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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.

AIM. Evaluation in comparative study the efficiency of first choice cytostatic therapy with calcineurin inhibitor cyclosporine A and nucleotide synthesis inhibitormycophenolatemofetil (MMF)/mycophenolate sodium in children with relapsing and frequently relapsing steroid-dependent and steroid-sensitive nephrotic syndrome (NS) with steroid toxicity.PATIENTS AND METHODS. Follow-up study with analysis of onset, clinical course and treatment includes 48 children ((29 boys (60 %) и 19 girls (40 %)) with relapsing and frequently relapsing NS, developedsteroid dependence and/or steroid toxicity.The efficiency of first choice cytostatic therapy with calcineurin inhibitor cyclosporine Ain 17 patients and nucleotide synthesis inhibitormycophenolatemofetil (MMF)/mycophenolate sodium in 31 patients is estimated in comparative study by analysis of 6 month remission rate and one year remission rate after treatment.RESULTS. Statistically significant differences in 6 month and one year remission rate after first choice cytostatic therapy with MMF/ mycophenolate sodium and cyclosporine in children are established. Remission of NS during 6 months after MMF/ mycophenolate sodium treatment was in 67,7 % (in 21 from 31 patients) unlike of that after cyclosporine – in 29,4 % (in 5 from 17 patients) (рCONCLUSION. Remission of relapsing and frequently relapsing steroid-dependent and steroid-sensitive with steroid toxicity NS during 6 months after first choice cytostatic therapy with MMF/ mycophenolate sodium and cyclosporine in children was in 67,7 % and 29,4 % respectively, during one year in 58,1 % and 23,5 % respectively. As the result of comparative study remission during 6 months and one year was statistically significant more often in children after first choice cytostatic therapy with MMF/ mycophenolate sodium.

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, 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.

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.

Introduction: There is a paucity of real-world data on mycophenolate mofetil/mycophenolate sodium in systemic sclerosis-related interstitial lung disease. Aim: To study the efficacy of mycophenolate mofetil/ mycophenolate sodium in systemic sclerosis-related interstitial lung disease. Methods: In this single-centre study, clinical, laboratory and imaging details of consecutive patients with systemic sclerosis-related interstitial lung disease receiving mycophenolate mofetil/mycophenolate sodium from rheumatology and pulmonology clinics between January 2008 and March 2017 were retrospectively retrieved. The change in percentage of predicted normal forced vital capacity at last follow-up visit as compared with baseline was studied. In addition, high-resolution computed tomography scans at baseline and 2-year follow-up visit were scored as either stable/improved or worsened by experienced thoracic radiologists blinded to the clinical details of patients. Results: Altogether, 88 patients (85.2% females) with mean age (SD) of 33.8 years (± 11.3) and median (interquartile range) duration of disease since non-Raynaud’s symptoms of 36 months (13.5–60) were studied. Diffuse systemic sclerosis comprised 85.2% of them. The mean baseline forced vital capacity was 61.2 ± 17.9% and median scores for ground glass opacities and fibrosis in high-resolution computed tomography were 0.5 (0–1.3) and 1 (0–1.3), respectively. At a median follow-up duration of 30 months (interquartile range = 16.5–49), the percentage of forced vital capacity improved by 1.8% (–3.82 to 9.07) as compared with baseline visit ( p = 0.02). In the 2-year follow-up, the ground glass opacity and fibrosis scores in high-resolution computed tomography improved in 17.3% and 7.7% of patients and stabilized in 63.5% and 78.8% patients, respectively. Conclusion: Mycophenolate mofetil/mycophenolate sodium was efficacious in improving /stabilizing forced vital capacity irrespective of the baseline high-resolution computed tomography lung scores in our patients with systemic sclerosis-related interstitial lung disease during the ⩾ 2-year follow-up period.

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.

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.

Background: One of the leading cause of mortality in various connective tissue diseases(CTD) like systemicsclerosis(SSc)is Interstitial lung disease(ILD). The various CTD which may present as ILD include systemicsclerosis (SSc), rheumatoid arthritis(RA),dermatomyositis (DM), primary Sjogren’s syndrome(pSS), mixtedconnective tissue disease(MCTD) and systemic lupus erythematosus (SLE).Objective: To compare the safety and tolerability of two salts of mycophenolate,i.e. mycophenolate mofetiland mycophenolate sodium in our patients with CTD-ILD.Patients and Method: Ourstudy was retrospective observational study; involving 70 patients diagnosedwith CTD-ILD and was treated with two formulations of Mycophenolate (Mofetil and Sodium) minimumfor six months with at least one follow-up during the period of May 2013 to April 2017 at tertiary carehospital from India. Fifty-six patients received MPS and fourteen patients received MMF. The details ofpatients obtained from case records were recorded in a proforma. Statistical analysis was performed usingGraph pad for frequency, mean and percentages.Results: In our study,most of the patients receivedMycophenolate sodium (n=56) with the BD dose regimenof 720 mg (n=36), 540 mg (n=18) and 180 mg (n=2). Patients treated with MMF 1000 mg (n=12) and 750mg (n=2) as BD dose regimen.The adverse events reported in this study were GI (diarrhoea), herpes zosterinfection, cytopenia, malignancies or any other infections. The incidence of diarrhea is most commonlyobserved in this study population. Out of 26 reported cases, 14 patients had an episode of diarrhea at leastonce and 12 patients had diarrhea attack twice the preceding year.Conclusions: Both formulations of Mycophenolate were tolerated well, and have low-dose corticosteroiduse with no discontinuation of therapy.

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: 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.

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.

Mycophenolate is often used in the management of systemic lupus erythematosus. It has often been associated with significant fetal embryopathy, including fetal loss and multiple anomalies. The Food and Drug Administration has directed that women should be counseled regarding this prior to initiating treatment with this drug. Isolated total anomalous pulmonary venous return (TAPVR) is a rare association seen with its use in pregnancy.

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.

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.

A renal allograft recipient developed cough with hemoptysis on the 1st postoperative day. A chest X-ray was performed which was suggestive of fluid overload. His fluid was restricted and diuretics were added. On the same day, his pulmonary infiltrates worsened and a computed tomography (CT) of the chest was carried out, which was suggestive of the right lower lobe consolidation and left pleural effusion. He underwent a bronchoscopy and the lavage was sent for cultures, which did not grow any infective organism. Besides routine antibiotics, treatment for possible cytomegalovirus, fungal infections, and pneumocystis infection was instituted. Noninvasive ventilation was started on day 8. A repeat CT of the chest on the postoperative day 8 showed further worsening of the pulmonary infiltrates. As all the initial cultures and serology were negative, a possibility of interstitial pneumonitis was considered. Mycophenolate sodium was considered as a possible cause of the lung infiltrates and was withdrawn. The patient showed progressive improvement. His antibiotics were withdrawn. He was discharged on day 14. A repeat CT 4 weeks post transplant showed significant improvement in his pulmonary pathology. The acute lung injury was considered to be a drug reaction secondary to mycophenolate sodium. In a renal allograft recipient with persistent pulmonary infiltrates, interstitial involvement secondary to drugs should be considered if the patient does not improve with the standard treatment measures.

Background:Lupus nephritis is the most important predictive factor of morbidity and mortality in SLE. Though Mycophenolate mofetil is recommended for induction and maintenance treatment of class III, IV V lupus nephritis, it is not approved by US or Taiwan FDA (TFDA). In previous reports of kidney transplantation, no efficacy differences were observed between mycophenolate sodium (Myfortic) and mycophenolate mofetil (Cellcept). However, no clinical trial was conducted to compare these two widely-used mycophenolic acid derivatives in lupus nephritis. In December, 2016, TFDA approved Mycophenolate sodium in treatment of lupus nephritis. For reimbursement issue, patients treated with mycophenolate mofetil were non-medically switched to mycophenolate sodium in Taiwan.Objectives:To compare the treatment efficacy of mycophenolate mofetil and mycophenolate sodium in lupus nephritis patients with non-medical switching.Methods:Between 2016 and 2018, a retrospective observational study enrolled 50 biopsy-proven LN patients in Taichung Veterans General Hospital, Taiwan. All these patients were initially treated with Cellcept for at least one year. Treatment response was evaluated by urinalysis and daily urine protein one year before and after switching to Myfortic.Results:Before switching, 72% patients were classified as responder if complete remission or partial remission were achieved, while 28% patients were categorized as non-responders (Table 1). After switching to Myfortic, 75% of the responder group achieved or maintained complete remission or partial response. In for non-responder group, 85.7% exhibited complete remission or partial response (Table 2). We did not observe new safety signals after switching.Table 2.Laboratory featuresNon-responder (N=14)Responder*(N=36)Total (n=50)pvalueAge31.12±11.4832.58±9.390.660Female23(88.5%)20(76.9%)43(82.7%)0.465Daily urine protein (g)4.44±4.404.43±3.810.835Creatine (mg/dl)1.44±0.921.22±1.160.212Renal pathology class0.649III6(23.1%)4(15.4%)10(19.2%)III+V2(7.7%)4(15.4%)6(11.5%)IV16(61.5%)15(57.7%)31(59.6%)IV+V2(7.7%)3(11.5%)5(9.6%)*complete remission and partial remission.Table 1.Comparative analysis of 328 SLE patients with and without lupus fatigueInitial treatment with CellceptNon-responderResponderp valueNon-medical switch to Myfortic0.705Non-responder2(14.3)9(25)Responder12(85.7)27(75)Conclusion:This real-world data indicated similar efficacy of Cellcept and Myfortic. Further prospective study is needed to confirm our findings.Disclosure of Interests:None declared

Patient: Male, 66-year-old Final Diagnosis: Drug-induced colitis Symptoms: Abdominal discomfort • anorexia • diarrhea • weight loss Medication: Enteric-coated mycophenolate sodium (Myfortic) Clinical Procedure: Colonoscopy • colon biopsy Specialty: Cardiology • Infectious Disease Objective: Rare disease Background: Mycophenolic acid is an immunosuppressive drug commonly used in solid organ transplantation to prevent acute and chronic allograft rejection. There are 2 common preparations of mycophenolic acid including mycophenolate mofetil (Cellcept), and enteric-coated mycophenolate sodium (Myfortic) which was developed to reduce the high rate of gastrointestinal side effects seen with Cellcept. Cases of mycophenolate mofetil induced colitis have been described in solid organ transplant patients and rarely in heart transplant patients, but enteric-coated mycophenolate sodium induced colitis is very rare and has not been reported in heart transplant patients. Case Report: A 66-year old male with an orthotopic heart transplant was admitted with diarrhea. The patient was on an immunosuppression regimen including mycophenolate mofetil for 10 weeks post-transplantation until complaining of soft stools and bloating. At this time, he was switched to enteric-coated mycophenolate sodium. At week 11 post-transplantation, the patient was admitted to the hospital with worsening diarrhea. Extensive workup was unrevealing. Colonoscopy with biopsy showed features of mycophenolic acid induced colitis. Enteric coated mycophenolate sodium was discontinued, and the patient’s diarrhea markedly improved over the next 48 hours. The patient had no signs of colitis or solid organ rejection at 7-month follow up appointment. Conclusions: Although a diagnosis of exclusion, enteric-coated mycophenolate sodium induced colitis should be considered in the differential of an orthotopic heart transplant patient with diarrhea as discontinuing the medication can improve symptoms and avoid costly workups, however, patients should be monitored closely for signs of rebound rejection.

The aim of the present study is to establish a population pharmacokinetic (PPK) model of mycophenolic acid (MPA) and limited sampling strategy models for the estimation of MPA exposure in Chinese adult renal allograft recipients following oral administration of enteric coated mycophenolate sodium (EC-MPS). A total of 74 sets of full pharmacokinetic profiles and 47 sets of MPA-sparing samples were collected from 102 renal transplant recipients who received oral EC-MPS. The MPA concentration was determined by an enzyme-multiplied immunoassay technique, and the pathophysiologic data were recorded. The PPK model was constructed using nonlinear mixed-effects modeling, and the limited sampling strategy models for MPA were established by using multiple regression analysis and the maximum a posteriori Bayesian assay based on 2 to 4 sampling time points following EC-MPS administration. The pharmacokinetics of MPA were best described by a 2-compartment model with a first-order absorption process and a lag time of absorption. The clearance of MPA was 12.3 ± 1.14 L/h. Comedicating with cyclosporine A was found to have a significant impact on the clearance/bioavailability of MPA (P < .01). Sampling strategies consisted of plasma concentration at 1.5, 2, 4 (C1.5-C2-C4) hours and 1.5, 2, 4, 6 (C1.5-C2-C4-C6) hours after EC-MPS administration were shown to be suitable for the estimation of the MPA area under the concentration-time curve in these patients. The PPK model was acceptable and can describe the pharmacokinetics of MPA in Chinese renal transplant recipients administered EC-MPS. The area under the concentration-time curve of MPA in Chinese renal transplant recipients could be estimated through a limited sampling strategy method, based on which individualized immunosuppressive regimens could be designed.

Introduction: Whether an early, short-term, adequate exposure to mycophenolic acid (MPA) under tacrolimus-based immunosuppression regimen in kidney transplantation from donation after circulatory death (DCD) was effective and safe is yet unknown. Material and Methods: The study was a single-center, retrospective, cohort study of DCD transplantation in China. Intensified and standard dosage regimens of enteric-coated mycophenolate sodium (EC-MPS) were week 1, 2,160 vs. 1,440 mg/day. The incidences of biopsy-proven acute rejection (BPAR), delayed graft function, infection, and patient and graft survival were compared between the 2 groups. Results: A total of 209 patients (n = 82 in intensified group and n = 127 in standard group) were enrolled from August 2013 to December 2014. The incidence of BPAR at 12 months was significantly lower in the intensified group as compared to that of the standard group. (2.4 vs. 10.2%, p = 0.035). The mean MPA area under curve (AUC) levels at day 7 was significantly higher in the intensified group than that in the standard group (66.18 ± 35.48 vs. 45.30 ± 23.5 mg·h/L, p < 0.001). MPA AUC levels were significantly decreased in patients with BPAR as compared to those with NO-BPAR. Conclusion: An early, short-term regimen of intensified EC-MPS with tacrolimus increased early MPA exposure and achieved a low rate of BPAR in kidney transplantation from DCD.

Background Immunosuppressant drugs for renal transplant mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS) cause gastrointestinal (GI) disorders. The specific site of GI tract targeted by MMF and EC-MPS remains unclear. Methods In this study, we investigated the effects of MMF and EC-MPS on stomach, duodenum, jejunum, ileum, colon and rectum using a rat model. Rats were randomized into five groups: control, MMF (100 mg/kg·d), mofetil (30 mg/kg·d), EC-MPS (72 mg/Kg·d), mofetil + EC-MPS. Each group was treated with drugs once a day for 7 days through intra-gastric gavage. Diarrhea grade of each rat were measured every day, as well as the body weight. Blood was collected by tail nick and Seven days later, the rats were sacrificed, GI tissues were collected for Histological research. Results The results showed that diarrhea grade and weight loss were significantly higher in MMF group than other groups. The pathological score of MMF group was significantly higher than EC-MPS group and EC-MPS + mofetil group in jejunum and ileum tissues, but not other segments of GI tract. Absorption of EC-MPS is delayed, compared to that of MMF. MPAG concentration in duodenum, jejunum and ileum tissues of MMF group is higher than EC-MPS group. Mofetil may increase the magnitude of MPA absorption. Conclusions Our data suggested that MMF might target jejunum and ileum and induce GI injury. EC-MPS causes less injury in GI tract than MMF, probably due to its kinetic property.

Background. Although colonic injury is a well-known complication of mycophenolic acid (MPA), the involvement of the upper gastrointestinal tract is less extensively documented. We present the occurrence of celiac-like duodenopathy manifested as a severe diarrhea syndrome in 2 renal transplant recipients on enteric-coated mycophenolate sodium. Methods. The patients belong to a setting of 16 renal transplant recipients under MPA suffering from chronic diarrhea in the absence of MPA-related colitis. Results. Both patients had a history of persistent diarrhea with significant weight loss. Colonic mucosa was unremarkable, whereas duodenal biopsies revealed celiac-like changes with increased epithelial cell apoptosis. Clinical symptoms completely resolved, and follow-up biopsies demonstrated normalization of histology after enteric-coated mycophenolate sodium withdrawal and switching to azathioprine. Conclusions. Celiac-like enteropathy seems to represent a rare side effect of MPA-associated immunosuppressive therapy and should be taken into account in the differential diagnosis of diarrhea in transplant recipients treated with MPA particularly in the absence of MPA-related colitis. As macroscopic lesions are usually missing, blind duodenal biopsies are necessary to establish the diagnosis.

Although multiple linear regression-based limited sampling strategies (LSSs) have been published for enteric-coated mycophenolate sodium, none have been evaluated for the prediction of subsequent mycophenolic acid (MPA) exposure. This study aimed to examine the predictive performance of the published LSS for the estimation of future MPA area under the concentration-time curve from 0 to 12 hours (AUC0-12) in renal transplant recipients.Total MPA plasma concentrations were measured in 20 adult renal transplant patients on 2 occasions a week apart. All subjects received concomitant tacrolimus and were approximately 1 month after transplant. Samples were taken at 0, 0.33, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours and 0, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 9, and 12 hours after dose on the first and second sampling occasion, respectively. Predicted MPA AUC0-12 was calculated using 19 published LSSs and data from the first or second sampling occasion for each patient and compared with the second occasion full MPA AUC0-12 calculated using the linear trapezoidal rule. Bias (median percentage prediction error) and imprecision (median absolute prediction error) were determined.Median percentage prediction error and median absolute prediction error for the prediction of full MPA AUC0-12 were15% for 4 LSSs, using the data from the same (second) occasion. One equation (1.583C1 + 0.765C2 + 0.369C2.5 + 0.748C3 + 1.518C4 + 2.158C6 + 3.292C8 + 3.6690) showed bias and imprecision15% for the prediction of future MPA AUC0-12, where the predicted AUC0-12 from the first occasion was compared with the full AUC0-12 from the second. All LSSs with an acceptable predictive performance included concentrations taken at least 6 hours after the dose.Only one LSS had an acceptable bias and precision for future estimation. Accurate dosage prediction using a multiple linear regression-based LSS was not possible without concentrations up to at least 8 hours after the dose.

Background Mycophenolic acid (MPA), a potent immunosuppressant, is widely used in solid organ transplantations. This study aimed to investigate the pharmacokinetics of enteric-coated mycophenolate sodium (EC-MPS) in Chinese adult renal allograft recipients and to generate optimal model equations for estimation of the MPA area under the concentration-time curve from 0 to 12 hours (AUC0-12 h), using a limited sampling strategy (LSS). Methods Serial blood samples were collected over 12 hours from 38 recipients of a primary living-related donor kidney graft treated with EC-MPS, tacrolimus, and corticosteroid. MPA concentrations were evaluated using an enzyme-multiplied immunoassay technique. The LSSs were developed and validated by multiple regression analysis using a 2-group method (test group, n = 19; validation group, n = 19). Results The best algorithms obtained from the test group were the following: 15.09 + 1.05 × C1.5 + 1.8 × C4 + 4.18 × C6 (for 3 time points, r = 0.902) and 10.44 + 0.7 × C1 + 1.22 × C2 + 1.75 × C4 + 4.36 × C6 (for 4 time points, r = 0.941). When these algorithms were tested in the validation group, there were no significant differences in prediction errors. Conclusions LSSs using time points of 1.5, 4, and 6 hours or 1, 2, 4, and 6 hours after dose provide effective and reliable estimations of the MPA AUC0-12 h in Chinese renal allograft recipients treated concomitantly with EC-MPS and tacrolimus during the early posttransplantation phase.

We assessed the relations between MPA, free MPA (fMPA) and MPA glucuronide (MPAG) pharmacokinetics and the clinical condition of renal transplant recipients treated with EC-MPS and tacrolimus (Tac) in the first post-transplant year. In 18 adult patients blood samples were collected up to 12 h after EC-MPS oral administration. EC-MPS metabolites’ plasma concentrations were determined using validated HPLC methods. All patients reached MPA area under the time–concentration curve (AUC0–12) above 30 µg h/mL. Most of the MPA, fMPA and all MPAG concentrations correlated significantly with respective AUC0–12 values. Some fMPA and all MPAG pharmacokinetic parameters correlated negatively with creatinine clearance and positively with creatinine concentration, whereas no such correlation was observed for MPA. Lower hemoglobin concentrations were observed in patients with higher MPA or fMPA C 0. The significant correlations between MPA C 3 as well as MPA C 4 and MPA AUC0–4 and MPA AUC0–12 may be of importance in further studies including larger number of patients in regard to establishing LSS. In patients treated with EC-MPS and Tac, monitoring MPA C 0 may be important, as too high MPA C 0 may contribute to anemia onset. In EC-MPS treated patients, MPAG concentration is related to renal function as MPAG pharmacokinetics were higher in patients with renal impairment.

BACKGROUND: Chronic lung allograft dysfunction (CLAD), Predominantly manifest as bronchiolitis obliterans syndrome (BUS), is the primary cause of morbidity and death after lung transplantation. We assessed the efficacy and safety of 2 de novo immunosuppression protocols to prevent BUS.METHODS: This was a multicenter, prospective, international, randomized (1:1) open-label superiority study of de novo enteric-coated mycophenolate sodium (MPS) vs delayed-onset everolimus (RAD), both arms in combination with cyclosporine (CsA) monitored by 2-hour post-dose (C-2) levels, and corticosteroids. Target C-2 levels were lower in the RAD group because RAD is known to potentiate CsA nephrotoxicity. Cytolytic induction therapy was not used. Patients were stratified at entry for cystic fibrosis. Confirmation of anastomotic healing was required for randomization. Primary efficacy was freedom from BUS Grade 1 on intention-to-treat (ITT) analysis. Secondary efficacy parameters were patient and graft survival and severity of rejection. Treatment failure was defined by graft loss, patient death, drug cessation, or need for other therapy.RESULTS: The 3-year freedom from BUS Grade 1 was 70% for MPS (n = 80) vs 71% for RAD (n = 84; p = 0.95 by log-rank) in ITT but was lower in the RAD arm of the per-protocol population (p = 0.03). The 3-year survival was 84% (MPS) vs 76% (RAD; p = 0.19 by log-rank). Thirteen patients switched from MPS vs 31 from RAD (p CONCLUSIONS: This 3-year ITT analysis found no significant difference between arms but was underpowered to accept the null hypothesis that RAD and MPS have equivalent efficacy in preventing BOS or death after lung transplantation. (C) 2015 International Society for Heart and Lung Transplantation. All rights reserved.

Optimal therapy and prognosis of crescentic-IgA nephropathy (C-IgAN) are not known. Reported treatment options for C-IgAN include combination of corticosteroids and cyclophosphamide for 6 months. The role of mycophenolate sodium in C-IgAN is unknown. We report a case of C-IgAN that was successfully treated with combination immunosuppressive therapy.

In this retrospective study, patients with idiopathic frequently-relapsing nephrotic syndrome (FRNS) (n=27) and steroid dependent nephrotic syndrome (SDNS) (n=13) who received enteric coated mycophenolate sodium (ECMS) for at least 6 months, were included for analysis. Primary outcome was response to ECMS, which was defined as complete if there were no relapses, partial response if there was 1 relapse and no response if there were 2 or more relapses within 6 months of initiation. The mean (SD) dose of ECMS was 985.24 (190.82) mg/m2/day. Thirty patients(75%) had complete response, eight (20%) had partial and two (5%) patients did not respond at 6 months. ECMS seems to be a safe and effective as steroid sparing agent in children with FRNS/SDNS.

Background: It remains unclear whether overall degree of immunosuppression or specific effects of individual immunosuppressive agents are causal for increased occurrence of BK polyomavirus (BKPyV) infection in renal transplant recipients (RTR).Methods: A prospective, multicenter, open-label randomized controlled trial in 361 de novo RTR was performed. A total of 224 RTR were randomized at 6months into three treatment groups with dual therapy consisting of prednisolone (Pred) plus either cyclosporine (CsA), mycophenolate sodium (MPS), or everolimus (EVL). Primary outcomes were incidence of BK viruria, BK viremia, and BKPyV-associated nephropathy (BKVAN).Results: From 6months, incidence of BK viruria in the MPS group (43.6%) was significantly higher than in the other groups (CsA: 16.9%, EVL: 19.8%) (P=.003). BKVAN was diagnosed in 3 patients, all treated with MPS (7.8%, P=.001). Longitudinal data analysis showed a lower BKPyV load and a significantly faster clearance of BK viruria in the CsA group compared to the MPS group (P=.03).Conclusions: Treatment with MPS was associated with an increased incidence of BK viruria. Dual immunosuppressive therapy with CsA and Pred was associated with the lowest rate of BKPyV replication and the fastest clearance of the virus.

tudy Objective To investigate the influence of single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (CYP2C8, CYP2J2, and UGT2B7) and transporters (ABCC2 and ABCG2) on dose and dose-adjusted trough blood concentrations (C:D ratio), clinical outcomes, and occurrence of adverse events of tacrolimus and mycophenolate sodium in Brazilian kidney transplant recipients. Design Pharmacogenetic analysis of patients enrolled in a previously published study. Patients One hundred forty-eight adult kidney transplant recipients treated with tacrolimus, enteric-coated mycophenolate sodium, and prednisone for 90 days posttransplantation. Measurements and Main Results ABCC2 c.−24C>T and c.3972C>T, ABCG2 c.421C>A, CYP2C8*3, CYP2J2 c.−76G>T, and UGT2B7 c.372A>G SNPs were determined by real-time polymerase chain reaction. The CYP3A5*3C SNP data were used to eliminate the confounding effect of this variant on the results. ABCC2 c.3972T allele carriers showed higher tacrolimus C:D values than did carriers of the c.3972CC genotype. The CYP2C8*3 variant was also associated with slightly higher tacrolimus C:D values and higher estimated glomerular filtration rate but only in CYP3A5-nonexpressing patients (CYP3A5*3C/*3C carriers). None of the SNPs were associated with mycophenolate sodium dose or episodes of biopsy-confirmed acute rejection or delayed graft function. The CYP2J2 c.−76T allele was associated with increased risk for treatment-induced nausea and/or vomiting (OR: 5.30, 95% confidence interval 1.49-18.79, pT polymorphism affected tacrolimus C:D in Brazilian kidney transplant recipients. Further, CYP2C8*3 and CYP2J2 c.−76G>T SNPs influenced the renal function of these patients and the occurrence of adverse events during treatment with tacrolimus and mycophenolate sodium.

Mycophenolic acid was first discovered in 1913 and first used clinically in the 1970s as an immunosuppressant to prevent organ transplantation rejection. It was later used in the treatment of psoriasis. However due to its side-effect profile and fears over its carcinogenic potential it was abandoned. From the late 1990s a prodrug, mycophenolate mofetil (MMF), was developed and more recently, enteric-coated mycophenolate sodium (EC-MPS), both of which have gained increasing use in the field of dermatology for a variety of skin conditions. This review discusses the pharmacology, mechanisms of action, side-effects and current clinical applications in dermatology of MMF and EC-MPS.

No evaluation of sex and race influences on mycophenolic acid (MPA) pharmacokinetics and adverse effects (AEs) during enteric-coated mycophenolate sodium (ECMPS) and tacrolimus immunosuppression are available. The primary objective of this study was to investigate the influence of sex and race on MPA and MPA glucuronide (MPAG) pharmacokinetics in stable renal transplant recipients receiving ECMPS and tacrolimus The pharmacokinetics of MPA and MPAG and their associated gastrointestinal AEs were investigated in 67 stable renal transplant recipients: 22 African American males (AAMs), 13 African American females (AAFs), 16 Caucasian males (CMs), and 16 Caucasian females (CFs) receiving ECMPS and tacrolimus. A validated gastrointestinal AE rating included diarrhea, dyspepsia, vomiting, and acid-suppressive therapy was completed. Apparent clearance, clearance normalized to body mass index (BMI), area under the concentration–time curve from time zero to 12 h (AUC12) and dose-normalized AUC12 (AUC*) were determined using a statistical model that incorporated gastrointestinal AE and clinical covariates. Males had more rapid apparent MPA clearance (CMs 13.8 ± 6.27 L/h vs. AAMs 10.2 ± 3.73 L/h) than females (CFs 8.70 ± 3.33 L/h and AAFs 9.71 ± 3.94 L/h; p = 0.014) with a race–sex interaction (p = 0.043). Sex differences were observed in MPA clearance/BMI (p = 0.033) and AUC* (p = 0.033). MPA AUC12 was greater than 60 mg·h/L in 57 % of renal transplant recipients (RTR) with 71 % of patients demonstrating gastrointestinal AEs and a higher score noted in females. In all patients, females exhibited 1.40-fold increased gastrointestinal AE scores compared with males (p = 0.024). Race (p = 0.044) and sex (p = 0.005) differences were evident with greater MPAG AUC12 in AAFs and CFs. Sex and race differences were evident, with females having slower MPA clearance, higher MPAG AUC12, and more severe gastrointestinal AEs. These findings suggest sex and race should be considered during MPA immunosuppression.

Enteric-coated mycophenolate sodium (EC-MPS) is effective and safe in preventing rejection after transplantation and is mainly transported by ABCs and OATPs and metabolized by UGTs. The genetic polymorphisms affect the inter-individual variation in drug disposition and elimination. The aims of this study were to develop a population pharmacokinetic (PK) model and to evaluate the influence of genetic and clinical factors on the PK of mycophenolic acid (MPA) in Korean renal transplant recipients. Population analysis of EC-MPS was performed using non-linear mixed effects modeling (NONMEM). After clinical and genetic factors were evaluated using a stepwise covariate method, we selected clinically relevant covariates considering covariate effects. The final model was validated by bootstrap and visual predictive check. At last, we performed the model-based simulations in order to explore an optimal dose to achieve target area under the curve (AUC) in hypothetical scenarios. From 166 plasma concentrations (n=34), a time-lagged two-compartment with a flip-flop model best describes the PK of MPA. The covariate analysis identified lower creatinine clearance (CLcr) and SLCO1B1 variant genotype were correlated with lower MPA clearance, on the contrary, UGT1A9 variant had decreased distribution of MPA, contributing to lower absorption. When considering to UGT1A9, SLCO1B1 genotypes, and renal function, the new recommended dose of 540 mg twice daily resulted in a higher success of achieving the target AUC0-12h in the 30-60 mg.h/L. CLcr, UGT1A9 and SLCO1B1 genotypes seem to be promising parameters to predict the pharmacokinetics with flip-flop phenomenon of EC-MPS in transplant recipient having stable renal function. This model on clinical practice may help prevent overexposure and achieve a proper AUC in the Korean population.

Background Two oral mycophenolic acid (MPA) formulations, immediate-release mycophenolate mofetil and enteric-coated mycophenolate sodium, have been shown to differ regarding some drug-drug interactions. The aim was to assess whether the effects of cyclosporine (CsA) on steady-state pharmacokinetics (PK) of MPA in renal transplant patients were affected by MPA formulation. Methods A prospective, stratified observational study based on therapeutic drug monitoring of MPA (6 total plasma concentrations over a 12-hour dosing interval, τ) in consecutive stable adult renal transplant recipients (n = 68). Results Patients treated with enteric-coated mycophenolate sodium (n = 45) or mycophenolate mofetil (n = 23) and with either CsA (microemulsion, n = 43) or tacrolimus (Tac) (immediate release, n = 25) were comparable regarding demographics, comorbidity, renal and liver functions, comedication, corticosteroid dose, CsA or Tac dose, and trough concentrations. Based on dose-normalized MPA concentrations and with adjustment for age, sex, body mass index, estimated glomerular filtration rate, and corticosteroid dose, CsA (as compared with Tac) consistently reduced MPA area under the concentration-time curve during the dosing interval at steady state overall [geometric mean ratio (GMR), 0.78; 95% confidence interval, 0.62-0.99] and by MPA formulation (by 22% and 21%, respectively), increased CLT/F,ss overall (1.31; 1.00-1.70) and by formulation (by 25% and 36%, respectively), reduced morning predose MPA concentration overall (0.59; 0.38-0.92) and by formulation (by 34% and 47%, respectively), increased peak-trough fluctuation overall (1.51; 1.06-2.17) and by formulation (by 58% and 45%, respectively), and prolonged tmax,ss overall (adjusted median difference 0.58, 0.04-1.12 hours) and by formulation (by 0.6 and 0.5 hours, respectively). Conclusions Qualitatively and quantitatively, the effect of CsA on steady-state PK of MPA is not conditional on MPA formulation.

MORE was a four-yr, prospective, observational study at 40 transplant centers in the US. Data were analyzed to evaluate changes in mycophenolic acid (MPA) dosing over time in 904 de novo kidney transplant recipients receiving enteric-coated mycophenolate sodium (EC-MPS, n = 616) or mycophenolate mofetil (MMF, n = 288) with tacrolimus. Induction therapy and steroid treatment were similar in the two subpopulations. The proportion of patients receiving the maximal recommended MPA dose was 80.5%, 43.9%, 39.2%, 34.6%, and 30.1% at baseline and years 1, 2, 3, and 4, respectively. More patients received the maximal recommended MPA dose with EC-MPS vs. MMF at month 1 (79.2% vs. 71.7%, p = 0.016), month 3 (68.5% vs. 56.9%, p = 0.001), and month 6 (52.9% vs. 44.0%, p = 0.028). Multivariate analysis showed the risk of biopsy-proven acute rejection, graft loss or death to be similar for EC-MPS vs. MMF. Estimated glomerular filtration rate (GFR) was similar with EC-MPS vs. MMF at all time points. There were no significant differences in any category of adverse event between the EC-MPS and MMF cohorts during follow-up, including gastrointestinal events. In conclusion, MPA dose was maintained more effectively in the first six months after kidney transplantation using EC-MPS vs. MMF, without an increase in adverse events.

Enteric-coated mycophenolate sodium (EC-MPS) and mycophenolate mofetil (MMF), two prodrugs of mycophenolic acid (MPA), have been used in immunosuppressive regimens. After being taken orally, both of them transform to MPA to achieve immune suppression effects; however, the main site of absorption and metabolism of EC-MPS is different from that of MMF in vivo. Therefore, combined application with related drugs may result in different MPA levels and have different clinical effects in kidney transplant recipients.To evaluate the efficacy of EC-MPS compared with MMF in Chinese renal transplant patients comedicated with a proton pump inhibitor (PPI).Our subjects were 88 patients who received renal transplants at the 309th Hospital of the Chinese PLA from May 2010 to April 2013. These were made up of two groups including 27 patients with EC-MPS and 61 with MMF. The immunosuppression regimen was EC-MPS/MMF + cyclosporine/tacrolimus + steroid hormone, comedicated with a PPI (omeprazole). The patients' levels of exposure of MPA within 1 week after operation were monitored. Clinical indicators such as incidence of delayed graft function and acute rejection, the rate of change of serum creatinine hemoglobin, leucocytes, and neutrophils, as well as clinical adverse drug reactions and drug conversion were analyzed retrospectively.The kidney function of patients recovered to normal in both the EC-MPS and MMF groups. The mean concentration to peak (Cmax), the mean half-life (t1/2), and the area under the concentration-time curve (AUC0-12) of MPA in the EC-MPS group were higher than those in the MMF group (P.05). This indicated that the pharmacokinetic parameters for MPA when EC-MPS is co-administered with a PPI in kidney transplant patients in China is better than for comedication with MMF and a PPI. The MMF group had a higher incidence of drug withdrawal because of higher infection rates, leucocyte decrease, and more gastrointestinal side effects than the EC-MPS group (P.05). No significant differences in the clinical effect on kidney transplant recipients were observed in the limited observation time.

Introduction: To discuss the significance of the recent observational case series from the Swiss Toxicological Information Centre (STIC). Mycophenolic acid (MPA) and its prodrug mycophenolate mofetil are immunosuppressive agents that are frequently prescribed in renal transplant recipients, and their safety profiles must be established. Areas covered: This case series and systemic literature analysis consists of 15 cases of MPA overdose from the STIC and a systemic analysis of the literature over the past 18 years. This study focuses on acute overdosing, the effects of which are presumably mild. In contrast, the effects of long-term overdosing may be much more severe. Substantial underreporting is likely. The pharmacokinetic monitoring of MPA is rarely performed, which is both striking and does not coincide with findings in academic literature. The scant data on pharmacokinetic monitoring presented demonstrated that MPA has a short terminal half-life, which suggests that decontamination and activated charcoal treatment in acute overdose may not be necessary. Expert opinion: The case series and systematic literature analysis of acute mycophenolate overdose represent an important contribution toward increasing the safety of MPA therapy. © 2014 Informa UK, Ltd.