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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.

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.

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.

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.

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.

This review aims to provide an extensive overview of the literature on the clinical pharmacokinetics of mycophenolate in solid organ transplantation and a briefer summary of current pharmacodynamic information. Strategies are suggested for further optimisation of mycophenolate therapy and areas where additional research is warranted are highlighted. Mycophenolate has gained widespread acceptance as the antimetabolite immunosuppressant of choice in organ transplant regimens. Mycophenolic acid (MPA) is the active drug moiety. Currently, two mycophenolate compounds are available, mycophenolate mofetil and enteric-coated (EC) mycophenolate sodium. MPA is a potent, selective and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), leading to eventual arrest of T- and B-lymphocyte proliferation. Mycophenolate mofetil and EC-mycophenolate sodium are essentially completely hydrolysed to MPA by esterases in the gut wall, blood, liver and tissue. Oral bioavailability of MPA, subsequent to mycophenolate mofetil administration, ranges from 80.7% to 94%. EC-mycophenolate sodium has an absolute bioavailability of MPA of approximately 72%. MPA binds 97–99% to serum albumin in patients with normal renal and liver function. It is metabolised in the liver, gastrointestinal tract and kidney by uridine diphosphate gluconosyltransferases (UGTs). 7-O-MPA-glucuronide (MPAG) is the major metabolite of MPA. MPAG is usually present in the plasma at 20- to 100-fold higher concentrations than MPA, but it is not pharmacologically active. At least three minor metabolites are also formed, of which an acyl-glucuronide has pharmacological potency comparable to MPA. MPAG is excreted into the urine via active tubular secretion and into the bile by multi-drug resistance protein 2 (MRP-2). MPAG is de-conjugated back to MPA by gut bacteria and then reabsorbed in the colon. Mycophenolate mofetil and EC-mycophenolate sodium display linear pharmacokinetics. Following mycophenolate mofetil administration, MPA maximum concentration usually occurs in 1–2 hours. EC-mycophenolate sodium exhibits a median lag time in absorption of MPA from 0.25 to 1.25 hours. A secondary peak in the concentration-time profile of MPA, due to enterohepatic recirculation, often appears 6–12 hours after dosing. This contributes approximately 40% to the area under the plasma concentration-time curve (AUC). The mean elimination half-life of MPA ranges from 9 to 17 hours. MPA displays large between- and within-subject pharmacokinetic variability. Dose-normalised MPA AUC can vary more than 10-fold. Total MPA concentrations should be interpreted with caution in patients with severe renal impairment, liver disease and hypoalbuminaemia. In such individuals, MPA and MPAG plasma protein binding may be altered, changing the fraction of free MPA available. Apparent oral clearance (CL/F) of total MPA appears to increase in proportion to the increased free fraction, with a reduction in total MPA AUC. However, there may be little change in the MPA free concentration. Ciclosporin inhibits biliary excretion of MPAG by MRP-2, reducing enterohepatic recirculation of MPA. Exposure to MPA when mycophenolate mofetil is given in combination with ciclosporin is approximately 30–40% lower than when given alone or with tacrolimus or sirolimus. High dosages of corticosteroids may induce expression of UGT, reducing exposure to MPA. Other co-medications can interfere with the absorption, enterohepatic recycling and metabolism of mycophenolate. Most pharmacokinetic investigations of MPA have involved mycophenolate mofetil rather than EC-mycophenolate sodium therapy. In population pharmacokinetic studies, MPA CL/F in adults ranges from 14.1 to 34.9 L/h (ciclosporin co-therapy) and from 11.9 to 25.4 L/h (tacrolimus co-therapy). Patient bodyweight, serum albumin concentration and immunosuppressant co-therapy have a significant influence on CL/F. The majority of pharmacodynamic data on MPA have been obtained in patients receiving mycophenolate mofetil therapy in the first year after kidney transplantation. Low MPA AUC is associated with increased incidence of biopsy-proven acute rejection. Gastrointestinal adverse events may be dose related. Leukopenia and anaemia have been associated with high MPA AUC, trough concentration and metabolite concentrations in some, but not all, studies. High free MPA exposure has been identified as a risk factor for leukopenia in some investigations. Targeting a total MPA AUC from 0 to 12 hours (AUC12) of 30–60 mg ∙ hr/L is likely to minimise the risk of acute rejection and may reduce toxicity. IMPDH monitoring is in the early experimental stage. Individualisation of mycophenolate therapy should lead to improved patient outcomes. MPA AUC12 appears to be the most useful exposure measure for such individualisation. Limited sampling strategies and Bayesian forecasting are practical means of estimating MPA AUC12 without full concentration-time profiling. Target concentration intervention may be particularly useful in the first few months post-transplant and prior to major changes in anti-rejection therapy. In patients with impaired renal or hepatic function or hypoalbuminaemia, free drug measurement could be valuable in further interpretation of MPA exposure.

▲ Mycophenolate sodium delayed release is an enteric-coated formulation designed to release the active agent (mycophenolic acid) in the small intestine. ▲ Mycophenolate sodium delayed release was equivalent in efficacy to, and had a similar tolerability profile as, mycophenolate mofetil in de novo renal transplant patients treated with ciclosporin (cyclosporin) and corticosteroids in a well designed study of 12 month’s duration. ▲ Maintenance renal transplant patients treated with ciclosporin and corticosteroids were converted from mycophenolate mofetil to mycophenolate sodium delayed release without any alteration in efficacy or tolerability in a well designed study of 12 month’s duration. ▲ The incidence of gastrointestinal adverse events with mycophenolate sodium delayed release was similar to that with mycophenolate mofetil.

Mycophenolate mofetil is one of the most frequently used immunosuppressive drugs in solid organ transplantation. Although the adverse effect profile of mycophenolate mofetil is comparatively benign, gastrointestinal adverse effects are a major concern. The adverse effects may require a dose reduction or discontinuation, thus limiting its clinical efficacy. Enteric-coated (EC) mycophenolate sodium is a new formulation of mycophenolic acid (MPA) that delivers the active moiety MPA, the same active moiety delivered by mycophenolate mofetil. It has been developed to help protect the upper gastrointestinal tract. It is implied that a reduction of adverse drug effects as well as a reduction of dose may improve efficacy and compliance. Noncompliance is often underestimated in solid organ transplant recipients, and adverse drug effects increase medication nonadherence. Recent clinical trials comparing EC mycophenolate sodium and mycophenolate mofetil in kidney recipients reported similar rates of efficacy and adverse effects. It is noteworthy that systemic MPA exposure is higher with EC mycophenolate sodium than with mycophenolate mofetil, without increased gastrointestinal toxicity. This finding is quite surprising, because part of MPA-associated gastrointestinal toxicity is related to its antiproliferative effect on enterocytes. However, enteric coating of MPA did not markedly reduce the number of gastrointestinal adverse effects. Further studies focusing on dosage, therapeutic drug monitoring and immunosuppressive regimens may reveal benefits of EC mycophenolate sodium for optimal individualised immunosuppression and improved compliance. At present, EC mycophenolate sodium is an alternative immunosuppressant to mycophenolate mofetil in kidney transplant recipients with an almost identical efficacy and safety profile.

Mycophenolic acid (MPA) exerts a potent immunosuppressive effect via a number of distinct mechanisms. Use of the mycophenolate mofetil (MMF) formulation is associated with significant efficacy benefits, but gastrointestinal adverse events frequently necessitate dose reductions, interruptions or discontinuation. Enteric-coated mycophenolate sodium (EC-MPS) delays the release of MPA until the small intestine. Pivotal trials in renal transplant patients have demonstrated equivalent efficacy and safety of EC-MPS and MMF. The myfortic® Prospective Multicenter Study (myPROMS) is an international clinical trial of EC-MPS, with 14 subprotocols and 1700 patients, in de novo and maintenance renal transplant patients receiving cyclosporine, with or without corticosteroids. Results from three myPROMS studies have confirmed that maintenance patients can be safely converted from MMF to EC-MPS. Evidence from the US and European myPROMS studies have shown that EC-MPS and cyclosporine provide good efficacy with a favorable safety profile (including gastrointestinal tolerability) regardless of whether higher or lower cyclosporine C2 targets are used. In terms of quality of life, interim results from the Patient Reported Outcomes in renal transplant patients with or without GastroIntestinal Symptoms (PROGIS) study suggest that the conversion of MMF-treated patients with gastrointestinal complaints to EC-MPS may be associated with a significant improvement in gastrointestinal burden, health-related quality of life and psychological well-being. However these data will need to be confirmed in a true controlled trial. Only limited data from clinical trials of EC-MPS in non-renal transplantation are currently available.