-
Transplant International : Official... May 2015The patent of mycophenolate mofetil (MMF) has expired, and for enteric-coated mycophenolate sodium (EC-MPS), this will happen in 2017. In the twenty years these drugs... (Review)
Review
The patent of mycophenolate mofetil (MMF) has expired, and for enteric-coated mycophenolate sodium (EC-MPS), this will happen in 2017. In the twenty years these drugs have been used, they have become extremely popular. In this review, the reasons for the popularity of mycophenolate are discussed, including the benefits compared to azathioprine. MMF and EC-MPS are therapeutically equivalent. Although neither is considered to be a narrow therapeutic index drug, this should not lead to careless switching between the innovator drug and generic formulations, or between one generic formulation and another. The pipeline of new immunosuppressive drugs is dry, and it is very likely that we will be using mycophenolate for many more years to come as a first-line immunosuppressive drug in our transplant population. Whether or not the development of donor-specific anti-HLA antibodies is related to drug exposure (mycophenolic acid concentrations) remains to be investigated.
Topics: Azathioprine; Clinical Trials as Topic; Drug Monitoring; Drugs, Generic; Genetic Variation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Tablets, Enteric-Coated
PubMed: 25758949
DOI: 10.1111/tri.12554 -
Cleveland Clinic Journal of Medicine May 2023C3 glomerulopathy (C3G) is a rare kidney disease that causes kidney dysfunction as a result of dysregulation of the complement system alternate pathway (AP). C3G...
C3 glomerulopathy (C3G) is a rare kidney disease that causes kidney dysfunction as a result of dysregulation of the complement system alternate pathway (AP). C3G encompasses 2 separate disorders, C3 glomerulonephritis and dense deposit disease. The presentation and natural history is variable and kidney biopsy is needed to confirm the diagnosis. The overall prognosis is poor with high recurrence rates after transplant. A better understanding of C3G is needed as is high-quality evidence to guide therapy, which currently includes mycophenolate mofetil and steroids for moderate to severe disease, and terminal complement blockade with anti-C5 therapy in unresponsive cases.
Topics: Humans; Kidney Diseases; Kidney; Mycophenolic Acid
PubMed: 37225259
DOI: 10.3949/ccjm.90.e-s1.01 -
Arthritis Research & Therapy Jul 2023Many clinical trial results are available to inform best practices in the treatment of patients with connective tissue disease-associated interstitial lung disease... (Review)
Review
Many clinical trial results are available to inform best practices in the treatment of patients with connective tissue disease-associated interstitial lung disease (CTD-ILD).Herein, we summarize the results of clinical trials, including patient-reported outcome instruments, for the treatment of patients with ILD associated with systemic sclerosis (SSc/scleroderma), rheumatoid arthritis, and idiopathic inflammatory myositis, the diseases with the most available data. For SSc-ILD, the US Food and Drug Administration approved nintedanib (a tyrosine kinase inhibitor) in 2020 and subcutaneous tocilizumab (an IL-6 receptor monoclonal antibody) in 2021. Rituximab was recently shown to have similar efficacy but better tolerability than intravenous cyclophosphamide (CYC) for CTD-ILD therapy. Scleroderma Lung Study II, conducted in patients with SSc-ILD, showed that oral CYC and mycophenolate mofetil (MMF) were comparable in their effects on lung function, but MMF was better tolerated. The increasing treatment armamentarium for patients with CTD-ILD offers physicians new opportunities to improve patient outcomes.
Topics: Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Connective Tissue Diseases; Cyclophosphamide; Mycophenolic Acid; Scleroderma, Systemic; Scleroderma, Localized; Lung
PubMed: 37422652
DOI: 10.1186/s13075-023-03090-y -
World Journal of Gastroenterology Aug 2014In liver transplantation, the efficacy of mycophenolate mofetil (MMF) has been confirmed in clinical trials and studies. However, therapeutic drug monitoring for... (Review)
Review
In liver transplantation, the efficacy of mycophenolate mofetil (MMF) has been confirmed in clinical trials and studies. However, therapeutic drug monitoring for mycophenolic acid (MPA) has not been fully accepted in liver transplantation as no long-term prospective study of concentration controlled vs fixed-dose prescribing of MMF has been done. This review addressed MPA measurement, pharmacokinetic variability and reasons of this variation, exposure related to acute rejection and MMF-associated side effects in liver transplant recipients. Limited sampling strategies to predict MPA area under the concentration-time curve have also been described, and the value of clinical use needs to be investigated in future. The published data suggested that a fixed-dosage MMF regimen might not be suitable and monitoring of MPA exposure seems helpful in various clinical settings of liver transplantation.
Topics: Drug Monitoring; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Transplantation; Models, Biological; Mycophenolic Acid; Predictive Value of Tests; Time Factors; Treatment Outcome
PubMed: 25152575
DOI: 10.3748/wjg.v20.i31.10715 -
Clinical Journal of the American... Sep 2020
Topics: Humans; Immunosuppressive Agents; Kidney Diseases; Mycophenolic Acid
PubMed: 32841154
DOI: 10.2215/CJN.11740720 -
Clinical Journal of the American... Oct 2016Therapeutic drug monitoring of mycophenolic acid can improve clinical outcome in organ transplantation and lupus, but data are scarce in idiopathic nephrotic syndrome....
BACKGROUND AND OBJECTIVES
Therapeutic drug monitoring of mycophenolic acid can improve clinical outcome in organ transplantation and lupus, but data are scarce in idiopathic nephrotic syndrome. The aim of our study was to investigate whether mycophenolic acid pharmacokinetics are associated with disease control in children receiving mycophenolate mofetil for the treatment of steroid-dependent nephrotic syndrome.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
This was a retrospective multicenter study including 95 children with steroid-dependent nephrotic syndrome treated with mycophenolate mofetil with or without steroids. Area under the concentration-time curve of mycophenolic acid was determined in all children on the basis of sampling times at 20, 60, and 180 minutes postdose, using Bayesian estimation. The association between a threshold value of the area under the concentration-time curve of mycophenolic acid and the relapse rate was assessed using a negative binomial model.
RESULTS
In total, 140 areas under the concentration-time curve of mycophenolic acid were analyzed. The findings indicate individual dose adaptation in 53 patients (38%) to achieve an area under the concentration-time curve target of 30-60 mg·h/L. In a multivariable negative binomial model including sex, age at disease onset, time to start of mycophenolate mofetil, previous immunomodulatory treatment, and concomitant prednisone dose, a level of area under the concentration-time curve of mycophenolic acid >45 mg·h/L was significantly associated with a lower relapse rate (rate ratio, 0.65; 95% confidence interval, 0.46 to 0.89; =0.01).
CONCLUSIONS
Therapeutic drug monitoring leading to individualized dosing may improve the efficacy of mycophenolate mofetil in steroid-dependent nephrotic syndrome. Additional prospective studies are warranted to determine the optimal target for area under the concentration-time curve of mycophenolic acid in this population.
Topics: Area Under Curve; Child, Preschool; Female; Glucocorticoids; Humans; Immunologic Factors; Male; Mycophenolic Acid; Nephrotic Syndrome; Prednisone; Recurrence; Retrospective Studies
PubMed: 27445161
DOI: 10.2215/CJN.00320116 -
European Journal of Medicinal Chemistry Jan 2018The series of 16 novel amino acid and peptide mycophenolic acid (MPA) derivatives was obtained as potential antibacterial agents. Coupling of MPA with respective amines...
The series of 16 novel amino acid and peptide mycophenolic acid (MPA) derivatives was obtained as potential antibacterial agents. Coupling of MPA with respective amines was optimized with condensing reagents such as EDCI/DMAP and T3P/TEA. Amino acid analogs were received both as methyl esters and also with the free carboxylic group. The biological activity of the products was tested on five references bacterial strains: Klebsiella pneumoniae ATCC 700603 (ESBL), Escherichia coli ATCC 8739, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus MRSA ATCC 43300, Staphylococcus aureus MSSA ATCC 25923. Peptide derivatives proved to be the most versatile ones, their MIC values relative to most strains was lower than MPA alone. It has been noted that the activity of amino acid derivatives depends on the configuration at the chiral center in the amino acid unit and methyl esters indicated better antimicrobial activity than analogs with free carboxylic group.
Topics: Amino Acids; Anti-Bacterial Agents; Dose-Response Relationship, Drug; Escherichia coli; Klebsiella pneumoniae; Microbial Sensitivity Tests; Molecular Structure; Mycophenolic Acid; Peptides; Pseudomonas aeruginosa; Staphylococcus aureus; Structure-Activity Relationship
PubMed: 29216563
DOI: 10.1016/j.ejmech.2017.11.094 -
Clinica Chimica Acta; International... Sep 2012In solid organ transplant patients, it is important to maintain a fine balance between preventing rejection and reducing adverse effects. Several immunosuppressive... (Review)
Review
In solid organ transplant patients, it is important to maintain a fine balance between preventing rejection and reducing adverse effects. Several immunosuppressive agents such tacrolimus, cyclosporine, sirolimus and everolimus require therapeutic drug monitoring. The study of germline variation of the genome has opened novel opportunities to individualize therapy. Among the currently available immunosuppressive agents, cyclosporine, tacrolimus and mycophenolic acid are in vitro substrates of the UGT1A and 2B families of glucuronidation enzymes. Mycophenolic acid, either given as mycophenolate mofetil or mycophenolate sodium, is the most frequently used antiproliferative immunosuppressant. Mycophenolic acid is a prodrug which is rapidly de-esterified in the gut wall, blood, liver and tissue to the active moiety, mycophenolic acid (MPA). MPA undergoes significant hepatic metabolism to several metabolites. The 7-hydroxyglucuronide MPA is the major metabolite and is inactive. This paper reviews the current status of the genetic associations between germline UGT variants and the pharmacokinetics and pharmacodynamics of mycophenolic acid. Our conclusive assessment of the studies conducted so far is that these germline markers are not ready to be used in the clinic to individualize mycophenolic acid dosing and improve outcome. Novel approaches are required to identify new genetic determinants of outcomes in transplantation.
Topics: Biomarkers; Glucuronosyltransferase; Humans; Immunosuppressive Agents; Mycophenolic Acid; Organ Transplantation; Polymorphism, Genetic
PubMed: 22327003
DOI: 10.1016/j.cca.2012.01.031 -
Drug Metabolism and Pharmacokinetics 2014Novel approaches applying quantitative clinical pharmacology or pharmacometrics have been increasingly embraced by the drug development community in the last decade.... (Review)
Review
Novel approaches applying quantitative clinical pharmacology or pharmacometrics have been increasingly embraced by the drug development community in the last decade. State-of-the-art population modeling and simulation enable better characterization and prediction of drug exposure. For narrow therapeutic index drugs such as mycophenolic acid (MPA) which exhibit large inter-individual variation in drug exposure, pharmacometric analysis can be of great clinical benefit. This review aims to summarize the recent progress of using pharmacometric tools toward individualized MPA therapeutics. The population pharmacokinetic models including those developed for special populations and Bayesian estimators for therapeutic drug management will be reviewed. Special attention will be given to new methodologies such as nonparametric population modeling and the physiological-based pharmacokinetics modeling (PBPK) that emerged recently as alternatives to the parametric population approach to predict MPA exposure. D-Optimal design strategies applied in clinical study design will also be reviewed. Lastly, the potential of using a pharmacodynamic based optimal treatment strategy by focusing on MPA's target enzyme inosine monophosphate dehydrogenase (IMPDH) will be discussed.
Topics: Bayes Theorem; Clinical Trials as Topic; Cohort Studies; Drug Monitoring; Humans; IMP Dehydrogenase; Immunosuppressive Agents; Models, Biological; Mycophenolic Acid; Pharmacokinetics; Statistics, Nonparametric
PubMed: 24351871
DOI: 10.2133/dmpk.dmpk-13-rv-112 -
BMC Microbiology May 2023Mycophenolic acid (MPA) is the active ingredient in the most important immunosuppressive pharmaceuticals. It has antifungal, antibacterial, antiviral, anti-psoriasis,...
Mycophenolic acid (MPA) is the active ingredient in the most important immunosuppressive pharmaceuticals. It has antifungal, antibacterial, antiviral, anti-psoriasis, and antitumor activities. Therefore, its overproduction in addition to gene expression analysis was our main target. Through this study, we isolated a novel potent mycophenolic acid (MPA) producer strain of the genus Penicillium from the refrigerated Mozzarella cheese and it was identified with the molecular marker ITS and benA genes as P. arizonenseHEWt1. Three MPA overproducer mutants were isolated by exposing the wild type to different doses of gamma-rays, and the fermentation conditions for the highest production of MPA were optimized. The results indicated that MPA amounts produced by the mutants MT1, MT2, and MT3 were increased by 2.1, 1.7, and 1.6-fold, respectively, compared with the wild-type. The growth of both mutant and wild-type strains on PD broth, adjusted to pH 6 and incubated at 25 °C for 15 d, were the best conditions for maximum production of MPA. In a silico study, five orthologs genes of MPA biosynthesizing gene clusters in P. brevicompactum were predicted from the genome of P. arizonense. Sequencing and bioinformatic analyses proved the presence of five putative genes namely mpaA, mpaC, mpaF, mpaG, and mpaH in the P. arizonense HEWt1 genome. Gene expression analysis by qRT-PCR indicated an increase in the transcription value of all annotated genes in the three mutants over the wild type. A highly significant increase in the gene expression of mpaC, mpaF, and mpaH was observed in P. arizonense-MT1 compared with wild-type. These results confirmed the positive correlation of these genes in MPA biosynthesis and are the first report regarding the production of MPA by P. arizonense.Kew word.Mycophenolic acid, Penicillium arizonense, mutagenesis, gene expression.
Topics: Mycophenolic Acid; Immunosuppressive Agents; Penicillium; Polymerase Chain Reaction
PubMed: 37198535
DOI: 10.1186/s12866-023-02884-z