Use Of Mycophenolic Acid Research Articles

The importance of determining the concentration of myco- phenolic acid in children with steroid-dependent nephrotic syndrome

Despite the significant effectiveness of steroid therapy, specialists face serious difficulties in managing patients with steroid-dependent nephrotic syndrome, which requires the prescription of immunosuppressive therapy. Among the available adjuvant drugs, mycophenolate mofetil stands out as a preferred option due to its safety profile, good tolerability, and high efficacy. Currently, only a few studies are presented in the literature on the effectiveness of the use of mycophenolic acid in children with nephrotic syndrome, which is explained by the complexity of the pharmacokinetics of the drug. The article presents the results of a study whose purpose was to evaluate the value of determining mycophenolic acid in patients with steroid-dependent nephrotic syndrome to maintain stable clinical and laboratory remission of the disease. The study examined 78 patients aged 1 to 18 years with steroid-dependent nephrotic syndrome. The results demonstrated that determination of mycophenolic acid concentrations in children with steroid-dependent nephrotic syndrome is an effective method for monitoring therapy for nephrotic syndrome in aunts. Determining the concentration of mycophenolic acid at the C0 point is a highly specific and sensitive method for predicting the development of relapses of the disease, while a mycophenolic acid concentration level of more than 3.2 μg/ml can serve as a minimum guideline for monitoring the use of mycophenolic acid in children with steroid-dependent nephrotic syndrome.

The Outcome of Critical-phase COVID-19 in Liver Transplant Recipients

Background: Considering the importance of assessing solid organ transplants, infected individuals with coronavirus disease 2019 (COVID-19), and the lack of information in this regard, this descriptive study aimed to investigate the clinical features, immunosuppressive agents, and out-comes of liver transplant recipients in the critical phase of infection with COVID-19. Methods: This descriptive cross-sectional study was conducted on 12 critically ill liver transplant recipients referred to Imam Reza and Montaseriyeh hospitals affiliated with Mashhad University of Medical Sciences, Mashhad, Iran, within 2020-21. The required data, including demographic and clinical information, were gathered and recorded in a checklist, and the correlations between varia-bles were assessed in SPSS software (version 24). Results: Hypertension, diabetes, and chronic kidney disease were reported in 83.3% (n = 10), 58.3% (n = 7), and 41.6% (n = 5) of patients, respectively. The administration of Mycophenolic ac-id was correlated with conjunctivitis (r = -0.67; P = 0.02), weakness (r = 0.77; P = 0.006), and sore throat (r = -0.67; P = 0.02). Ground glass opacity was reported in all patients, which was along with consolidation in 90.9% of the cases, and acute pulmonary embolism was found in 36.3% of the sub-jects. Finally, 66.7% (n = 8) of patients passed away. Among immunosuppressive agents, only the use of Mycophenolic acid was correlated with the outcome (r = -0.77; P = 0.006). Conclusion: Due to the high rate of mortality among liver transplant recipients in the critical phase of COVID-19, earlier and more aggressive treatment with antiviral and antibacterial agents should be performed in this group of patients.

Mycophenolate mofetil in therapy of primary nephrotic syndrome in children

Idiopathic nephrotic syndrome is the most common glomerular disease in children, with a prevalence of 1.15–16.9 cases per 100,000 children per year worldwide. In some cases, nephrotic syndrome has a frequently relapsing course or dependence on steroid therapy is formed, which leads to the appointment of immunosuppressive therapy. So far, in clinical practice, there is no unambiguous approach among physicians to the management of patients with nephrotic syndrome, especially when it comes to the further choice of immunosuppressive therapy. Because of the serious side effects of long-term corticosteroid use, doctors prescribe steroid adjuvants to maintain remission and limit the cumulative effect of glucocorticosteroids. Among adjuvants, mycophenolate mofetil, with mycophenolic acid as the active ingredient, is believed to be the most preferred option due to fewer adverse events, acceptable tolerability and, at the same time, high efficacy. This article describes the advantages and features of the use of mycophenolic acid in clinical practice, provides data on pharmacodynamics and drug monitoring, and discusses issues of personalized medicine.

Clinical Patterns, Survival, Comorbidities, and Treatment Regimens in 149 Patients With Pemphigus in Tuscany (Italy): A 12-Year Hospital-Based Study.

IntroductionPemphigus encompasses a group of muco-cutaneous autoimmune bullous diseases characterized by the loss of adhesion between keratinocytes. The disease is associated with increased morbidity and mortality.Materials and MethodsWe characterized clinical patterns, survival, comorbidities, and drug prescriptions in patients with pemphigus referred to the Section of Dermatology of the University of Florence from January 2010 to December 2021.ResultsA total of 149 patients were identified (female/male sex ratio = 2.0). Median age at diagnosis was 57.7 ± 17.2 years; 108 patients were diagnosed with pemphigus vulgaris (PV) (72.5%) and 35 (23.5%) with pemphigus foliaceus (PF). Paraneoplastic pemphigus (PNP) and IgA-pemphigus accounted for three patients each. The overall survival rate was 86.9%. Accordingly, 14 (9%) patients died during the study period. The average age at death was 77.8 ± 9.3. Age at diagnosis was a risk factor for death in patients with pemphigus. Average concentration of Dsg3-IgG and Dsg1-IgG was 85.6 ± 68.8 and 75.9 ± 68.4, respectively. The most serious comorbid diseases included cerebro- and cardiovascular accidents and malignancies. Regarding the treatment regimen, we found a substantially stable use of systemic steroids in the 2010–2018 period; the prevalence of use of mycophenolic acid increased, whereas that of azathioprine decreased. The use of rituximab showed the highest increase in the 2013–2018 period. Proton-pump inhibitors and antibiotics were the most frequently prescribed non-immunomodulating drugs.ConclusionsIn this large series of the patients, patients with pemphigus showed a high incidence of serious comorbid diseases, highlighting the importance of a multidisciplinary approach for a proper management of the patients. Rituximab was the immunomodulating drug showing the highest increase in use over time, reflecting the growing evidence of its efficacy as a first-line treatment in pemphigus.

Limited Sampling Strategy for Estimation of Mycophenolic Acid Exposure in Adult Chinese Heart Transplant Recipients.

Background: With the increasing use of mycophenolic acid (MPA) formulations in organ transplantation, the need for personalized immunosuppressive therapy has become well recognized based on therapeutic drug monitoring (TDM) for avoidance of drug-related toxicity while maintaining efficacy. Few studies have assessed area under the 12 h concentration-time curve of MPA (MPA-AUC0–12h) in heart transplant recipients who received mycophenolate mofetil (MMF) dispersible tablets (MMFdt). The aim of the study was to investigate the pharmacokinetics (PK) of MMFdt combined with tacrolimus and further to develop a practical method for estimation of MPA-AUC0–12h using a limited sampling strategy (LSS). Methods: A prospective study in a single center was performed in patients who continuously administrated with MMFdt or MMF capsule (MMFc) for at least 7 days after cardiac transplantation from 2018 to 2020. A total of 48 Chinese adult heart transplant recipients were enrolled. Blood samples were collected before and 0.5, 1, 1.5, 2, 4, 6, 8, 10 and 12 h after MMF administration. The validated high-performance liquid chromatography combined with tandem mass spectrometry method was used to measure MPA concentrations. Non-compartmental pharmacokinetic (PK) analysis was applied to calculate the data obtained from individual recipients by WinNonlin. LSS models were developed for MPA-AUC0–12h prediction with multivariate stepwise regression analysis. Results: A large inter-individual variability was observed in AUC0–12h, Tmax, Cmax, MRT0–12h, t1/2 and CL/F after multiple dosing of MMFdt. However, no significant differences were observed between main PK parameters of MMFdt and MMFc. The best estimation of MPA-AUC0–12h was achieved with four points: MPA-AUC0–12h = 8.424 + 0.781 × C0.5 + 1.263 × C2 + 1.660 × C4 + 3.022 × C6 (R 2 = 0.844). The mean prediction error (MPE) and mean absolute prediction error (MAPE) of MPA-AUC0–12h were 2.09 ± 14.05% and 11.17 ± 8.52%, respectively. Both internal and external validations showed good applicability for four-point LSS equation. Conclusion: The results provide strong evidence for the use of LSS model other than a single time-point concentration of MPA when performing TDM. A four-point LSS equation using the concentrations at 0.5, 2, 4, 6 h is recommended to estimate MPA-AUC0–12h during early period after transplantation in Chinese adult heart transplant recipients receiving MMFdt or MMFc. However, proper internal and external validations with more patients should be conducted in the future.

Paternal safety of the use of mycophenolic acid in kidney transplant recipients. Results of the EMVARON study.

The use of mycophenolic acid (MPA) in women during pregnancy causes an increase in miscarriages and birth defects with a typical embryopathy profile. Although epidemiological data does not suggest a greater risk among the offspring of male kidney transplant recipients, the European Medicines Agency and The Spanish Agency of Medicines and Medical Devices introduced the recommendation of using contraceptive methods. We conducted a national retrospective study in 15 Spanish Kidney Transplant Centers to evaluate the frequency of miscarriages and birth defects between the offspring from male kidney transplants recipients. We included 151 males who had fathered 239 offspring, 225 under MPA and 14 without MPA. The results of our study showed an incidence of miscarriages in the MPA group of 9.8%, and of birth defects of 4%. We observed an incidence of miscarriages between the offspring fathered by kidney transplant males under MPA lower than the general population. The incidence of birth defects was similar to the incidence described in other studies and the fact that we did not find the typical embryopathy profile makes it difficult to associate them to the use of MPA. Because of that, we urge the European and Spanish Agencies to reconsider their recommendations for males.

Administration of mycophenolic acid is not associated with malformations in descendants from kidney transplanted males.

BackgroundIn pregnant women, the use of Mycophenolic acid (MPA) is associated with teratogenicity. Recently, the European Medicines Agency (EMEA) and the Spanish Agency of Medicine and Sanitary Products (AEMPS) warned about the potential teratogenic effects of MPA. These adverse events may occur even in children from males on treatment with MPA. However, evidence of malformations in offsprings of male kidney transplanted patients (KT) exposed to MPA is limited. Thus, the present study aimed to evaluate the incidence of offspring malformations in children of renal transplanted males under MPA.Materials and methodsWe conducted a retrospective study in which we evaluated the incidence of malformations in descendants from male recipients that were exposed or not to MPA before and at the time of conception. Two groups of patients were evaluated. Those exposed to MPA (MPA group, n = 20) and the non-MPA group (n = 13) that included patients that did not receive AZA (n = 5) and eight that did receive AZA (n = 8) at the time of conception.ResultsA total of forty-nine post-transplant conceptions were identified from 33 different renal transplanted males. MPA was used as the immunosuppressant in 28 of the conceptions. Males from the non-MPA group fathered the other 21 children. Median time from grafting to conception was 6.1 (IQR 2.4–11.1) years, and it was similar between groups. There were eight miscarriage episodes, 2 in the non-MPA group and 6 in the MPA group although differences were not reached. After that, all patients had children without problems. No malformations were detected in any of the 49 regardless whether they were exposed or not to MPA.ConclusionsNo evidence of MPA-associated malformations was observed in descendants of kidney transplanted males on treatment with MPA. Further research is warranted to confirm our findings to properly advice transplanted males keen to procreate.

Mycophenolic Acid-Induced Developmental Defects in Zebrafish Embryos.

With the increasing use of mycophenolic acid (MPA) in solid organ transplantation, some clinical studies indicate that it is also a human teratogen. However, it is unknown by which mechanism MPA acts as a teratogen. Mycophenolic acid was a selective blocker of de novo purine synthesis, and its immunosuppressive effect is mediated by the inhibition of inosine monophosphate dehydrogenase, which could be a target for MPA-induced toxicity as well. The aim of our study was to examine the direct influence of MPA exposure on zebrafish (Danio rerio) embryos. Morphological defects including tail curvature and severe pericardial edema in zebrafish embryos caused by MPA (3.7-11.1 µmol/L) were found in a dose-dependent manner. The teratogenic index (25% lethal concentration value (LC25)/no observed adverse effect level ratio) was 16, which indicated MPA as a teratogen. Quantitative polymerase chain reaction analysis revealed that the expression level of impdh1b and impdh2 was significantly reduced by MPA treatment at 8 µmol/L (equals to LC25 level). All the toxic effects could be partially reversed by the addition of 33.3 µmol/L guanosine. Our results indicated that MPA impairs the development of zebrafish embryos via inhibition of impdh activity, which subsequently caused a guanosine nucleotide depletion in vivo.

A comprehensive review of the published assays for the quantitation of the immunosuppressant drug mycophenolic acid and its glucuronidated metabolites in biological fluids.

Therapeutic use of mycophenolic acid (MPA) is steadily on the rise in combination with other immunosuppressant drugs in transplantation patients. The biotransformation of MPA resulted in the formation of glucuronide metabolites, MPAG and AcMPAG. There are a plethora of assays validated for the analysis of MPA alone or with MPAG/AcMPAG in various biological specimens including plasma/serum, urine, ultrafiltrate, saliva, PBMC, dried blood spots, tissue extract, tumor biopsies and vitreous humor. Based on the need for experimental work, a proper choice of the assay and internal standard may be made using the choices in the literature. While the chemical methods involving high-performance liquid chromatography (HPLC) or LC coupled with triple quadrupole mass spectrometry (LC-MS/MS) are popular, enzymatic assays, in spite of their higher bias, have been used for the routine drug monitoring of MPA. The objectives of the present review are: (a) to provide a focused systematic compilation of the HPLC or LC-MS/MS methods for MPA, MPAG and/or AcMPAG published in the last decade (2005 to current) to enable visual comparison of the methods; (b) to compare and contrast a few enzymatic assays with those of the chemical methods; and (c) to discuss relevant issues/limitations and perspectives on select assays under various subheadings.

Trends in the use of maintenance immunosuppressive drugs among liver transplant recipients in Taiwan: a nationwide population-based study.

During the past two decades, many novel immunosuppressive drugs have been approved for transplant recipients. Trends in the use of maintenance immunosuppressants after liver transplantation in Asia are unclear. Thus, we aimed to analyze the prescription trends in maintenance immunosuppressive drugs among liver transplant recipients in Taiwan and compare the results with the trends reported from western countries. We conducted a retrospective nationwide population-based study utilizing the National Health Insurance Research Database (NHIRD) to analyze the prescribing patterns of immunosuppressants used in Taiwanese liver transplant recipients from 2000 to 2009. A total of 1686 liver transplant patients and their prescriptions of immunosuppressants were analyzed. The 5-year survival rate of liver transplant recipients was 79.6%. In 2009, the major immunosuppressive therapy among liver transplant recipients was a dual-drug regimen with tacrolimus and mycophenolic acid (57.3%). Among the calcineurin inhibitors (CNI), the use of cyclosporine decreased from 58.9% to 12.5%, while the use of tacrolimus notably increased from 23.3% to 77.5%. The use of azathioprine decreased from 21.3% to 0.4%, while the use of mycophenolic acid increased from 56.1% to 76.5%. Among the mammalian target of rapamycin (mTOR) inhibitors, sirolimus was approved in 2002, and its use increased to 8.7% in 2009. In the first 3 months after liver transplantation, a total of 17 different regimens were used in 2009, compared with seven regimens in 2000. Although the CNI-based combination obviously remains the major regimen, our results reveal a trend toward individualized immunosuppressive regimens among Taiwanese liver transplant recipients. Copyright © 2016 John Wiley & Sons, Ltd.

An Early Viral Response Predicts the Virological Response to Ribavirin in Hepatitis E Virus Organ Transplant Patients.

Ribavirin is efficient at treating chronic hepatitis E virus infection in solid-organ transplant patients. However, the early kinetics of viral replication under therapy and the impact of immunosuppressant regimens on viral replication are unknown: thus, determining the aim of our study. Thirty-five patients with a solid-organ transplant and chronic hepatitis E virus infection were given ribavirin for 3 months. The hepatitis E virus (HEV) RNA concentrations were determined before treatment, at days 7, 15, and 21 and at months 1, 2, and 3 during therapy and after ribavirin cessation. A sustained virological response (SVR) occurred in 63%. Decreased viral concentration within the first week post-ribavirin therapy was an independent predictive factor for SVR, and a decreased HEV concentration of 0.5 log copies/mL or greater had an 88% positive predictive value. No correlation between ribavirin trough level on day 7 or at month 2 with a virological response or an SVR was observed. Before therapy, HEV RNA concentration was significantly greater in patients receiving mechanistic target of rapamycin inhibitor-based immunosuppression compared to patients given calcineurin inhibitors. The use of mycophenolic acid did not impact on the response to ribavirin. An early response to ribavirin can be used to define the optimal duration of therapy in the setting of HEV infection.

Pharmacoeconomic analysis of using drugs containing mycophenolic acid in kidney transplant recipients in the context of domestic pharmaceutical market

Aim. The use of mycophenolic acid (MPA) in patients after kidney transplantation made it possible to achieve significant results in reducing the number of acute rejection of kidney in recipients, and increasing the long-term survival of transplant.Methods and results. With the aim of evaluation of the clinical and economic feasibility of conversion kidney transplant recipients from EC-MPS to MMF in the setting of Ukrainian pharmaceutical market, pharmacoeconomic cost minimization method has been investigated a coefficient of «missed opportunities» in the conversion to a less expensive therapy has been calculated, and the analysis of the impact on the budget has been performed.Conclusion. It has been determined, that the results of pharmacoeconomic calculations present the strong evidence of the economic advantage of MMF over EC-MPS and the feasibility of MMF in patients receiving immunosuppressive therapy with MPA.

Trends in Maintenance Immunosuppressive Drugs Used in Taiwanese Kidney Transplant Recipients: An Analysis of the National Health Insurance Research Database

Trends in maintenance immunosuppressive drugs used among Taiwanese kidney transplant recipients have not been reported before. We examined the National Health Insurance Research Database to analyze trends in maintenance immunosuppressive drugs used in Taiwanese kidney transplant recipients for the years 2002–2009. The new case number of kidney transplant recipients ranged from 302 to 673 per year. In 2009, 5276 kidney transplant recipients received immunosuppressive therapy. The 5-year renal graft survival rate of kidney transplant recipients was 93%. In 2009, the most common immunosuppressive therapy among Taiwanese kidney transplant recipients was a triple regimen that included tacrolimus, mycophenolate mofetil, and corticosteroid. There was a significant increase in the use of a tacrolimus-based regimen from 35.1%–58.2%, while the use of cyclosporine decreased from 62.2%–24.8% (P < .05). The percentage of calcineurin inhibitor–free regimen increased from 2.7%–17%. Moreover, the use of Rapamune dramatically increased from 8.2%–22.6% in 2002–2004. However, the percentage of kidney transplant recipients using Rapamune maintained 23 ± 1.6% in 2004–2009. The use of mycophenolic acid remained stable at about 74.9 ± 3.2% in 2002–2009. As predicted, the use of Imuran decreased from 6.9%–3.5%. In summary, although calcineurin inhibitors remained the mainstay of immunosuppressive drugs, these findings suggest a general trends toward individualized regimens and the use of calcineurin inhibitor–free and mammalian target of rapamycin inhibitors–based regimens in Taiwanese kidney transplant recipients.

The Evolution of Population Pharmacokinetic Models to Describe the Enterohepatic Recycling of Mycophenolic Acid in Solid Organ Transplantation and Autoimmune Disease

With the increasing use of mycophenolic acid (MPA) as an immunosuppressant in solid organ transplantation and in treating autoimmune diseases such as systemic lupus erythematosus, the need for strategies to optimize therapy with this agent has become increasingly apparent. This need is largely based on MPA's significant between-subject and between-occasion (within-subject) pharmacokinetic variability. While there is a strong relationship between MPA exposure and effect, the relationship between drug dose, plasma concentration and exposure (area under the concentration-time curve [AUC]) is very complex and remains to be completely defined. Population pharmacokinetic models using various approaches have been proposed over the past 10 years to further evaluate the pharmacokinetic and pharmacodynamic behaviour of MPA. These models have evolved from simple one-compartment linear iterations to complex multi-compartment versions that try to include various factors, which may influence MPA's pharmacokinetic variability, such as enterohepatic recycling and pharmacogenetic polymorphisms. There have been major advances in the understanding of the roles transport mechanisms, metabolizing and other enzymes, drug-drug interactions and pharmacogenetic polymorphisms play in MPA's pharmacokinetic variability. Given these advances, the usefulness of empirical-based models and the limitations of nonlinear mixed-effects modelling in developing mechanism-based models need to be considered and discussed. If the goal is to individualize MPA dosing, it needs to be determined whether factors which may contribute significantly to variability can be utilized in the population pharmacokinetic models. Some pharmacokinetic models developed to date show promise in being able to describe the impact of physiological processes such as enterohepatic recycling. Most studies have historically been based on retrospective data or poorly designed studies which do not take these factors into consideration. Modelling typically has been undertaken using non-controlled therapeutic drug monitoring data, which do not have the information content to support the development of complex mechanistic models. Only a few recent modelling approaches have moved away from empiricism and have included mechanisms considered important, such as enterohepatic recycling. It is recognized that well thought-out sampling schedules allow for better evaluation of the pharmacokinetic data. It is not possible to undertake complex absorption modelling with very few samples being obtained during the absorption phase (which has often been the case). It is important to utilize robust AUC monitoring which is now being propagated in the latest consensus guideline on MPA therapeutic drug monitoring. This review aims to explore the biological factors that contribute to the clinical pharmacokinetics of MPA and how these have been introduced in the development of population pharmacokinetic models. An overview of the processes involved in the enterohepatic recycling of MPA will be provided. This will summarize the components that complicate absorption and recycling to influence MPA exposure such as biotransformation, transport, bile physiology and gut flora. Already published population pharmacokinetic models will be examined, and the evolution of these models away from empirical approaches to more mechanism-based models will be discussed.

Pharmacokinetic evaluation of mycophenolate mofetil for pemphigus

Introduction: Pemphigus is an autoimmune blistering disease of the skin and mucous membranes characterized by the development of autoantibodies against the desmosomal proteins, desmoglein-1 and -3. Before the advent of corticosteroids, therapy was almost fatal. The introduction of high-dose corticosteroid therapy has reduced mortality rates to ∼ 10%, but long-term use of steroids can lead to side effects, many of which are severe and associated with significant morbidity. Thus, the major goal of pemphigus therapy has been to reduce the patient's cumulative exposure to systemic corticosteroids. Over the last 2 decades, a range of corticosteroid-sparing immunosuppressive agents have been described, but these therapies are not without potentially serious complications. Despite the range of treatment options, a proportion of patients do not achieve remission, while others show an initial treatment response but remain poorly controlled. The recent availability of mycophenolate mofetil (MMF), originally developed for preventing allograft rejection, appears to be effective in autoimmune blistering diseases in combination with systemic corticosteroid or as a monotherapy.Areas covered: This review aims to provide an extensive overview of the literature on the clinical pharmacokinetics of MMF in pemphigus treatment and a brief summary of current pharmacodynamic information. After completing this learning activity, readers should be able to summarize the pharmacology of MMF as an immunosuppressant; recognize its potential role in the treatment of pemphigus, including general dosing guidelines and laboratory monitoring schedules, use in patient populations and potential adverse effects; and identify future considerations and developing areas of research regarding the use of mycophenolic acid in the treatment of autoimmune blistering diseases.Expert opinion: Current morbidity of pemphigus is largely iatrogenic, caused by side effects of the long-term, high-dose corticosteroid therapy that is necessary to sustain disease control. MMF demonstrates complex pharmacokinetics and displays large between-subject pharmacokinetic variability. Experience with MMF has demonstrated long-term safety and tolerability in the treatment of pemphigus.

Consensus Report on Therapeutic Drug Monitoring of Mycophenolic Acid in Solid Organ Transplantation

With the increasing use of mycophenolic acid (MPA) in solid organ transplantation, the need for more accurate drug dosing has become evident. Personalized immunosuppressive therapy requires better strategies for avoidance of drug-related toxicity while maintaining efficacy. Few studies have assessed the clinical usefulness of therapeutic drug monitoring (TDM) of MPA in solid organ transplantation in a prospective way, and they have produced opposing results. To provide clinicians with an objective and balanced clinical interpretation of the current scientific evidence on TDM of MPA, a consensus meeting involving 47 experts from around the world was commissioned by The Transplantation Society and held in Rome on November 20 to 21, 2008. The goal of this consensus meeting was to offer information to transplant practitioners on clinically relevant pharmacokinetic characteristics of MPA, to rationalize the basis for currently advised target exposure ranges for MPA in various types of organ transplantation, and to summarize available methods for application of MPA TDM in clinical practice. Although this consensus report does not evaluate the final role of MPA TDM in transplantation, it seeks to examine the current scientific evidence for concentration-controlled dosing of MPA.

Chronic Kidney Disease after Liver Transplantation: Recent Evidence

Chronic kidney disease is a common complication after liver transplantation with an incidence ranging between 20% and 80%. Studies of renal function after liver transplantation have yielded conflicting results: the wide range in incidence rates of chronic kidney disease (CKD) following liver transplantation is related to the methods for measuring kidney function, and various criteria for defining renal dysfunction, among others. An important cause of CKD among liver transplant recipients is calcineurin inhibitor-based immunosuppression. Additional predictors of CKD post-liver transplantation include pre-transplant kidney function, peri-operative acute kidney failure, age, and hepatitis C. A recent meta-analysis of observational studies revealed that, in the subgroup of studies provided with glomerular filtration rate at baseline, the summary estimate of relative risk and 95% confidence intervals (CI) for developing chronic renal failure among liver transplant recipients with diminished renal function at transplant was 2.12 (95% CI, 1.01-4.46, p=0.047). Acute renal insufficiency is common immediately after liver transplantation, whereas the course of CKD after liver transplantation appears progressive over time. Only preliminary information exists on kidney pathological findings in recipients of liver transplants with CKD. Introduction of the Model for End-stage Liver Disease for the allocation of liver grafts has not increased the occurrence of renal dysfunction following liver transplantation. Chronic kidney disease following liver transplantation increases cardiovascular burden dramatically. The use of mycophenolic acid- or sirolimus-based immunosuppression in calcineurin-inhibitors sparing protocols is an area of intense research.

Convenient syntheses of the in vivo carbohydrate metabolites of mycophenolic acid: reactivity of the acyl glucuronide

Following in vivo use of mycophenolic acid, the O-aryl and O-acyl glucuronides, as well as the recently discovered O-aryl glucoside (Scheme 1), are all found as metabolites. We describe convenient preparations of all three derivatives. The phenolic glycosides are obtained by phase-transfer-catalysed alkylation of methyl mycophenolate in very high yield, as an excellent alternative to the Königs-Knorr reaction. We carefully optimised our earlier synthesis of the acyl glucuronide to give a highly pure product in a much improved yield. Finally, we describe the value of a synthetic acyl glucuronide in demonstrating its reactivity towards a known target protein with superior response to the naturally obtained material.

Estimation of the area under the curve for mycophenolic acid in adult renal transplant patients with concomitant tacrolimus using a limited sampling strategy

The aim of this study was to develop a limited sampling strategy (LSS) for monitoring the use of mycophenolic acid (MPA) in maintenance therapy with tacrolimus (TCL) in renal transplant patients. Eighteen adult patients receiving a first transplant were investigated. All patients were treated with a combination of TCL, steroid and mycophenolate mofetil (MMF). Besides the predose trough concentration (C(0)), whole blood samples were taken for measurement of the MPA concentration at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 h for a 14-point 12-h pharmacokinetic (PK) profile. Using stepwise linear regression analysis, an abbreviated area under the concentration time curve (AUC) was calculated using all 14, and any combination of sampling points to give an estimating equation with up to three predictors. The equation derived from C(2), C(7) and C(12,) for AUC estimation: AUC = (2.05 x C(2)) + (8.51 xC(7)) + (2.29 x C(12)) + 4.24. was found to be optimal. Using this formula, there was an excellent correlation between the estimated 3-point AUC and AUC(0-12 h). To assess the agreement between the abbreviated methods and the full PK profile, we plotted the average AUC of the abbreviated estimates and the full PK profile. This Bland-Altman analysis indicated good agreement to within +/-2 SD and a prediction variability of 7.56 microg x h/mL. Our proposed three-sampling-point estimate of AUCs is clinically acceptable. However, the sampling times are inconvenient for outpatients, and is recommended only for monitoring MMF treatment of inpatients with suspected toxicity or at high risk of organ rejection.

Use of mycophenolic acid in non-transplant renal diseases

Mycophenolic acid (MPA) is a relatively new immuno-suppressive drug, used since the nineties for theprevention of rejection in kidney transplantation.MPA has not only proved effective in preventingrejection, being even superior to azathioprine, but alsoseems to cause less adverse effects than otherimmunosuppressive drugs [1]. Because of these favour-able experiences with MPA in renal transplantation,the drug is currently used in patients with liver, lungand bone marrow transplantation as well. Given itsfavourable profile, MPA has also been used inautoimmune diseases. Following many cases andopen series on the successful use of MPA, mostly inthe form of mycophenolate mofetil (MMF), in renal,rheumatological, gastrointestinal, ophthalmological,dermatological and neurological autoimmune diseases,the first controlled studies have been published or areunderway.MPA is the active metabolite of the two currentlyavailable formulations: mycophenolate mofetil (MMF,Cellcept ) and the slow release formulation enteric-coated mycophenolate sodium (EC-MPS, Myfortic ).The mode of action and the pharmacokinetics of MPAare elegantly described by Allison [2]. In short, MPA isa non-alkylating drug that suppresses the immuneresponse by inhibiting the proliferation of activatedlymphocytes. MPA blocks the enzyme inosine mono-phosphate dehydrogenase (IMPDH), which is essentialfor the de novo synthesis of the purine guanine, andthereby inhibits lymphocytes from proliferating. Whilelymphocytes depend completely on IMPDH forsynthesis of guanine, most other human cells useother pathways for this synthesis, and are therefore notor less affected by the anti-proliferative effect of MPA.In addition, MPA has anti-fibrotic effects, as reviewedby Eugui [3].Following oral ingestion, both MMF and EC-MPSare resorbed and hydrolysed to MPA, which isconjugated in the liver into inactive mycophenolicacid glucuronide before being almost completelycleared by the kidney. Altered pharmacokinetics inpatients with renal insufficiency might explain theincreased rate of adverse effects, which can bemanaged by decreasing the dose of MMF [4]. MPAis not substantially cleared by peritoneal or haemodial-ysis [4].We hereby review the clinical experience with MPAin the treatment of renal diseases.