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Journal of Clinical Pharmacology Dec 2021Mycophenolic acid exhibits significant interpatient pharmacokinetic variability attributed to factors including race, sex, concurrent medications, and enterohepatic...
Mycophenolic acid exhibits significant interpatient pharmacokinetic variability attributed to factors including race, sex, concurrent medications, and enterohepatic circulation of the mycophenolic acid glucuronide metabolite to mycophenolic acid. This conversion by enterohepatic circulation is mediated by the multidrug resistance-associated protein 2, encoded by ABCC2. This study investigated ABCC2 haplotype associations with mycophenolic acid pharmacokinetics in 147 stable kidney transplant recipients receiving mycophenolic acid in combination with calcineurin inhibitors. The role of the ABCC2 genotypes -24C>T (rs717620), 1249C>T (rs2273697), and 3972C>T (rs3740066) were evaluated in prospective, cross-sectional pharmacokinetic studies of stable recipients receiving mycophenolic acid and either tacrolimus or cyclosporine. Haplotype phenotypic associations with mycophenolic acid pharmacokinetic parameters were computed using THESIAS (v. 3.1). Four ABCC2 haplotypes with estimated frequencies greater than 10% were identified (H1:CGC [wild type], H9:CGT, H2:CAC, H12:TGT). There were no differences in haplotype frequencies by either race or sex. There were significant associations of pharmacokinetic parameters with ABCC2 haplotypes for mycophenolic acid clearance (L/h), mycophenolic acid AUC (mg·h/L), and the ratio of mycophenolic acid glucuronide to mycophenolic acid AUC . The wild-type haplotype ABCC2 CGC had greater mycophenolic acid AUC (P = .017), slower clearance (P = .013), and lower mycophenolic acid glucuronide to mycophenolic acid AUC ratio (P = .047) compared with the reduced function ABCC2 haplotype CGT. These differences were most pronounced among patients receiving tacrolimus cotreatment. No phenotypic associations were found with the cyclosporine-mycophenolic acid regimen. Variation in ABCC2 haplotypes contributes to subtherapeutic mycophenolic acid exposure and influences interpatient variability in pharmacokinetic phenotypes based on concurrent calcineurin inhibitor treatment.
Topics: Adult; Area Under Curve; Calcineurin Inhibitors; Cross-Sectional Studies; Enterohepatic Circulation; Female; Haplotypes; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Multidrug Resistance-Associated Protein 2; Mycophenolic Acid; Prospective Studies
PubMed: 34169529
DOI: 10.1002/jcph.1932 -
Oxidative Medicine and Cellular... 2022Mycophenolic acid (MPA) may cause gastrointestinal adverse effects by damaging the intestinal epithelial barrier, the underlying mechanisms remain elusive. Studies have...
Mycophenolic acid (MPA) may cause gastrointestinal adverse effects by damaging the intestinal epithelial barrier, the underlying mechanisms remain elusive. Studies have demonstrated that oxidative stress caused by reactive oxygen species (ROS) is linked to tight junction (TJ) proteins and apoptosis, both of which cause abnormalities in intestinal barrier function. Mitochondria, one of the main sources of ROS and abnormally high levels of ROS are linked to mitochondrial dysfunction. The aim of this study was to investigate whether MPA induces intestinal barrier dysfunction through regulation of the mitochondrial ROS. MPA-induced intestinal injury model in Kunming mice and Caco-2 cells. The effect of MPA on Caco-2 cell viability was measured by MTT; tissue diamine oxidase and endotoxin expression were determined by ELISA; expression of total proteins of ZO-1, occludin, Bax, Bcl-2, and mitochondrial proteins of Cytochrome C and Bax was measured by Western blot; and the localization of Cytochrome C with MitoTraker was observed by immunofluorescence staining. Caco-2 cell apoptosis, ROS levels, and mitochondrial membrane potential were detected by flow cytometry, while intramitochondrial ROS levels were observed by MitoSOX fluorescence staining. The results showed that MPA increased intracellular and mitochondrial ROS production to promote oxidative stress and the antioxidant NAC effectively restored ZO-1 and occludin expressions, reduced apoptosis in intestinal epithelial cells. Furthermore, we found that low concentrations of MPA caused mitochondrial damage, induced hyperpolarization of the mitochondrial membrane potential and the translocation of Cytochrome C and Bax proteins from the cytoplasm to the mitochondria. The mitochondrial protectant SS-31 reduces intracellular and intramitochondrial ROS, upregulates TJ, and reduces apoptosis. Our studies suggest that MPA-induced intestinal barrier dysfunction and is mediated, at least in part, by impairing mitochondrial function and promoting oxidative stress.
Topics: Animals; Apoptosis; Caco-2 Cells; Cytochromes c; Humans; Intestinal Mucosa; Mice; Mitochondria; Mycophenolic Acid; Occludin; Reactive Oxygen Species; bcl-2-Associated X Protein
PubMed: 35847589
DOI: 10.1155/2022/4195699 -
International Journal of Antimicrobial... May 2024Human adenovirus (HAdV) and cytomegalovirus (HCMV) cause high morbidity and mortality in patients undergoing solid organ transplantation (SOT) and haematopoietic stem...
Human adenovirus (HAdV) and cytomegalovirus (HCMV) cause high morbidity and mortality in patients undergoing solid organ transplantation (SOT) and haematopoietic stem cell transplantation (HSCT). Immunosuppressors are used universally to prevent graft-vs-host disease in HSCT and graft rejection in SOT. The long-term use of these drugs is associated with a high risk of infection, but there is also evidence of their specific interference with viral infection. This study evaluated the antiviral activity of immunosuppressors commonly used in clinical practice in SOT and HSCT recipients in vitro to determine whether their use could be associated with reduced risk of HAdV and HCMV infection. Cyclophosphamide, tacrolimus, cyclosporine, mycophenolic acid, methotrexate, everolimus and sirolimus presented antiviral activity, with 50% inhibitory concentration (IC) values at low micromolar and sub-micromolar concentrations. Mycophenolic acid and methotrexate showed the greatest antiviral effects against HAdV (IC=0.05 µM and 0.3 µM, respectively) and HCMV (IC=10.8 µM and 0.02 µM, respectively). The combination of tacrolimus and mycophenolic acid showed strong synergistic antiviral activity against both viruses, with combinatory indexes (CI) of 0.02 and 0.25, respectively. Additionally, mycophenolic acid plus cyclosporine, and mycophenolic acid plus everolimus/sirolimus showed synergistic antiviral activity against HAdV (CI=0.05 and 0.09, respectively), while methotrexate plus cyclosporine showed synergistic antiviral activity against HCMV (CI=0.29). These results, showing antiviral activity in vitro against both HAdV and HCMV, at concentrations below the human C values, may be relevant for the selection of specific immunosuppressant therapies in patients at risk of HAdV and HCMV infections.
Topics: Humans; Immunosuppressive Agents; Antiviral Agents; Adenoviruses, Human; Cytomegalovirus; Drug Synergism; Inhibitory Concentration 50; Mycophenolic Acid; Tacrolimus; Cyclosporine; Cytomegalovirus Infections
PubMed: 38401774
DOI: 10.1016/j.ijantimicag.2024.107116 -
Gastroenterologia Y Hepatologia Oct 2020SARS-CoV-2 infection has produced a pandemic with serious consequences for our health care system. Although liver transplant patients represent only a minority of the... (Review)
Review
SARS-CoV-2 infection has produced a pandemic with serious consequences for our health care system. Although liver transplant patients represent only a minority of the population, the hepatologists who follow these patients have tried to coordinate efforts to produce a protocol the management of immunosuppression during SARS-CoV-2 infection. Although there are no solid studies to support general recommendations, experiences with other viral infections (hepatitis C, cytomegalovirus) suggest that management of immunosuppression without mycophenolate mofetil or m-Tor inhibitors (drugs that are also associated with leukopenia and lymphopenia) may be beneficial. It is also important to pay attention to possible drug interactions, especially in the case of tacrolimus, with some of the treatments with antiviral effect given in the context of COVID 19 (lopinavir/ritonavir, azithromycin). Finally, the immunosuppressive effect of immunomodulating drugs (tocilizumab and similar) administered to patients with severe lung disease should be taken into account. The mechanisms of action of the different immunosuppressive drugs are reviewed in this article, as well as their potential effect on SARS-CoV-2 infection, and suggests guidelines for the management of immunosuppression.
Topics: Adaptive Immunity; Antiviral Agents; Betacoronavirus; COVID-19; Calcineurin Inhibitors; Contraindications, Drug; Coronavirus Infections; Disease Susceptibility; Drug Interactions; Everolimus; Glucocorticoids; Humans; Immunity, Innate; Immunocompromised Host; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Mycophenolic Acid; Pandemics; Pneumonia, Viral; Postoperative Complications; SARS-CoV-2; Sirolimus; TOR Serine-Threonine Kinases; COVID-19 Drug Treatment
PubMed: 32646657
DOI: 10.1016/j.gastrohep.2020.06.003 -
Journal of Clinical Pharmacology Oct 2019Tacrolimus or cyclosporine is prescribed with mycophenolic acid posttransplant and contributes to interpatient variability in mycophenolic acid pharmacokinetics and...
Tacrolimus or cyclosporine is prescribed with mycophenolic acid posttransplant and contributes to interpatient variability in mycophenolic acid pharmacokinetics and response. Cyclosporine inhibits enterohepatic circulation of the metabolite mycophenolic acid glucuronide, which is not described with tacrolimus. This study investigated mycophenolic acid pharmacokinetics and adverse effects in stable renal transplant recipients and the association with calcineurin inhibitors, sex, and race. Mycophenolic acid and mycophenolic acid glucuronide area under the concentration-time curve from 0 to 12 hours (AUC ) and apparent clearance were determined at steady state in 80 patients receiving cyclosporine with mycophenolate mofetil and 67 patients receiving tacrolimus with mycophenolate sodium. Gastrointestinal adverse effects and hematologic parameters were evaluated. Statistical models evaluated mycophenolic acid pharmacokinetics and adverse effects. Mycophenolic acid AUC was 1.70-fold greater with tacrolimus (68.9 ± 30.9 mg·h/L) relative to cyclosporine (40.8 ± 17.6 mg·h/L); P < .001. Target mycophenolic acid AUC of 30-60 mg·h/L was achieved in 56.3% on cyclosporine compared with 34.3% receiving tacrolimus (P < .001). Mycophenolic acid clearance was 48% slower with tacrolimus (10.6 ± 4.7 L/h) relative to cyclosporine (20.5 ± 10.0 L/h); P < .001. Enterohepatic circulation occurred less frequently with cyclosporine (45%) compared with tacrolimus (78%); P < 0.001; with a 2.9-fold greater mycophenolic acid glucuronide AUC to mycophenolic acid AUC ratio (P < .001). Race did not affect mycophenolic acid pharmacokinetics. Gastrointestinal adverse effect scores were 2.2-fold higher with tacrolimus (P < .001) and more prominent in women (P = .017). Lymphopenia was more prevalent with tacrolimus (52.2%) than cyclosporine (22.5%); P < 0.001. Calcineurin inhibitors and sex contributed to interpatient variability in mycophenolic acid pharmacokinetics and adverse effects post-renal transplant, which could be attributed to differences in enterohepatic circulation.
Topics: Antibiotics, Antineoplastic; Area Under Curve; Calcineurin Inhibitors; Cyclosporine; Drug Interactions; Enterohepatic Circulation; Female; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Lymphopenia; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Transplant Recipients
PubMed: 31062373
DOI: 10.1002/jcph.1428 -
Transplantation Oct 2019The immunosuppressive agent mycophenolate is used extensively in kidney transplantation, yet dosing strategy applied varies markedly from fixed dosing... (Review)
Review
The immunosuppressive agent mycophenolate is used extensively in kidney transplantation, yet dosing strategy applied varies markedly from fixed dosing ("one-dose-fits-all"), to mycophenolic acid (MPA) trough concentration monitoring, to dose optimization to an MPA exposure target (as area under the concentration-time curve [MPA AUC0-12]). This relates in part to inconsistent results in prospective trials of concentration-controlled dosing (CCD). In this review, the totality of evidence supporting mycophenolate CCD is examined: pharmacological characteristics, observational data linking exposure to efficacy and toxicities, and randomized controlled trials of CCD, with attention to dose optimization method and exposure achieved. Fixed dosing of mycophenolate consistently leads to underexposure associated with rejection, as well as overexposure associated with toxicities. When CCD is driven by pharmacokinetic calculation to a target concentration (target concentration intervention), MPA exposure is successfully controlled and clinical benefits are seen. There remains a need for consensus on practical aspects of mycophenolate target concentration intervention in contemporary tacrolimus-containing regimens and future research to define maintenance phase exposure targets. However, given ongoing consequences of both overimmunosuppression and underimmunosuppression in kidney transplantation, impacting short- and long-term outcomes, these should be a priority. The imprecise "one-dose-fits-all" approach should be replaced by the clinically proven MPA target concentration strategy.
Topics: Allografts; Area Under Curve; Consensus; Dose-Response Relationship, Drug; Evidence-Based Medicine; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney; Kidney Transplantation; Mycophenolic Acid; Observational Studies as Topic; Time Factors
PubMed: 31584924
DOI: 10.1097/TP.0000000000002762 -
Transplantation and Cellular Therapy Sep 2023Adding sirolimus to graft-versus-host disease (GVHD) prophylaxis with cyclosporin and mycophenolate mofetil (MMF) reduced the risk of grade II-IV acute GVHD after... (Randomized Controlled Trial)
Randomized Controlled Trial
Adding sirolimus to graft-versus-host disease (GVHD) prophylaxis with cyclosporin and mycophenolate mofetil (MMF) reduced the risk of grade II-IV acute GVHD after nonmyeloablative (NMA) allogenic hematopoietic stem cell transplantation (HSCT) with an HLA-matched unrelated donor in a randomized clinical trial. We analyzed real-life data to investigate the impact of implementing the triple-drug regimen with cyclosporin, MMF and sirolimus as standard GVHD prophylaxis after NMA HSCT with an HLA-matched unrelated donor at our institution. We studied all adult patients (age ≥18 years) who underwent NMA HSCT with an HLA-matched unrelated donor at Rigshospitalet, Copenhagen University Hospital, Denmark between 2018 and 2021 and received GVHD prophylaxis with cyclosporin, MMF and sirolimus (triple-drug group [TDG]). Comparisons were made with a historical cohort who received tacrolimus and MMF as GVHD prophylaxis after HLA-matched unrelated donor NMA HSCT between 2014 and 2017 (control group [CG]). Outcomes were grade II-IV and grade III-IV acute GVHD, chronic GVHD, relapse, nonrelapse mortality (NRM) and overall survival (OS). A total of 264 patients were included (TDG, n = 137; CG, n = 127). Median age was 66 years (interquartile range [IQR], 58 to 69 years) in the TDG and 63 years (IQR, 57 to 68 years) in the CG. Acute myeloid leukemia and myelodysplastic syndrome were the most frequent indications for HSCT in both groups (TDG, 33% and 23%, respectively; CG, 36% and 22%, respectively). The cumulative incidence at day +110 of grade II-IV GVHD was 17% (95% confidence interval [CI] 11% to 23%) in the TDG versus 29% (95% CI, 21% to 37%) in the CG (P = .02, Gray's test) and that of grade III-IV acute GVHD was 3% (95% CI, 0 to 6%) versus 5% (95% CI, 1% to 8%), respectively (P = .4, Gray's test). In a Cox regression model adjusted for age, donor age and female donor to male recipient the risk of grade II-IV acute GVHD was lower in the TDG compared to the CG (hazard ratio [HR], .51; 95% CI .30 to .86; P = .01). The 2-year OS was 77% (95% CI, 70% to 84%) in the TDG and 69% (95% CI, 61% to 77%) in the CG (P = .04), and this difference remained significant after adjustment for age and Karnofsky Performance Status (HR, .65; 95% CI, .42 to .99; P = .04). The 2-year cumulative incidences of chronic GVHD, relapse and NRM were 60% (95% CI, 51% to 69%), 21% (95% CI, 13% to 28%), and 12% (95% CI, 6% to 17%), respectively, in the TDG and 62% (95% CI, 54% to 71%), 27% (95% CI, 19% to 35%) and 14% (95% CI, 8% to 20%), respectively, in the CG. Multivariable analyses revealed no difference in the risk of chronic GVHD (HR, .91; 95% CI, .65 to 1.26; P = .56), relapse (HR, .70; 95% CI, .42 to 1.15; P = .16) or NRM (HR, .56; 95% CI, .31 to 1.05; P = .07). After changing the standard GVHD prophylaxis in patients undergoing NMA HSCT with an HLA-matched unrelated donor from tacrolimus and MMF to cyclosporin, MMF and sirolimus, we observed a reduction in the incidence of grade II-IV acute GVHD and improved 2-year OS.
Topics: Adult; Humans; Male; Female; Middle Aged; Aged; Adolescent; Tacrolimus; Unrelated Donors; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease; Sirolimus; Mycophenolic Acid; Cyclosporine; Recurrence
PubMed: 37301257
DOI: 10.1016/j.jtct.2023.05.022 -
International Journal of Molecular... Sep 2022Coronaviruses as possible cross-species viruses have caused several epidemics. The ongoing emergency of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has...
Coronaviruses as possible cross-species viruses have caused several epidemics. The ongoing emergency of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has posed severe threats to the global economy and public health, which has generated great concerns about zoonotic viruses. Swine acute diarrhea syndrome coronavirus (SADS-CoV), an alpha-coronavirus, was responsible for mass piglet deaths, resulting in unprecedented economic losses, and no approved drugs or vaccines are currently available for SADS-CoV infection. Given its potential ability to cause cross-species infection, it is essential to develop specific antiviral drugs and vaccines against SADS-CoV. Drug screening was performed on a total of 3523 compound-containing drug libraries as a strategy of existing medications repurposing. We identified five compounds (gemcitabine, mycophenolate mofetil, mycophenolic acid, methylene blue and cepharanthine) exhibiting inhibitory effects against SADS-CoV in a dose-dependent manner. Cepharanthine and methylene blue were confirmed to block viral entry, and gemcitabine, mycophenolate mofetil, mycophenolic acid and methylene blue could inhibit viral replication after SADS-CoV entry. This is the first report on SADS-CoV drug screening, and we found five compounds from drug libraries to be potential anti-SADS-CoV drugs, supporting the development of antiviral drugs for a possible outbreak of SADS-CoV in the future.
Topics: Alphacoronavirus; Animals; Antiviral Agents; COVID-19; Methylene Blue; Mycophenolic Acid; SARS-CoV-2; Swine
PubMed: 36232553
DOI: 10.3390/ijms231911250 -
Clinical and Translational Science May 2023Tacrolimus (TAC) and mycophenolic acid (MPA) provide maintenance immunosuppression and is dosed empirically in elderly kidney transplant recipients (KTRs) resulting in...
Tacrolimus (TAC) and mycophenolic acid (MPA) provide maintenance immunosuppression and is dosed empirically in elderly kidney transplant recipients (KTRs) resulting in health inequities. Limited immunosuppressive pharmacokinetics are available comparing adult ages. This secondary analysis compared TAC and MPA pharmacokinetics and adverse effects (AEs) among young, middle-aged, and elderly Black and White KTRs. The 12-h TAC and MPA pharmacokinetics with AE evaluation were conducted in 67 stable KTRs greater than or equal to 6 months post-transplant. TAC regimens were adjusted to target troughs. MPA regimens were adjusted using clinical response. Participants were: young: less than or equal to 40 years; middle age: greater than 40 to 60 years, and elderly greater than 60 years. Noncompartmental pharmacokinetic analysis determined area under the concentration-time curve 0-12 h (AUC ), clearance (CL), and CL/body mass index (BMI) with 0-h troughs. MPA enterohepatic recirculation (EHR), MPA-AUC /MPA-AUC , and MPA glucuronide (MPAG)-AUC /MPA-AUC were determined. Univariate analysis of variance (ANOVA) was conducted using SAS version 9.4. No group differences were noted for estimated glomerular filtration rate, MPA, and TAC doses. EHR was reduced in elderly with decreased MPA-AUC /MPA-AUC (p = 0.049) and increased MPAG-AUC /MPA-AUC (p = 0.036). MPA troughs (p = 0.045) were reduced in the elderly. TAC CL/BMI (p = 0.043) was reduced in the elderly. For therapeutic MPA AUC : 30-60 mg·h/L, 34.3% KTRs achieved this target with 55.2% greater than the therapeutic range. 77.6% KTR were in the TAC AUC target: 100-190 ng·h/mL and 19.4% were below this range with no age relationship. In 44% young, 26% middle-age and 7.8% elderly subjects achieved target AUC for both medications (p = 0.036). Neurologic AEs were manifested in the elderly (p = 0.014). Immunosuppressive pharmacokinetics demonstrated age-related differences with reduced TAC CL/BMI and MPA EHR and increased neurologic AE in the elderly. This immunosuppressive regimen may require age-adjusted individualization to optimize allograft function.
Topics: Adult; Middle Aged; Aged; Humans; Tacrolimus; Mycophenolic Acid; Kidney Transplantation; Area Under Curve; Immunosuppressive Agents; Health Inequities
PubMed: 36840340
DOI: 10.1111/cts.13495 -
Clinical Journal of the American... Jul 2020The overall kidney survival among lupus nephritis patients has improved with currently used induction immunosuppression regimens of corticosteroids and either... (Review)
Review
The overall kidney survival among lupus nephritis patients has improved with currently used induction immunosuppression regimens of corticosteroids and either cyclophosphamide or mycophenolate mofetil; however, there still remains a significant number of lupus nephritis patients who do not achieve remission with these regimens. Investigators have looked at other immunosuppressive regimens for lupus nephritis, and there has been interest in the use of calcineurin inhibitors in this regard. Calcineurin inhibitors are potentially an attractive option because of their established ability to inhibit T cell function, attenuate proteinuria through non-immunologic means, and their safety in pregnancy and lactation. In this review, we discuss the findings and limitations of selected trials that evaluated the use of calcineurin inhibitors in the treatment of lupus nephritis, either with corticosteroids alone or as a component of multitarget therapy when combined with mycophenolate mofetil. There may be a role for calcineurin inhibitors among patients with heavy proteinuria, as well as younger patients with refractory lupus nephritis. The multitarget therapy trials reveal higher rates of remission compared with mycophenolate mofetil alone and cyclophosphamide; however, some trials highlight the possibility of more infectious adverse events. We discuss the need for further study of calcineurin inhibitors in more diverse patient populations and the need for trials with longer follow-up with "hard" endpoints beyond proteinuria reduction, such as worsening CKD or repeat protocol biopsies, given the calcineurin inhibitors ability to reduce proteinuria non-immunologically and thus increased rate of relapse when the drug is tapered. While there may indeed be a space for calcineurin inhibitors to help increase remission rates in lupus nephritis patients, more work is needed to help address the questions the studies available to date have yet to answer.
Topics: Adrenal Cortex Hormones; Calcineurin Inhibitors; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid; Randomized Controlled Trials as Topic
PubMed: 32152065
DOI: 10.2215/CJN.13761119