods The current literature is reviewed and the experience of a tertiary referral centre is reported. Results The long-lasting remission in several systemic diseases, such as Crohn's disease, severe atopic dermatitis, Wegener's granulomatosis and microscopic polyangioitis, rheumatoid arthritis, pemphigus vugaris, and psoriasis, have been proven. Recent publications have have recently confirmed the satisfactory control of uveitis with MMF in a large cohort of patients. Moreover, the long-term control of cystoid macular oedema (CMO) unresponsive to the traditional therapy has been described, as well as for the choroidal neovascularization (CNV). Conclusion Non-infectious uveitis is one of the leading causes of visual impairment in ophthalmology. Steroids can control such disease, even though a long-term treatment is not recommended: several complications, such as high blood sugar level, osteoporosis, blood cell abnormalities, cataract and glaucoma, can occur. MMF is a reversible, non competitive, selective inhibitor of the de-novo pathway of purine synthesis; mycophenolic acid has a strong effect to Type II isoform of inosine monophosphate dehydrogenase enzyme, providing a stronger cytostatic effect on lymphocytes than on other cells types, with minor action to Type I expressed in most other cells. The specific action of MMF on selected targets makes it a promising drug for the control of non-infectious intraocular inflammations. [source]

Factors affecting kidney-transplant outcome in recipients with lupus nephritis

CLINICAL TRANSPLANTATION, Issue 3 2008
Hongying Tang
Abstract:, Background:, Factors associated with outcome in renal transplant recipients with lupus nephritis have not been studied. Methods:, Using the data from the United States Renal Data System of patients transplanted between January 1, 1995 through December 31, 2002 (and followed through December 31, 2003) (n = 2882), we performed a retrospective analysis of factors associated with long-term death-censored graft survival and recipient survival. Results:, The number of pretransplant pregnancies incrementally increased the risk of graft failure [hazard ratio (HR) 1.54, p < 0.05] in the entire subgroup of females and in the subgroup of recipients aged 25,35 yr. Recipient and donor age had an association with both the risk of graft failure (HR 0.96, p < 0.001; HR 1.01, p < 0.005) and recipient death (HR 1.04, p < 0.001; HR 1.01, p < 0.05). Greater graft-failure risk accompanied increased recipient weight (HR 1.01, p < 0.001); African Americans compared with whites (HR 1.55, p < 0.001); greater Charlson comorbidity index (HR 1.17, p < 0.05); and greater panel reactive antibody (PRA) levels (HR 1.06, p < 0.001). Pretransplant peritoneal dialysis as the predominant modality had an association with decreased risk of graft failure (HR 0.49, p < 0.001), while prior transplantation was associated with greater risk of graft failure and recipient death (HR 2.29, p < 0.001; HR 3.59, p < 0.001, respectively) compared with hemodialysis (HD). The number of matched human leukocyte antigens (HLA) antigens and living donors (HR 0.92, p < 0.05; HR 0.64, p < 0.001, respectively) was associated with decreased risk of graft failure. Increased risk of graft failure and recipient death was associated with nonuse of calcineurin inhibitors (HR 1.89, p < 0.005; HR 1.80, p < 0.005) and mycophenolic acid (MPA) (including mycophenolate mofetil and MPA) or azathioprine (HR 1.41, p < 0.05; HR 1.66, p < 0.01). Using both cyclosporine and tacrolimus was associated with increased risk of graft failure (HR 2.09, p < 0.05). Using MPA is associated with greater risk of recipient death compared with azathioprine (HR 1.47, p < 0.05). Conclusion:, In renal transplant recipients with lupus nephritis, multiple pregnancies, multiple blood transfusions, greater comorbidity index, higher body weight, age and African American race of the donor or recipient, prior history of transplantation, greater PRA levels, lower level of HLA matching, deceased donors, and HD in pretransplant period have an association with increased risk of graft failure. Similarly, higher recipient and donor age, prior transplantations, and higher rate of pretransplant transfusions are associated with greater risk of recipient mortality. Using neither cyclosporine nor tacrolimus or using both (compared with tacrolimus) and neither MPA nor azathioprine (compared with azathioprine) was associated with increased risk of graft failure and recipient death. Using MPA is associated with greater risk of recipient death compared with azathioprine. Testing these results in a prospective study might provide important information for clinical practice. [source]

Long-term results of mycophenolate mofetil as part of immunosuppressive induction therapy after liver transplantation

CLINICAL TRANSPLANTATION, Issue 3 2006
Jan M. Langrehr
Abstract:, Background:, The addition of mycophenolate mofetil (MMF) to the induction protocol resulted in a lower incidence of rejection episodes. However, the question whether MMF should be administered in combination with tacrolimus or cyclosporine has not been answered yet. In our study, we report on the long-term results of triple induction therapy after orthotopic liver transplantation (OLT), consisting of MMF and low-dose corticosteroids, in combination with either tacrolimus or cyclosporine. Methods:, Between March 1996 and April 1997, 120 consecutive patients, who underwent OLT at our institution, were enrolled in this study. Of these patients, 80 received triple induction therapy consisting of cyclosporine and MMF (40) or tacrolimus and MMF (40), in combination with low-dose corticosteroids, whereas the remaining 40 patients served as ,MMF-free' control group receiving dual induction therapy with tacrolimus and corticosteroids. Besides the eight-yr follow-up of patient and graft survival, clinical data were also reviewed for episodes of rejection and infection. Additionally, the early post-operative pharmacokinetics of mycophenolic acid (MPA, immunological active metabolite of MMF) were evaluated. Results:, Long-term results provided higher patient and graft survival after tacrolimus/MMF-based induction therapy than after cyclosporine/MMF-based induction therapy. However, the tacrolimus-based control protocol yielded similar results and, therefore, no significantly superior effect was observed when MMF was added. The same observation was made for incidence of rejection and infection episodes. AUC and Cmax of MPA increased in combination with tacrolimus compared with cyclosporine. Conclusions:, Although pharmacological synergy between tacrolimus and MMF was observed, MMF showed no significant beneficial effects in the immunosuppressive induction protocol, neither in combination with tacrolimus nor with cyclosporine. [source]