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Introduction: Mycophenolic acid (MPA) is an active metabolite of mycophenolate mofetil and mycophenolate sodium which are widely prescribed to prevent organ rejection after solid organ transplantations. However, MPA induced many side effects on gastrointestinal tract and haematological system. Objectives: The purpose of this study is to establish a high-performance liquid chromatography (HPLC) method to determine the MPA concentration in plasma in order to optimize the treatment efficacy of MPA or apply to bioequivalence studies. MPA and visnadine (as an internal standard) were extracted from plasma samples with methanol by solid phase extraction using Osis HLB 1cc cartridge. 10 µL of sample extract was injected onto LiChroCART®125-4 (C18 reversed-phase column) at 43 °C on a Waters 2695 XE system. The signals were detected by PDA detector (photodiodes array) at 254 nm. The mobile phase was a mixture of acetonitrile and phosphate buffer (pH 3) with a flow rate of 1 mL/min. The validation criteria included: selectivity, linearity, accuracy, precision, recovery, lower limit of quantification. Results: Total chromatographic runtime was 15 min. MPA and visnadine were found at 6.45 and 10.79 min, respectively. MPA concentrations were in the linear range from 0.25 to 50 µg/mL. The coefficient of variation (CV) of mean intra-day and inter-day precision levels for MPA was less than 7.5%. The lower limit of quantification was 0.25 µg/mL. No interference was found in the assay. Conclusion: A simple and reliable HPLC method was developed to quantify the MPA concentration in plasma.

A reliable method has been validated using ultra-performance liquid chromatography mass spectrometry (MS)/MS for simultaneous evaluation of human plasma concentration of mycophenolic acid (MPA) and its major metabolites both total and free form. All analytes were extracted from plasma by simple protein precipitation procedure with methanol. Samples for determination of their free form concentration require a preanalytic spin through an ultrafiltration system. The chromatographic separation was completed using C18column at 0.3 ml/min with a gradient condition. Method validation was performed as the United State Food and Drug Administration guidelines for bio-analytical methods concerning precision, accuracy, linearity, selectivity, recovery, and matrix effect. Linearity was obtained over concentration of 0.05–4, 0.5–60, and 0.025–3 μg/ml for total MPA, mycophenolic acid glucuronide (MPAG) and mycophenolic acid acyl-glucuronide (AcMPAG), respectively. The linearity of the method for free form of analytes was confirmed in the range of 10–500, 125–10,000, and 0.5–300 ng/ml for MPA, MPAG, and AcMPAG, respectively. The intra- and interday accuracy ranged from 85.73%–102.01% for total form, and 87.23%–111.89% for free form, and the precisions of all analytes were lower than 15%. The mean recoveries of the analytes ranged from 85.54% to 94.76% and the matrix factor ranged from 0.88–1.06. The developed method is rapid, sensitive and convenient for pharmacokinetic study or therapeutic drug monitoring in patients after oral administration of enteric-coated mycophenolate sodium or mycophenolate mofetil.

BackgroundMycophenolic acid (MPA) is widely utilized as an immunosuppressant in kidney and liver transplantation, with reports suggesting an independent relationship between MPA concentrations and adverse allograft outcome. Proton-pump inhibitors (PPIs) may have variable effects on the absorption of different MPA formulations leading to differences in MPA exposure.MethodsA multicentre, randomized, prospective, double-blind placebo-controlled cross-over study was conducted to determine the effect of the PPI pantoprazole on the MPA and its metabolite MPA-glucuronide (MPA-G) area under the curve (AUC) >12 h (MPA-AUC12 h) in recipients maintained on mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS). We planned a priori to examine separately recipients maintained on MMF and EC-MPS for each pharmacokinetic parameter. The trial (and protocol) was registered with the Australian New Zealand Clinical Trials Registry on 24 March 2011, with the registration number of ACTRN12611000316909 (‘IMPACT’ study).ResultsOf the 45 recipients screened, 40 (19 MMF and 21 EC-MPS) were randomized. The mean (standard deviation) recipient age was 58 (11) years with a median (interquartile range) time post-transplant of 43 (20–132) months. For recipients on MMF, there was a significant reduction in the MPA-AUC12 h [geometric mean (95% confidence interval) placebo: 53.9 (44.0–65.9) mg*h/L versus pantoprazole: 43.8 (35.6–53.4) mg*h/L; P = 0.004] when pantoprazole was co-administered compared with placebo. In contrast, co-administration with pantoprazole significantly increased MPA-AUC12 h [placebo: 36.1 (26.5–49.2) mg*h/L versus pantoprazole: 45.9 (35.5–59.3) mg*h/L; P = 0.023] in those receiving EC-MPS. Pantoprazole had no effect on the pharmacokinetic profiles of MPA-G for either group.ConclusionsThe co-administration of pantoprazole substantially reduced the bioavailability of MPA in patients maintained on MMF and had the opposite effect in patients maintained on EC-MPS, and therefore, clinicians should be cognizant of this drug interaction when prescribing the different MPA formulations.

Laparoscopic sleeve gastrectomy induces weight loss via the creation of a restrictive gastric tube for early satiety and is associated with an accelerated gastric transit time. A prospective, single-dose pharmacokinetic study was performed, prior to and after laparoscopic sleeve gastrectomy, for tacrolimus, extended-release tacrolimus, mycophenolate mofetil, and enteric-coated mycophenolate sodium. The study included 12 morbidly obese patients in chronic renal failure. The median decrease in body mass index was 8.8 kg/m2 with an excess body weight loss of 54.9%. The AUC24 of all drugs were increased after laparoscopic sleeve gastrectomy by 46%, 55%, 77%, and 74%, respectively. The maximum concentrations were increased for tacrolimus, extended-release tacrolimus, and mycophenolate mofetil by 43%, 46%, and 65%. The apparent total clearances were decreased for tacrolimus, mycophenolate mofetil, and enteric-coated mycophenolate sodium by 36%, 57%, and 38%. Laparoscopic sleeve gastrectomy can be associated with significant changes in pharmacokinetics of the drugs evaluated. The mechanism is likely decreased apparent drug clearance due to an increased drug exposure (from a more distal site of intestinal absorption with decreased intestinal metabolism), or decreased clearance (liver metabolism). Adapting the monitoring of immunosuppression will be important to avoid overdosing and potential side effects.

Background Mycophenolate mofetil (MMF) is extensively used for induction and maintenance therapy in patients with lupus nephritis (LN). Enteric-coated mycophenolate sodium (EC-MPS) was developed to reduce the adverse gastrointestinal effects of MMF. However, the therapeutic efficacy of MMF and EC-MPS in LN remains unclear. This study aimed to examine the treatment effects of EC-MPS in LN patients with prior MMF exposure. Methods In this medical records review study, we included 54 LN patients, of whom 34 converted from MMF to EC-MPS at equimolar doses in 2016-2018 (nonmedical switching group) and 20 received continuous MMF treatment. Patients achieving complete remission or partial remission before the conversion were categorized as responders, whereas those who had never achieved complete remission or partial remission were categorized as nonresponders. Results Baseline proteinuria was higher in the nonmedical switching group. Although elevation in proteinuria was observed after nonmedical switching, the serum creatinine concentration and estimated glomerular filtration rate both improved. Responders in the nonmedical switching group had lower proteinuria and higher complement 3 levels. In the subgroup analysis, albeit the modest increase in daily urine protein, anti-double-stranded DNA antibody levels, estimated glomerular filtration rate, and complements 3 and 4 seemed comparable after conversion. Conclusion Switching to EC-MPS demonstrated a similar short-term renal response to continuous MMF treatment in LN patients. Prospective randomized trials are required to verify our findings.

The dual antiproliferative mechanism of mycophenolate appears to be beneficial in Graves’ orbitopathy (GO). Safety data from the two published mycophenolate trials and the original database of the European Group on Graves’ Orbitopathy (EUGOGO) trial were systematically analyzed. Treatment efficacy stratified by individual visual parameters of activity and severity were compared. A total of 129 adverse events (AE) involving 50 patients (29.4%) were noted among all mycophenolate-treated patients. Mycophenolate sodium plus intravenous glucocorticoid (MPS + GC) group of the EUGOGO trial recorded significantly more AE (55.4% versus 4.6% of patients affected) and serious adverse events (SAE) (12.5% versus 0%) than mycophenolate mofetil (MMF) group of the Chinese trial. None of those SAE was side effect (SE). Most SE in MPS + GC group were mild. Gastrointestinal disorders, infection and liver dysfunction affected 8.8%, 7.1% and 1.2% of all mycophenolate-treated patients (versus 5.4%, 5.4% and 1.2% of all patients on GC monotherapy, respectively). MPS + GC did not significantly increase the risk of infection or liver dysfunction when compared to GC monotherapy. No cytopenia, serious infection or treatment-related mortality was reported. The much higher AE rates of mycophenolate trials in other autoimmune diseases or transplantations suggested that major mycophenolate toxicities were mostly dose- and duration dependent. Mycophenolate, either as monotherapy or as combination, achieved better overall response than GC monotherapy. The risk–benefit ratio of low-dose mycophenolate treatment in active moderate-to-severe GO is highly favorable given its reassuring safety profile with low rate of mild-to-moderate SE and promising efficacy.

Mycophenolate mofetil (MMF) or enteric coated mycophenolate sodium (EC-MPS) and steroids are used for induction and maintenance therapy in severe lupus nephritis (LN). Blood concentrations of mycophenolic acid (MPA), the active metabolite of these drugs varies among LN patients. The objective of this study was to examine whether concentration controlled (CC) dosing (via therapeutic drug monitoring) of EC-MPS result in a higher proportion of participants achieving target exposure of MPA compared to fixed dosing (FD). An additional aim of the study was to evaluate the influence of CC dosing on clinical outcomes. Nineteen participants were randomly assigned either to FD or CC group. All the participants were eligible to have free and total measurements of MPA over a period of 8-12 hours on three different occasions. Area under the concentration-time curve between 0 and 12 hours (AUC0-12) was calculated using non-compartmental method. Dose of EC-MPS was titrated according to AUC0-12 in the CC group. Thirty-two AUC0-12 measurements were obtained from 9 FD and 9 CC participants. Large interpatient variability was observed in both groups but was more pronounced in FD group. There were no significant differences between FD and CC participants in any pharmacokinetic parameters across the study visits except for total C0 (FD 2.0 ± 0.3 mg/L vs. CC 1.1 ± 0.3; p = 0.01) and dose-normalised C0 (FD 2.9 ± 0.2 mg/L/g vs. CC 2.1 ± 0.7 mg/L/g; p = 0.04) at the second visit and total AUC0-12 (FD 66.6 ± 6.0 mg[BULLET OPERATOR]h/L vs. CC 35.2 ± 11.4 mg[BULLET OPERATOR]h/L; p = 0.03) at the third visit. At the first study visit, 33.3% of the FD and 11.1% of the CC participants achieved the target AUC (p = 0.58). From the second visit, none of the FD participants, compared to all the CC participants, achieved target AUC0-12 (p = 0.01). More CC participants achieved remission compared to FD participants (absolute difference of -22.2, 95% confidence interval -0.19-0.55; p = 0.62). The mean free MPA AUC0-12 was significantly lower in those who had complete remission. CC participants reached target AUC0-12 quicker. Larger studies are required to test clinical efficacy.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Mycophenolic acid (MPA) is commonly used following renal transplant. Saliva MPA concentrations may reflect the pharmacologically active form of MPA in plasma. Therapeutic drug monitoring using saliva is convenient and non-invasive. This study examined the correlation between total and free plasma and saliva MPA concentrations following enteric-coated mycophenolate sodium (EC-MS) administration in renal transplant recipients. Total and free plasma and saliva MPA concentrations were measured simultaneously in 20 adult renal transplant recipients 1–2 months’ post-transplant. Thirteen samples were taken pre-dose and at specified time points up until 12 h post-dose. When considering all time points, correlation between total plasma and saliva MPA was r2 = 0.51 and between free plasma and saliva MPA concentrations r2 = 0.41. The correlation between total plasma MPA area under the concentration–time curve (AUC) or free plasma AUC and saliva MPA AUC was r2 = 0.25 and r2 = 0.13, respectively. The correlation between total plasma MPA AUC and total plasma MPA trough (C0) concentrations was r2 = 0.51, and between total plasma MPA AUC and saliva MPA trough concentrations, r2 = 0.03. Measurement of MPA concentration in saliva cannot currently replace plasma measurement for therapeutic drug monitoring of MPA following EC-MS administration. Additional studies are required to examine the relationship between MPA saliva concentrations and patient outcomes.

Mycophenolic acid, the active metabolite for mycophenolate mofetil and mycophenolic sodium, is a strong, noncompetitive, reversible inhibitor of inosine monophosphate dehydrogenase, the key enzyme in de novo synthesis of guanosine nucleotides leading to selective inhibition of lymphocyte proliferation. Mycophenolic acid has been evaluated as induction and remission maintenance agent in the treatment of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Since the course of disease of AAV usually requires long term immunosuppression, mycophenolate has been explored as a less toxic agent compared to cyclophosphamide and azathioprine. Mycophenolate is a potent immunosuppressive agent in the therapy of AAV, non-inferior to other available drugs with comparable side effect profile. Therefore, it could be a valuable alternative in cases of toxicity with life threatening side effects or intolerance to cyclophosphamide or azathioprine, in cases with high cumulative dose of cyclophosphamide, but also in cases with insufficient response. Several studies have shown a higher relapse rate following discontinuation of mycophenolate or in mycophenolate treated subjects that raises concerns about its usefulness in the treatment of AAV. This review describes the efficacy of mycophenolate in AAV as remission induction agent, as remission maintenance agent, and as therapeutic option in relapsing AAV disease, the relapse rate following discontinuation of mycophenolate, and the adverse events related to mycophenolate treatment.

Tacrolimus or cyclosporine is prescribed with mycophenolic acid posttransplant and contributes to interpatient variability in mycophenolic acid pharmacokinetics and response. Cyclosporine inhibits enterohepatic circulation of the metabolite mycophenolic acid glucuronide, which is not described with tacrolimus. This study investigated mycophenolic acid pharmacokinetics and adverse effects in stable renal transplant recipients and the association with calcineurin inhibitors, sex, and race. Mycophenolic acid and mycophenolic acid glucuronide area under the concentration-time curve from 0 to 12 hours (AUC(0–12h)) and apparent clearance were determined at steady state in 80 patients receiving cyclosporine with mycophenolate mofetil and 67 patients receiving tacrolimus with mycophenolate sodium. Gastrointestinal adverse effects and hematologic parameters were evaluated. Statistical models evaluated mycophenolic acid pharmacokinetics and adverse effects. Mycophenolic acid AUC(0–12h) was 1.70-fold greater with tacrolimus (68.9 ± 30.9 mg·h/L) relative to cyclosporine (40.8 ± 17.6 mg·h/L); P < .001. Target mycophenolic acid AUC(0–12h) of 30–60 mg·h/L was achieved in 56.3% on cyclosporine compared with 34.3% receiving tacrolimus (P < .001). Mycophenolic acid clearance was 48% slower with tacrolimus (10.6 ± 4.7 L/h) relative to cyclosporine (20.5 ± 10.0 L/h); P < .001. Enterohepatic circulation occurred less frequently with cyclosporine (45%) compared with tacrolimus (78%); P < 0.001; with a 2.9-fold greater mycophenolic acid glucuronide AUC(0–12h) to mycophenolic acid AUC(0–12h) ratio (P < .001). Race did not affect mycophenolic acid pharmacokinetics. Gastrointestinal adverse effect scores were 2.2-fold higher with tacrolimus (P < .001) and more prominent in women (P = .017). Lymphopenia was more prevalent with tacrolimus (52.2%) than cyclosporine (22.5%); P < 0.001. Calcineurin inhibitors and sex contributed to interpatient variability in mycophenolic acid pharmacokinetics and adverse effects post-renal transplant, which could be attributed to differences in enterohepatic circulation.

Background Neuromyelitis optica spectrum disorders (NMOSD) is an autoimmune astrocyte disease that mainly affects the optic nerve and spinal cord resulting in blindness or paralysis. Mycophenolate mofetil (MMF) is one of the available immunotherapies with purported beneficial effects for patients with NMOSD. The present review aimed to conduct an update systematic review and meta-analysis for the efficacy of mycophenolate mofetil in the treatment of NMOSD and analyze main factors affecting the efficacy of mycophenolate mofetil. Methods The following Medical Subject Heading (MeSH) and related entry terms are used to search English literature in PubMed, MEDLINE and CENTRAL databases, respectively. MeSH include: Neuromyelitis optic and Mycophenolic Acid; entry terms include: NMO Spectrum Disorder, NMO Spectrum Disorders, Neuromyelitis Optica (NMO) Spectrum Disorder, Neuromyelitis Optica Spectrum Disorders, Devic Neuromyelitis Optica, Neuromyelitis Optica, Devic, Devic's Disease, Devic Syndrome, Devic's Neuromyelitis Optica, Neuromyelitis Optica (NMO) Spectrum Disorders, Mycophenolate Mofetil, Mofetil, Mycophenolate, Mycophenolic Acid Morpholinoethyl Ester, Cellcept, Mycophenolate Sodium, Myfortic, Mycophenolate Mofetil Hydrochloride, Mofetil Hydrochloride, Mycophenolate, RS 61,443, RS-61,443, RS61443; (note: literature retrieval operators “AND” “OR” “NOT” are used to link MeSH with Entry Terms.) 30 studies were included in this systematic review and 14 studies were included in meta-analysis. The main efficacy indicators were the difference of the annualized relapse rate (ARR) between before and after mycophenolate mofetil treatments. Results In 14 studies involving 930 patients (815 women, 115 men), the ARR were reduced by an average of −1.17 (95%CI, −1.28 to −1.07). Conclusion Our systematic review and update meta-analysis provide new evidences that mycophenolate mofetil can substantially reduce ARR ratio.

Objective It is still unclear whether mycophenolic acid (MPA) doses should be adjusted for older patients. Therefore, we compared the pharmacokinetics of MPA, mycophenolic acid glucuronide (MPAG), and free MPA (fMPA) between older and younger renal transplant recipients. Methods We included 12 patients 60 years within the first year after renal transplantation, who were receiving enteric-coated mycophenolate sodium, tacrolimus, and steroids. Blood samples were collected up to 12 hours after drug administration. Results MPA and fMPA pharmacokinetics were similar for patients 60 years; however, the MPA area under the concentration-time curve from 0 to 12 hours (AUC0-12) was 1.2-fold lower in the older patients. MPAG pharmacokinetics were more than 1.5-fold higher in patients >60 years, which might be related to deteriorated renal function in older people. Moreover, the mean (MPAG AUC0-12)/(MPA AUC0-12) ratio was more than 2-fold higher in patients >60 years. The second maximal MPA concentration was more frequently observed in patients 60 years had MPA AUC0-12 >30 μg·h/mL within 22 to 114 days after transplantation. Conclusions MPA therapeutic monitoring should be recommended in enteric-coated mycophenolate sodium--treated patients >60 years because MPA AUC0-12 exceeded the recommended value in half of the studied patients.

Immunosuppressive therapy is used in solid organ transplant treatment, and mycophenolic acid (MPA) is one of the immunosuppressive drugs most used worldwide. It is a potent, selective, non-competitive, and reversible inosine monophosphate dehydrogenase (IMPDH) inhibitor that acts to inhibit guanine synthesis. To improve solubility, MPA is used as the prodrug mycophenolate mofetil (MMF) or as an enteric-coated mycophenolate sodium salt (EC-MPS). It is metabolized into mycophenolic acid phenyl glucuronide (MPAG), the inactive and major metabolite, and into acyl glucuronide (AcMPAG), pharmacologically active. In kidney transplantation, combined immunosuppressive therapy with cyclosporine (CsA) and tacrolimus (Tac) is widely used, showing beneficial effects. This paper aimed to review papers published in the last two decades and discuss factors that can interfere with the pharmacokinetics of MPA. Data collected confirm that MPA plasma levels should be monitored to evaluate immunosuppressive therapy since pharmacokinetics can be influenced by factors such as interpatient variability, coadministration of other immunosuppressive agents, post-transplant period, renal function, and dose. However, to perform drug monitoring, costs and facility may be limitations. Monitoring MPAG together with MPA would be a great improvement in therapy as it represents a big part of MPA levels and can be related to the increase of adverse effects.

Background : The absorption rates of mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS) may be influenced by the concomitant use of omeprazole. Methods : One hundred kidney transplant patients were recruited during their outpatient visits, including 50 on MMF and 50 on EC-MPS. At the clinic, a predose mycophenolic acid (MPA) sample (C0) was collected; subsequently, the participants received the proton-pump inhibitor omeprazole along with either MMF or EC-MPS. Two more blood samples were collected at 1.5 and 3.5 hours and used to estimate an area under the curve (AUC) from zero to 12 hours [AUC (0-12)]. Results : The mean number of months after transplant was 92 months. The median AUC (0-12) and C0 results were 62.2 mg·h/L and 2.0 mg/L for the MMF group and 71.9 mg·h/L and 1.8 mg/L for the EC-MPS group (P = 0.160 and 0.225, respectively). Interestingly, 54% of the MMF group and 62% of the EC-MPS group showed AUCs above the target values. The correlation between MPA C0 and the predicted AUC was poor in both groups. Conclusion : Omeprazole can be safely co-administered with either MMF or EC-MPS, as it did not compromise the MPA exposure. Unexpectedly, however, a high percentage of patients presented MPA AUCs exceeding the target value, highlighting the importance of periodically assessing MPA level.

The aim of this study was to characterize the pharmacokinetics of mycophenolic acid (MPA) and MPA glucuronide (MPAG) in Chinese renal transplant patients taking enteric-coated mycophenolate sodium (EC-MPS). Limited sampling strategies (LSSs) were developed to estimate the area under the concentration curve from 0 to 12 hours (AUC0-12h) of total and free MPA. Another objective was to investigate the correlation between high-performance liquid chromatography (HPLC) and enzyme-multiplied immunoassay technology (EMIT) for total MPA determination.Serial blood samples were collected over 12 hours from 15 patients who were administered multiple doses of EC-MPS. LSS was developed by multiple stepwise regression analysis. Measurement by HPLC and EMIT was compared using Passing-Bablok regression and Bland-Altman analysis.Normalized to 720 mg twice daily, the AUC0-12h of total MPA and MPAG was 43.0 ± 17.4 and 653 ± 329 mg·h/L, respectively, whereas the free MPA AUC0-12h was 1.368 ± 0.988 mg·h/L. The free fraction of MPA was 3.01% ± 3.15%. The combination of C2h-C4h-C6h and C2h-C4h-C6h-C8h was found to be superior to estimate total and free MPA simultaneously. The EMIT showed an acceptable correlation with HPLC, with an AUC0-12h overestimation of 11.32% ± 15.77%.The pharmacokinetic profile of total and free MPA and its main metabolite MPAG was examined in Chinese adult renal transplant patients receiving EC-MPS. The use of LSS to estimate individual free and total MPA exposure could be useful in optimizing patient care.

Elderly patients are increasingly likely to be recipients of transplants. However, the pharmacokinetics of mycophenolic acid (MPA) in this population are yet to be studied in detail. The objective of this study was to assess whether there were differences in MPA pharmacokinetic parameter values between elderly recipients and younger-adult recipients during the 6 months immediately following renal transplantation.In this analysis, the longitudinal 12-h pharmacokinetics of MPA, administered as enteric-coated mycophenolate sodium (EC-MPS), were evaluated in 44 elderly renal transplant recipients and compared with the corresponding pharmacokinetics of MPA in 31 younger adult recipients. Measurements were performed at 7, 30, 60, 90, and 180 days post-transplantation. All patients received tacrolimus and prednisone.The elderly patients were 30 years older than the younger controls, with a predominance of males and Caucasians. Elderly patients had lower serum albumin than the younger controls during the first 6 months after transplantation. The mean estimated total body MPA clearance of the elderly recipients was not significantly different from that of the controls at any analyzed time point (the mean clearance across all time points was 0.31 ± 0.17 vs 0.30 ± 0.25 L/h/kg). MPA exposure, as evaluated from the area under the 12-h time versus measured MPA concentration (adjusted for dose/body weight) curve, did not differ between the groups at any time point (mean exposure across all time points was 4.68 ± 3.61 vs 5.95 ± 4.29 µg·h/mL per mg/kg for the elderly recipients and the controls).These data show that the pharmacokinetics of MPA in elderly renal transplant recipients were no different to those of younger-adult recipients in this study population. CLINICALTRIALS.GOV: NCT 01631058.

BACKGROUND Enteric-coated mycophenolate sodium is frequently used in renal transplantation. The pharmacokinetic profile of mycophenolic acid (MPA) shows a broad range of time-to-maximum concentration (Tmax) that limits the use of a single MPA concentration to calculate the area under the time-concentration curve (AUC). For both research and clinical MPA monitoring, measuring a complete AUC is troublesome to the center and patients. METHODS We obtained 171 complete MPA-AUC12h (0, 20, 40, 60, 90, 120, 180, 240, 360, 480, 600, and 720 minutes) from 59 adult (54 ± 16 years) patients (29 men and 43 whites) who have been receiving stable doses of tacrolimus/enteric-coated mycophenolate sodium and steroids. We used the 59 curves drawn at 31 ± 4 days after transplantation to develop the abbreviated equations, and the remaining 112 curves drawn at 109 ± 59 days were used to validate them. We used 5 other proposed equations to estimate MPA-AUC (eAUC) (4 with enzyme-multiplied immunoassay technique assay and one with high-performance liquid chromatography [HPLC]) and then used these results to compare with our measured AUC, the bias, and the 10% and 30% accuracy. MPA was measured by ultraperformance liquid chromatography coupled to a tandem mass spectrometry, and AUC was calculated by the trapezoidal rule. RESULTS For both MPA-measuring methods, enzyme-multiplied immunoassay technique and ultraperformance liquid chromatography coupled to a tandem mass spectrometry, the Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (HCFMUSP) equations, and others that measure MPA up to 6 hours after the dose had an acceptable low bias with more results in the 10%-30% range than those using data collected until 4 hours. A highly adequate eAUC is obtained using blood collected at 8 hours. CONCLUSIONS This analysis offers blood-sampling alternatives for MPA monitoring depending on the precision needed.

Background: Immunosuppressive agents are still inefficient in preventing biopsy-proven acute rejection (BPAR) after expanded criteria donor (ECD) kidney transplantation. The aim of this study was to investigate the relationships between early immunosuppressive exposure and the development of BPAR. Methods: We performed a retrospective study of 58 recipients of ECD kidney transplantation treated with enteric-coated-mycophenolate sodium, tacrolimus (Tac), and prednisone. The levels of mycophenolic acid-area under the curve (MPA-AUC)0-12h and Tac C0 were measured at the 1st week and the 1st month posttransplant, respectively. The correlation was assessed by multivariate logistic regression. Results: The occurrence rates of BPAR and antibody-mediated rejection were 24.1% and 10.3%, respectively. A low level of MPA-AUC0-12h at the 1st week posttransplant was found in BPAR recipients (38.42 ± 8.37 vs. 50.64 ± 13.22, P < 0.01). In addition, the incidence of BPAR was significantly high (P < 0.05) when the MPA-AUC0-12h level was

BACKGROUND This study was designed to analyze the clinical implications of mycophenolic acid trough concentration monitoring. MATERIAL AND METHODS We collected data of patients with mycophenolic acid trough concentration monitoring after their first kidney transplant between November 2006 and March 2015 who were prescribed tacrolimus, mycophenolate, and methylprednisolone. Analyses were performed on 3 periods: 1 month, 1 month to 1 year, and after 1 year post-transplantation. To analyze factors related to acute cellular rejection, logistic regression was used for 1 month, while Cox analysis was used during 1 month to 1 year and after 1 year post-transplantation. RESULTS In the 145 patients receiving mycophenolate mofetil, mean tacrolimus trough ≥7.0 ng/mL (OR=0.177, CI=0.060-0.524, p=0.002) and mean mycophenolic acid trough ≥1.7 mg/L (OR=0.190, CI=0.040-0.896, p=0.036) were protective for rejection during 1 month. Mean mycophenolic acid trough ≥1.7 mg/L (HR=0.179, CI=0.040-0.806, p=0.025) and ≥0.7 mg/L (HR=0.142, CI=0.028-0.729, p=0.019) were related to better rejection-free survival during 1 month to 1 year and after 1 year, respectively. In 399 patients receiving enteric-coated mycophenolate sodium, mean tacrolimus trough ≥7.0 ng/mL (OR=0.258, CI=0.131-0.507, p

Background: Pediatric patients with steroid-resistant nephrotic syndrome (SRNS) and focal segmental glomerulosclerosis (FSGS) may relapse and current second line agents include mycophenolate mofetil. However, there is no current information about the use of the sodium salt of mycophenolic acid (SMPA) in this population. Objectives: We conducted a prospective study on the efficacy and pharmacokinetics of SMPA in children with FSGS. Patients and Methods: Patients without NPHS2 pathogenic variants received SMPA at dosages between 460 to 720 mg/m2/d for 12 months after previous treatments failure. Clinical and biochemical assessments were performed. Blood samples were obtained after the first dose and at steady state (3 months after the onset of treatment) and total and free mycophenolic acid (MPA) was quantitated using HPLC-UV. Results: Two patients showed partial remission after the 12-month period of SMPA treatment with a notable decrease in proteinuria and an increase in serum albumin levels. Maximum MPA concentrations after the first dose and at steady state were 11.6 µg/mL and 10.5 µg/mL, respectively, without drug accumulation. Maximum MPA free levels after the first dose and at steady state were 192.9 and 120.6 ng/mL, respectively. MPA levels became undetectable after 4 hours of the administration in all cases. Conclusions: SMPA is a promising agent for pediatric patients with SRNS and FSGS but SMPA schedule of treatment should be revised with shorter intervals of administration and higher doses than those used in the present study in order to attain higher systemic exposures and accumulation of the immunosuppressant drug. Further efficacy and pharmacokinetic studies should be performed to confirm these findings.

Background/aimsTo evaluate the efficacy, safety and tolerability of enteric-coated mycophenolate sodium (EC-MPS) in combination with low-dose corticosteroids compared with a monotherapy with low-dose corticosteroids in subjects with non-infectious intermediate uveitis (IU).MethodsOpen-label, prospective, controlled, randomised multicentre trial. Patients were randomised in a 1:1 ratio to either the treatment group (prednisolone plus EC-MPS) or control group (prednisolone monotherapy). Patients in the control group who relapsed within 6 months changed to the crossover group (prednisolone plus EC-MPS). Maximum treatment duration was 15 months. The primary endpoint was the time to first relapse in the treatment group and control group.ResultsForty-one patients at eight sites were analysed. Twenty-two patients were allocated to the treatment group, with 19 patients in the control group. A first relapse occurred in 9 patients (40.9%) in the treatment group and 15 patients (78.9%) in the control group (p=0.03). The median time to the first relapse was >15 months for the treatment group and 2.8 months for the control group (p=0.07). The probability of relapse-free survival at month 15 was estimated to be 52.9% in the treatment group and 19.7% in the control group (p=0.01). 15 patients changed to the crossover group. Of these, only four patients developed a second relapse. No safety concerns arose during the trial. Only one patient had to discontinue EC-MPS due to increased liver enzymes.ConclusionEC-MPS can be considered an effective and well-tolerated immunosuppressive drug to prevent relapses in patients with chronic IU.Trial registration numberEUDRACT number: 2009-009998-10, Results.

A new rapid and accurate method for determining the mycophenolic acid concentration in human blood plasma using HPLC with tandem mass-spectrometric detection (HPLC-MS/MS) and deproteinization for sample preparation was developed. The method was validated according to the Guideline for Validation of Bioanalytical Methods of EMEA and Guidelines for Examination of Drugs. This method was used to study the pharmacokinetics of mycophenolate sodium.

The new rapid, selective and stable method has been developed for determining the concentration of mycophenolic acid in blood plasma by high performance liquid chromatography with tandem mass spectrometric detection (HPLC-MS/MS) using deproteinization for sample preparation. Validation of the procedure was conducted in accordance with the Guidelines for Validation of Bioanalytical methods (EMEA) and Guidelines for Examination of Drugs. The procedure has been used to study the pharmacokinetics of mycophenolate sodium.

Most patients have serious digestive complications after renal transplantation. Therefore, it is important to protect gastrointestinal function to improve the survival rate of transplant patients. Proton pump inhibitors (PPIs) such as lansoprazole and rabeprazole are widely administered to renal transplant patients with mycophenolic acid (MPA) in the perioperative period. PPIs are metabolized by cytochrome (CYP) 2C19 enzymes. Mycophenolate sodium (MYF) and mycophenolate mofetil (MMF) have been used in immunosuppression. Clinically relevant drug-drug interactions have been described between immunosuppressive drugs. In the present study, we investigated the drug interaction between MPA and lansoparazole or rabeprazole and the impact of CYP2C19 polymorphisms on these drug interactions after renal transplantation.A total of 125 renal transplant patients taking MPA derivatives between 2012 and 2016 were included in this study. The 125 patients were divided into 6 groups: MMF/tacrolimus/steroid together with lansoprazole or rabeprazole; MYF/tacrolimus/steroid together with lansoprazole or rabeprazole and without PPI. The single nucleotide polymorphisms of CYP2C19 were determined by the polymerase chain reaction-restriction fragment length polymorphism. Plasma concentrations of MPA were measured by cloned enzyme donor immunoassay. Clinical parameters such as incidence of delayed graft function and acute rejection, the rate of change of serum creatinine, toxicity, and gastrointestinal adverse effects were analyzed retrospectively.The mean concentrations of MPA in the MYF group were higher than those in the MMF group. The mean dose-adjusted blood concentration of MPA coadministered with lansoprazole was lower than that of MPA with rabeprazole or without PPI in MMF and MYF groups (P .05). In patients with the CYP2C19*2/*2 genotype, the mean concentrations of MMF with lansoprazole were significantly lower than those with rabeprazole with MMF or without PPI (P .05). Gastrointestinal side effects were significantly higher in MMF with lansoprazole group than in MYF with lansoprazole group (P .05). However, no differences were found according to genotype distribution in all groups (P.05).Polymorphisms in CYP2C19 are related to the metabolic oxidation of drugs to varying degrees. Both genetic and clinical factors in pharmacokinetics may help to make further progress toward individualized therapy to yield maximum efficacy with minimal side effects.

Background Mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (MPS) is now commonly used in pediatric intestinal transplantation (Tx), but to date, no clear recommendations regarding the dosing regimen have been made in this population. The aim of this study was to determine the MMF/MPS dosage required to achieve an area under the plasma concentration-time curve from 0 to 12 hours (AUC0-12) for mycophenolic acid (MPA) greater than 30 mg·h·L in children after intestinal transplantation. Methods A pharmacokinetic study was conducted in 8 children (median, 9.4 years; range, 0.75-15.8 years) at a median time of 113 months (range, 1.5-160 months) after intestinal transplantation. Results MMF was initially introduced at a low median starting dose of 687 mg·m·d (range, 310-1414 mg·m·d). One of the 3 patients who received MPS and 2 of the 6 patients who received MMF had an MPA AUC0-12 value below 30 mg.h.L. The median MMF dosage had to be increased by 91% (1319 mg·m·d versus 687 mg·m·d) to reach AUC0-12 values above the defined target level of 30 mg·h·L. Conclusions When used in combination with tacrolimus and steroids, an initial MMF dose of 600 mg/m twice a day would be recommended to children after intestinal transplantation to achieve MPA exposure similar to those observed in adults and children after the transplantation of other organs. Further studies are required to recommend a suitable dosage for pediatric intestinal transplant recipients who receive MPA.

Mycophenolic acid (MPA) has being used clinically for organ rejection prophylaxis. Recent studies have revealed that MPA can also act as a chemo-sensitizing agent when used in combination with various chemotherapeutic agents in a cancer type-specific manner, including with oxaliplatin on oral squamous cell carcinoma (OSCC) cells. To prepare for the analysis of a novel drug delivery route for MPA absorption via oral mucosa as a potential therapeutic product, it is essential to develop and validate a highly sensitive analytical method for the quantification of MPA in biological samples for pharmacokinetic and tissue distribution studies. Herein, we report a sensitive, specific and reproducible UPLC-MS/MS method to do so. Blank rat plasma or tongue tissue homogenates coupled with griseofulvin, as internal standard, was used for generating standard curves ranging from 0.5 to 1000 ng/mL (r > 0.9990) for both plasma and tongue tissue homogenates. The chromatographic separation was achieved by a reverse phase ACE Excel 2 Super C18 column with a flow rate of 0.4 mL/min under gradient elution. Mass detection was performed under positive ionization electrospray. Inter- and intra-day accuracy and precision of the assay were ≤15% in both plasma and tongue tissue homogenates. The matrix effect was non-significant and extraction recovery rates were within 87.99% and 109.69% in plasma and tongue homogenates, respectively. The validity of this assay has been confirmed by measuring MPA in rat plasma for pharmacokinetics following intravenous administration of 0.5 mg/kg of mycophenolate sodium, as well as monitoring MPA in rat tongues for tissue distribution and detecting MPA that diffused into systemic circulation following a 4-h transmucosal delivery of 357 μg/cm2 of mycophenolate sodium.

Introduced in 1995, mycophenolate mofetil (MMF) would become the most powerful antiproliferative agent in the field of organ transplantation, thereby supplanting azathioprine, the first antiproliferative agent introduced in the early 1960s. Its association with tacrolimus greatly improved kidney transplant (KT) prognosis by significantly reducing the incidence of posttransplant acute rejection. MMF is also reputed to be a safe medication, but the frequency of the gastrointestinal complications associated with it, even minor ones, has induced the marketing of a second molecule called enteric-coated mycophenolate sodium. This late form of mycophenolate was supposed to be better tolerated thanks to its pharmacokinetic properties but the studies did not show significant differences between the two molecules. Otherwise, the combination of MMF with tacrolimus has significantly increased the risk of infections, particularly viral, and of neoplasia. To reduce this risk and avoid any situation of under or overexposure while remaining effective, only a strict and long-term monitoring of MMF allows the maintenance of already established therapeutic targets within the predefined ranges. In KT, individualizing the prescription and targets of MMF according to immunologic risk, global immunosuppression, and posttransplant period, as for other immunosuppressants, is open to discussion and may be beneficial.

Background Mycophenolate has been shown to be effective in glomerular disease. However, the role of mycophenolate in the first-line treatment of adult-onset idiopathic minimal change disease (MCD) has not been systematically studied in a randomized fashion. Aim To evaluate the therapeutic efficacy of enteric-coated mycophenolate sodium combined with low-dose corticosteroid as first-line treatment for MCNS. Design A prospective, open-label, randomized clinical trial. Methods Twenty adult patients with biopsy proven MCD were recruited and randomly assigned to receive either enteric-coated Mycophenolate Sodium (EC-MPS) plus low-dose prednisolone (Group 1: Prednisolone 0.25 mg/kg/day, n = 10) or standard-dose prednisolone (Group 2: Prednisolone 1 mg/kg/day, n = 10). Results After 24 weeks of therapy, eight patients in Group 1 vs. seven of patients in Group 2 achieved complete remission (P = 0.606). Both groups showed a significant reduction of urine protein excretion (P < 0.05) and increased serum albumin (P < 0.001) vs. baseline levels. However, no significant between-group differences were demonstrated. The relapse rate was also similar in both groups. Both treatment regimens were well tolerated but there were more patient reported adverse effects in the standard-dose prednisolone group. Conclusion EC-MPS plus low-dose prednisolone is non-inferior to standard-dose prednisolone therapy in inducing clinical remission and preventing relapse in adult-onset idiopathic MCD and is associated with better tolerability and less adverse effects. This trial is registered with the ClinicalTrials.gov number NCT01185197.

The aim of the research was to investigate the pharmacokinetics (PK) of enteric-coated mycophenolate sodium (EC-MPS) by quantification of the active metabolite of mycophenolic acid (MPA) after multiple escalating oral doses in Han kidney transplant recipients. A total of 28 Han postoperative kidney transplant recipients were given a multiple-dose of 540, 720 or 900 mg of EC-MPS two times a day in combination with tacrolimus for 6 days. Blood specimens were collected at each time point from 0 to 12 h after EC-MPS administration. MPA plasma concentrations were measured by UPLC—UV. The relationship between the EC-MPS dose and its PK parameters was assessed. In the range from 540 to 900 mg, Cmax and AUC0—12h did not increase with dose escalation. The AUC0—12h, Cmax, C0 and Tmax for the 540 720 and 900 mg doses were not significantly different, respectively (P >0.05). AUC0—12 h and Cmax were increased less than proportionally with increasing EC-MPS dose levels. Inter-individual variability in AUC0—12h, Cmax and C0 were considerable. Nonlinear PK relationships were found from the doses of 540–900 mg of EC-MPS., Graphical abstract This research investigated the pharmacokinetics (PK) of enteric-coated mycophenolate sodium (EC-MPS) by quantification of the active metabolite of mycophenolic acid (MPA) after multiple escalating oral doses in Han kidney transplant recipients. Nonlinear PK properties were discovered at doses ranging from 540 to 900 mg after multiple-dose administration. This may have important contributions to clinical practice. fx1

Background: The enteric-coated mycophenolate sodium (EC-MPS), whose active constituent is mycophenolic acid (MPA), has been widely clinically used for organ transplant recipients. However, its absorption is delayed due to its special designed dosage form, which results in difficulty to monitor the exposure of the MPA in patients receiving the EC-MPS. This study was aimed at developing a relatively practical and precise model with limited sampling strategy to estimate the 12-hour area under the concentration–time curve (AUC0–12 h) of MPA for Chinese renal transplant recipients receiving EC-MPS. Methods: A total of 36 Chinese renal transplant recipients receiving the EC-MPS and tacrolimus were recruited in this study. The time point was 2 weeks after the transplantation for all the patients. The MPA concentrations were measured with enzyme-multiplied immunoassay technique for 11 blood specimens collected predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours after the morning dose of EC-MPS. The measured AUC was calculated with these 11 points of MPA concentrations with the linear trapezoidal rule. Limited sampling strategy was used to develop models for estimated AUC in the model group (n = 18). The bias and precision of different models were evaluated in the validation group (n = 18). Results: C4 showed the strongest correlation with the measured AUC. The best 3 time point equation was 6.629 + 8.029 × C0 + 0.592 × C3 + 1.786 × C4 (R2 = 0.910; P < 0.001), whereas the best 4 time point equation was 3.132 + 5.337 × C0 + 0.735 × C3 + 1.783 × C4 + 3.065 × C8 (R2 = 0.959; P < 0.001). When evaluated in the validation group, the 4 time point model had a much better performance than the 3 time point model: for the 4 time point model: R2 = 0.873, bias = 0.505 [95% confidence interval (CI), −10.159 to 11.170], precision = 13.370 (95% CI, 5.186–21.555), and 77.8% of estimated AUCs was within 85%–115% of the measured AUCs; for the 3 time point model: R2 = 0.573, bias = 6.196 (95% CI, −10.627 to 23.018), precision = 21.286 (95% CI, 8.079–34.492), and 50.0% of estimated AUCs was within 85%–115% of the measured AUCs. Conclusions: It demanded at least 4 time points to develop a relatively reliable model to estimate the exposure of MPA in renal transplant recipients receiving the EC-MPS. The long time span needed restricted its application, especially for the outpatients, but it could be a useful tool to guide the personalized prescription for the inpatients.

Results from clinical studies indicate that azathioprine and enteric-coated mycophenolate sodium (EC-MPS) are safe and potent drugs in the treatment of atopic dermatitis (AD).(1-5) However, published data from large groups of non-selected patients is non-existent to date which hampers generalization to daily practice. In addition, head-to-head trials in which azathioprine and EC-MPS are compared, have never been performed. The primary objective was to perform an analysis of drug survival for azathioprine and EC-MPS in a long-term daily practice cohort of patients with AD. The secondary objective was to identify determinants of drug survival. This article is protected by copyright. All rights reserved.

Background Considerable interest exists in identifying calcineurin inhibitor (CNI)-free and thus, less-toxic immunosuppressive regimens, with mycophenolic acid (MPA)-based treatments being a suitable approach. Because pharmacokinetic analyses of MPA treatments in stable CNI-free renal transplant recipients are lacking, the authors aimed at comparing the steady-state pharmacokinetic characteristics of MPA in patients on stable treatment with mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS) plus prednisone (≤5 mg/d). Methods In the prospective, nonrandomized, open-label study, patients with stable transplant function since ≥6 months received their routine single dose of either MMF (n = 12) or EC-MPS (n = 11). The MPA plasma concentration was recorded over 12 hours. Parameters assessed were predose MPA concentration (C0), postdose minimum and maximum concentration (Cmin and Cmax), time to maximum concentration (Tmax), and area under the concentration-time curve (AUC) for the 12-hours of exposure (AUC0-12). Results Baseline characteristics were comparable between both the groups. Consistent with enteric coating, the mean Tmax was significantly longer after the intake of EC-MPS compared with MMF (2.2 versus 0.8 hours; P = 0.0002). The exposure measures Cmin, Cmax, and AUC0-12 were not significantly different despite the higher mean MPA equivalent dose in patients receiving MMF compared with those receiving EC-MPS (85% versus 64% of the recommended single dose, respectively). Exposures as reflected by the median AUC0-12 values were 50.7 and 58.7 mg·h·L with MMF and EC-MPS, respectively (P = 0.340). All patients achieved a target AUC of >30 mg·h·L, and 61% had an AUC of >50 mg·h·L. Conclusions The study provides first results on the steady-state pharmacokinetics of the 2 MPA drugs in CNI-free immunosuppressant regimens. Pharmacokinetic parameters measured in this study under real-life conditions were comparable in patients receiving MMF or EC-MPS.

Background Therapeutic drug monitoring of mycophenolic acid (MPA) is usually performed with a limited sampling strategy (LSS), which relies on a limited number of blood samples and subsequent extrapolation of the global exposure to MPA. LSS is usually performed successfully with mycophenolate mofetil (MMF), but data on enteric-coated mycophenolate sodium (EC-MPS) are scarce. Here, we evaluated the feasibility of 6-h LSS therapeutic drug monitoring with EC-MPS compared with MMF monitoring among kidney transplant recipients. Methods Sixty-two patients who received EC-MPS during the first 6 months of transplantation were compared with a matched group of 64 MMF-treated kidney transplant recipients. The area under the curve (AUC) was computed by LSS using multiple concentration time points (0, 1, 2, 3 and 6 h post-dose) and a trapezoidal rule. Patients had MPA therapeutic drug monitoring performed on two occasions, one within 2 weeks and the second after 3-4 months of transplantation. Results EC-MPS monitoring and MMF therapeutic drug monitoring were not interpretable in 34.5% (n = 40/116) and 1.8% (n = 2/112) of patients, respectively {relative risk [RR] 19.3 [95% confidence interval (CI) 4.8-78.0]; P < 0.0001}. The main cause of abnormal EC-MPS therapeutic drug monitoring was delayed absorption of both the previous evening and the morning dose, resulting in MPA plasma levels before the next morning dose being higher than MPA plasma levels measured at 1, 2 and 3 h after taking EC-MPS. Cyclosporin in association with MMF significantly increased the risk of low AUC values (30% during the first 6 months of renal transplantation. Delayed pharmacokinetics was the main reason. In contrast, the risk of therapeutic drug monitoring failure was substantially lower with MMF., SCOPUS: ar.j, info:eu-repo/semantics/published

Clinical results point to a better gastrointestinal tolerability with enteric-coated mycophenolate sodium as compared to mycophenolate mofetil. However, some transplant recipients who are treated with enteric-coated mycophenolate sodium still experience gastrointestinal symptoms. We herein present two cases of renal transplant recipients with severe gastrointestinal symptoms who were switched from enteric-coated mycophenolate sodium to mizoribine, and the symptom reversal effects were evaluated using the Gastrointestinal Symptom Rating Scale. The results of this study showed a significant improvement in severe gastrointestinal symptoms in renal transplant recipients after converting from enteric-coated mycophenolate sodium to mizoribine.