Mycophenolic Acid Trough Research Articles

Predicting Mycophenolic Acid Area under the Curve with Mycophenolic Acid Trough in De Novo Renal Transplantation

Predicting Mycophenolic Acid Area under the Curve with Mycophenolic Acid Trough in De Novo Renal Transplantation

Mycophenolate Mofetil Effect and Trough Level Under 2-Year Old in Pediatric Living Donor Liver Transplantation

Introduction Mycophenolate mofetil (MMF) is prodrug of mycophenolic acid to improve oral bioavailability. MMF are mainly used as third agent immunosuppression for renal sparing and anti-rejection in liver transplantation. However there have been only few reports of MMF use for very young children after living donor liver transplantation (LDLT). The purpose of this study was to examine the safety and efficacy based on mycophenolic acid (MA) trough level in the under 2 –year old patients. Methods The patients under 2-year old who received LDLT between Nov. 2015 and October 2017 were enrolled. Our standard tacrolimus and steroid based immunosuppression were administrated. MMF was added to selected children for the indications including renal sparing, refractory acute cellular rejection (ACR), fulminant hepatitis and preexisting antibody. MMF was administrated twice a day orally. First MMF was given at dosage of 40-50mg/kg/day. Dose was increased to target MA trough level 3 ng/ml. Body weight, height, MMF dosage, MA trough level, ACR episode, serum cystatin C and adverse effects were analyzed. Results Seven patients received MMF for renal sparing (n=2), refractory ACR (n=2), fulminant hepatitis (n=2) and preexisting antibody (n=1). Original diseases were biliary atresia (n=5) and fulminant hepatitis (n=2). Median age at transplant was 7 months (ranged 6month to 12month). Median first administration of MMF were post-operative day (POD) 18 (ranged POD 1 to POD 39). Observation period ranged 51 to 730 days. Last available median trough level was 2ng/ml (ranged1.4 to 3.3 ng/ml). Median dose were 84mg/kg and 2012 mg/m2 at last available median trough level. Regression line between MMF dose and MA trough level was Y=1.1*10^3X-0.54. Correlation coefficient was 0.81. There was no ACR episode after MMF was administrated. Average cystatin C serum level was decreased from 1.69 mg/L to 1.08mg/L in renal sparing patients (n=2). One patient whose indication was refractory ACR discontinued MMF due to infection. Other patients were tolerable to MMF without adverse effect. Discussion MMF is now commonly used in pediatric liver transplant recipients, but no clear recommendations about the dosing regimen have been made for very young child. Recommend pediatric dose is 300-600mg/m2/day, however young child require more MMF dose to maintain MA trough level in our study. Even if most patients received higher dose that previously documented for pediatric dose, they did not show adverse effect. The patient developed infection might be over immunosuppression because of treating ACR. MMF showed good anti ACR effect at higher dose. Conclusion MMF use for the patients under 2-year old after LDLT were tolerable. However they required more dose than that of older patients.

The utility of trough mycophenolic acid levels for the management of lupus nephritis.

Monitoring of mycophenolic acid (MPA) levels may be useful for effective mycophenolate mofetil (MMF) dosing. However, whether commonly obtained trough levels are an acceptable method of surveillance remains debatable. We hypothesized that trough levels of MPA would be a poor predictor of area under the curve (AUC) for MPA. A total of 51 patients with lupus nephritis who were on MMF 1500 mg twice a day and had a 4-h AUC done were included in this study. MPA levels were measured prior to (C0) and at 1 (C1), 2 (C2) and 4 (C4) h, followed by 1500 mg of MMF. The MPA AUC values were calculated using the linear trapezoidal rule. Regression analysis was used to examine the relationship between the MPA trough and AUC. Differences in the MPA trough and AUC between different clinical and demographic categories were compared using t-tests. When grouped by tertiles there was significant overlap in MPA, AUC 0-4 and MPA trough in all tertiles. Although there was a statistically significant correlation between MPA trough levels and AUC, this association was weak and accounted for only 30% of the variability in MPA trough levels. This relationship might be even more unreliable in men than women. The use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was associated with increased MPA trough levels and AUC at 0-4 h (AUC0-4). Trough levels of MPA do not show a strong correlation with AUC. In clinical situations where MPA levels are essential to guide therapy, an AUC0-4 would be a better indicator of the adequacy of treatment.

Development of a Formula to Correct Particle-Enhanced Turbidimetric Inhibition Immunoassay Values so That it More Precisely Reflects High-Performance Liquid Chromatography Values for Mycophenolic Acid.

BackgroundMycophenolic acid (MPA) concentration measured by homogeneous particle-enhanced turbidimetric inhibition immunoassay (PETINA) may be overestimated due to its cross-reactivity with pharmacologically inactive MPA glucuronide (MPAG), as well as other minor metabolites, accumulated with renal function impairment or co-administered cyclosporine A. In contrast, high-performance liquid chromatography (HPLC) is precise because it can exclude the cross-reactivity. In this study, we assumed HPLC values for MPA (HPLC-MPA) as a reference and aimed to develop a formula correcting PETINA values for MPA (PETINA-MPA) to more precisely reflect HPLC-MPA.MethodsMPA trough concentrations were measured both by HPLC-UV and PETINA in 39 samples issued from 39 solid-organ transplant recipients. MPAG concentrations were also measured using HPLC UV assay. We determined the impacts of renal function and coadministered calcineurin inhibitor on concentrations of MPA and MPAG measured by HPLC. Then, we evaluated the difference between PETINA-MPA and HPLC-MPA. Finally, we develop a formula to reflect HPLC-MPA by using multilinear regression analysis.ResultsMPAG concentration was negatively correlated with estimated glomerular filtration rate (eGFR) (R2 = 0.376, P < 0.001), although MPA was not correlated with eGFR. There were no significant differences in MPA or MPAG concentrations per dose between the patients who were co-administered tacrolimus versus cyclosporine A. Finally, we developed the formulas to reflect HPLC-MPA:Formula 1: Estimated MPA concentration = 0.048 + 0.798 × PETINA‐MPAFormula 2: Estimated MPA concentration = − 0.059 + 0.800 × PETINA‐MPA + 0.002 × eGFRHowever, there was no significant improvement in the coefficient of determination with addition of eGFR in the formula, suggesting that HPLC-MPA can be well predicted by only 1 variable, PETINA-MPA.ConclusionsThis study developed a formula so that PETINA-MPA can be corrected to more precisely reflect HPLC-MPA.

Clinical Implication of Mycophenolic Acid Trough Concentration Monitoring in Kidney Transplant Patients on a Tacrolimus Triple Maintenance Regimen: A Single-Center Experience.

BackgroundThis study was designed to analyze the clinical implications of mycophenolic acid trough concentration monitoring.Material/MethodsWe collected data of patients with mycophenolic acid trough concentration monitoring after their first kidney transplant between November 2006 and March 2015 who were prescribed tacrolimus, mycophenolate, and methylprednisolone. Analyses were performed on 3 periods: 1 month, 1 month to 1 year, and after 1 year post-transplantation. To analyze factors related to acute cellular rejection, logistic regression was used for 1 month, while Cox analysis was used during 1 month to 1 year and after 1 year post-transplantation.ResultsIn the 145 patients receiving mycophenolate mofetil, mean tacrolimus trough ≥7.0 ng/mL (OR=0.177, CI=0.060–0.524, p=0.002) and mean mycophenolic acid trough ≥1.7 mg/L (OR=0.190, CI=0.040–0.896, p=0.036) were protective for rejection during 1 month. Mean mycophenolic acid trough ≥1.7 mg/L (HR=0.179, CI=0.040–0.806, p=0.025) and ≥0.7 mg/L (HR=0.142, CI=0.028–0.729, p=0.019) were related to better rejection-free survival during 1 month to 1 year and after 1 year, respectively. In 399 patients receiving enteric-coated mycophenolate sodium, mean tacrolimus trough ≥7.0 ng/mL (OR=0.258, CI=0.131–0.507, p<0.001) and mean mycophenolic acid trough ≥2.1 mg/L (OR=0.507, CI=0.264–0.973, p=0.041) were protective for rejection during 1 month. Mean mycophenolic acid trough ≥1.7 mg/L (HR=0.519, CI=0.289–0.932, p=0.028) and ≥0.7 mg/L (HR=0.208, CI=0.072–0.602, p=0.004) were related to better rejection-free survival during 1 month to 1 year and after 1 year, respectively.ConclusionsMycophenolic acid trough concentration monitoring can be useful in preventing acute cellular rejection in patients receiving tacrolimus, mycophenolate, and methylprednisolone.

A Retrospective Study on Mycophenolic Acid Drug Interactions: Effect of Prednisone, Sirolimus, and Tacrolimus With MPA.

Mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is widely used as an antirejection drug after renal transplantation. There is growing evidence supporting the notion that there is substantial variability in the intra- and interpatient exposure to MPA. Drug interactions involving MPA with tacrolimus, steroids, and sirolimus have been understudied. The objective of this study was to determine the relationship between MPA, steroids, tacrolimus, and sirolimus. MPA trough concentrations from 37 pediatric renal transplant recipients (mean age 7.6 years at transplant) followed for a median follow-up of 7.8 years were analyzed retrospectively and 2131 dose-normalized MPA trough concentrations were evaluated against all known covariates including all concomitant immunosuppressant drug doses and exposure, age, albumin, hematocrit, and estimated glomerular filtration rate (eGFR). Age, hematocrit, and estimated glomerular filtration rate affected the dose-normalized MPA trough concentrations. The authors used appropriate linear regression univariate models and created 5 different multivariate models to examine individual drug-drug interactions (DDIs). Although the authors' findings support the notion that there is a DDI between MMF and both sirolimus and steroids, the sample size was small, and these findings should be confirmed in future studies. The authors found no DDIs between tacrolimus and MMF, the prodrug of MPA. These findings are important because there is a tendency to under-dose MMF early and to overdose late after transplantation. The DDI between sirolimus and MMF has not been described. Although therapeutic drug monitoring of MMF therapy is often not performed, the data presented here indicate a necessity for therapeutic drug monitoring. This is especially true when converting from tacrolimus to sirolimus, as a way to avoid MPA underexposure and organ rejection.

Exposure to Mycophenolate and Fatherhood

BackgroundMycophenolic acid (MPA) is the active immunosuppressive substance in both mycophenolate mofetil and mycophenolate sodium, and it is widely used after organ transplantation. In women, taking MPA is teratogenic and may also influence spermatogenesis. There is a lack of knowledge regarding outcome of pregnancies fathered by men exposed to MPA.MethodsWe compared outcomes in pregnancies fathered by renal transplant men per whether they had been exposed to MPA or not at time of conception. A nationwide population-based retrospective cohort study was performed. Data from the Norwegian Renal Registry with all renal transplanted men alive between January 1, 1995 and December 31, 2015 were included, and relevant outcome data were extracted from the Medical Birth Registry of Norway.ResultsDuring the given time, 230 immunosuppressed renal transplanted men fathered 350 children (155 on MPA/195 not on MPA). There were no significant increased risks of malformation (3.9% vs. 2.6%, P = 0.49) in MPA exposed versus unexposed cohorts of children. The average dose (±SD) of mycophenolate was 1.42 ± 0.3 g/day and the individual median MPA trough concentration in the time period of anticipated conception and pregnancy was 2.8 ± 1.6 mg/L. Birth weight was similar in exposed and unexposed cohorts of children; 3381 ± 681 g vs. 3429 ± 714 g (P = 0.53).ConclusionsPaternal exposure to MPA did not increase the risk of adverse birth outcomes in children fathered by male kidney transplanted patients. These results are reassuring and support the continuation of paternal MPA treatment before, during, and after conception.

Usefulness of mycophenolic acid monitoring with PETINIA for prediction of adverse events in kidney transplant recipients

Background Therapeutic drug monitoring of mycophenolic acid (MPA) is required to optimize the immunosuppressive effect and minimize toxicity. We validated a new particle-enhanced turbidimetric inhibition immunoassay (PETINIA) for the determination of MPA levels and evaluated the relationship of MPA trough level with drug-related adverse events. Methods PETENIA and liquid chromatography-mass spectrometry (LC-MS) were used to determine MPA concentrations from 54 kidney transplant recipients (KTRs). Agreement between PETINIA and LC-MS results was assessed by Passing-Bablok regression and the Bland-Altman plot method. The association of adverse events with MPA trough level obtained by PETINIA was analyzed. Results PETINIA revealed a good agreement with the LC-MS; Regression analysis gave an equation of y = 1.27x − 0.12 (r2 = 0.975, p < 0.001). PETINIA showed a systemic positive bias with a mean difference of 0.66 mg/L compared to LC-MS. However, the magnitude of the positive bias decreased to 0.44 mg/L within the therapeutic range of MPA. Multiple logistic regression showed that MPA trough level determined by PETINIA was an independent risk factor for adverse events (odds ratio 2.28, 95% CI 1.25–4.16, p = 0.007). MPA trough level predicted adverse events with a sensitivity of 77.8% and a specificity of 86.7% using a cut-off level of 5.25 mg/L. Conclusions Good correlation between the two methods indicates that PETINIA is an acceptable method for the monitoring of MPA therapeutic levels. Furthermore, MPA trough level obtained by PETINIA is a useful monitoring tool to minimize toxicity in KTRs.

Developmental changes of MPA exposure in children.

Developmental changes (ontogeny) of drug disposition of Mycophenolate mofetil (MMF) have been understudied. The charts of 37 pediatric renal transplant recipients (median age 7.3 years, median follow-up 7.8 (IQR 6.6, 14.3 years) who had regular mycophenolic acid (MPA) trough level monitoring in combination with tacrolimus (n = 31) or sirolimus (n = 6) therapy were analyzed retrospectively for their dose-normalized MPA exposure, steroid dose, albumin, hematocrit, and cystatin C estimated glomerular filtration rate (eGFR). Using appropriate univariate and multivariate methods, we determined whether MPA exposure was age dependent when controlling for the confounders. Dose-normalized MPA trough levels could be calculated in 2,128 (median 45/patient) instances. Spearman rank correlation analysis revealed that age correlated with dose-normalized MPA trough level for both body weight and body surface area, as well as serum albumin, hematocrit, steroid dose, and eGFR. In the multivariate analysis, serum albumin and steroid dose were not significant, and hematocrit only being significant when the youngest group of patients < 6 years of age was compared. eGFR was the most important confounder, but age dependency remained significant when controlling for all confounders. Small children are at a significantly greater risk for low MPA trough levels than adolescents, highlighting the need for pharmacokinetic monitoring of MPA.

What is the intrapatient variability of mycophenolic acid trough levels?

TDM of MPA, the active compound of MMF, is rarely used despite its substantial intra- and interpatient variability. Little is known about the utility of long-term MPA TDM. Data are expressed as mean (one standard deviation). All available data from 27 renal transplant recipients (mean age at transplantation: 7.7 [5.0] yr) with an average follow-up of 9.3 (4.6) yr were analyzed. MPA levels were measured using the EMIT. GFR was measured using cystatin C and eGFR was calculated using the Filler formula. Intrapatient CV of the trough level was calculated as the ratio of the mean divided by one standard deviation. Mean cystatin C eGFR was 56.9 (24.4) mL/min/1.73 m(2) . There was a weak but significant correlation between the MPA trough level and the AUC (Spearman r = 0.6592, p < 0.0001). A total of 1964 MPA trough levels (73 [45]/patient) were measured, as compared to 3462 Tac trough levels (144 [71]/patient). The average MPA trough level was 3.01 (1.26) mg/L and the average trough Tac level was 7.3 (1.8) ng/mL. Intrapatient CV was statistically higher (p = 0.00093) for MPA at 0.68 (0.29) when compared to Tac with a CV of 0.46 (0.12). CV did not correlate with eGFR. Intrapatient MPA trough level CV is significantly higher than for Tac, while CV for both MPA and Tac was high. MPA trough level monitoring may be a feasible monitoring option to improve patient exposure and possibly outcomes.

Mycophenolic mofetil optimized pharmacokinetic modelling, and exposure-effect associations in adult heart transplant recipients

Mycophenolic acid (MPA) area under the curve (AUC) has been associated with graft outcome. The aims of our study were: (1) to develop pharmacokinetic tools to optimize MPA inter-dose AUC estimation in heart transplant patients; and (2) to investigate the relationships between acute allograft rejection and MPA AUC, trough level (C0) or mycophenolate mofetil (MMF) dose.Two independent modeling approaches (parametric and non parametric) were used to fit 56 rich MPA pharmacokinetic (PK) profiles collected from 40 adult heart transplant recipients enrolled in the PIGREC study, receiving MMF and a calcineurin inhibitor (CNI), in the first year post-transplantation. In addition, associations between drug exposure (MPA C0, AUC and MMF dose) and acute rejection or MMF adverse events were investigated using time-dependent Cox models with stratification on the type of calcineurin inhibitor. Exposure threshold values were investigated using ROC curve analysis.The 2 models developed fit adequately the data and the use of their combination yielded 100% consistency with the measured AUC in terms of strategy of dose adjustment (maintain, increase or decrease). MPA measured AUC adjusted on CNI exposure was significantly associated with rejection (per unit increase: HR [95% CI]=0.97 [0.95–0.99], p=0.0122), while no effect was shown for adverse events attributable to MMF. An AUC threshold of 50mg×h/L was proposed (sensitivity=77%, specificity=25%) beyond which the risk of rejection was significantly increased (low vs. high: HR=3.48 [1.21–10.0], p=0.0204).The tools developed have already been made available to the heart transplant community on our ISBA website (https://pharmaco.chu-limoges.fr).

Intensified Mycophenolate Mofetil Dosing and Higher Mycophenolic Acid Trough Levels Reduce Severe Acute Graft-versus-Host Disease after Double-Unit Cord Blood Transplantation

Although mycophenolate mofetil (MMF) has replaced corticosteroids as immunosuppression in cord blood transplantation (CBT), optimal MMF dosing has yet to be established. We intensified MMF dosing from every 12 to every 8 hours to augment graft-versus-host disease (GVHD) prophylaxis in double-unit cord blood transplantation (dCBT) and evaluated outcomes according to the total daily MMF dose/kg in 174 dCBT recipients (median age, 39 years; range, 1 to 71) who underwent transplantation for hematologic malignancies. Recipients of an MMF dose ≤ the median (36 mg/kg/day) had an increased day 100 grade III and IV acute GVHD (aGVHD) incidence compared with patients who received >36 mg/kg/day (24% versus 8%, P = .008). Recipients of ≤ the median dose who had highly HLA allele (1 to 3 of 6) mismatched dominant units had the highest day 100 grade III and IV aGVHD incidence of 37% (P = .009). This finding was confirmed in multivariate analysis (P = .053). In 83 patients evaluated for mycophenolic acid (MPA) troughs, those with a mean week 1 and 2 trough < .5 μg/mL had an increased day 100 grade III and IV aGVHD of 26% versus 9% (P = .063), and those who received a low total daily MMF dose and had a low mean week 1 and 2 MPA trough had a 40% incidence (P = .008). Higher MMF dosing or MPA troughs had no impact on engraftment after myeloablation. This analysis supports intensified MMF dosing in milligram per kilogram per day and MPA trough level monitoring early after transplantation in dCBT recipients.

Mycophenolic Acid Metabolites Acyl-Glucuronide and Glucoside Affect the Occurrence of Infectious Complications and Bone Marrow Dysfunction in Liver Transplant Recipients.

BACKGROUND Mycophenolic acid (MPA) prodrugs are anti-proliferative immunosuppressive agents commonly used after organ transplantation. Although they are generally well tolerated by patients, adverse effects may occur. It is postulated that MPA metabolites could also contribute to these adverse effects. MATERIAL AND METHODS The objective of this study was the assessment of concentrations of total MPA and its metabolites, phenyl glucuronide (MPAG), acyl glucuronide (AcMPAG) and glucoside (GluMPA), using liquid chromatography combined with mass spectrometry (LC/MS/MS) in two groups: kidney transplant recipients and liver transplant patients. Associations of MPA and its metabolites with adverse effects were analyzed. RESULTS The study group consisted of 211 recipients of liver or kidney transplants who received immunosuppressive therapy, including MPA prodrugs. Multivariant analysis showed a positive influence of MPA on gastroenterotoxicity in kidney transplant recipients. In liver patients, gastroenterotoxicity was associated with lower MPAG concentrations. A positive influence of AcMPAG on bacterial infections in liver transplant patients was observed. In liver transplant recipients, a positive influence of MPA and a negative influence of GluMPA levels on the PLT count were revealed. MPA and its metabolites did not influence the hemoglobin levels in both groups. There were no significant relationships among MPA, its metabolites and WBC counts. CONCLUSIONS In kidney transplant recipients, total MPA trough concentration is associated with gastroenterotoxicity and its monitoring could have important role in management of gastrointestinal complications. The quantification of AcMPAG in liver recipients receiving MPA may be helpful in avoiding bacterial infections. GluMPA seems to have a toxic effect on thrombopoiesis.

Short-term Pharmacokinetic Study of Mycophenolate Mofetil in Neonatal Swine

BackgroundMycophenolate mofetil (MMF) is an effective immunosuppressive agent that has been frequently used in laboratory animals including swine; however, the pharmacokinetic properties of MMF in swine have not been studied. This short-term study was designed to evaluate the feasibility and the pharmacokinetic profiles of MMF therapy in neonatal swine. Materials and MethodsTwelve neonatal pigs were randomized into four groups including one control and three treated groups with oral MMF administered at 0.5, 1, and 2 g/m2/d for 4 days, divided by 2 half-doses at 9:00 and 17:00 (except day 4 during which MMF was not administered at 17:00). Blood samples were collected at 9:00 on days 0, 2, 3 and 4 for complete blood count and hepatic/renal function examination; the trough concentration of plasma mycophenolic acid (MPA) was also determined. On days 2 and 4, blood was collected to determine the area under the curve (AUC) of plasma MPA concentration. Animal body-weight growth and manifestations of MMF side-effects such as anorexia, vomiting, and diarrhea were also observed. ResultsMMF has no acute hepatic/renal toxicity in newborn pigs; however, less body-weight growth was observed in treated groups. In the control group, a spontaneous increase of lymphocyte count was observed; in contrast, MMF therapy with doses of 1 and 2 g/m2/d reduced both lymphocyte and monocyte counts of piglets. Oral MMF had high bioavailability in neonatal swine. MPA-AUC0-12h of doses 0.5, 1, and 2 g/m2/d was 22.00 ± 3.32, 57.57 ± 34.30, and 140.00 ± 19.70 μg × h/mL, respectively. Neither MPA trough concentration (MPA-C0), nor MPA maximum concentration (MPA-Cmax) or MPA-AUC0-6h had high correlation with MMF-dose. For surveillance of MPA exposure, MPA-C0 had significant correlation with MPA-AUC0-12h (Spearman's ρ = 0.933, AUC0-12h = 17.882 × C0 + 14.479, r2 = 0.966). ConclusionTo reach adequate drug exposure and to reduce dose-dependent side effects, an MMF dose of 1 g/m2/d is recommended to be used as an initial dose for immunosuppressive therapy in piglets, and MPA-C0 monitoring is the most practical strategy for experimental transplantation study.

Association of Serum Mycophenolic Acid (MPA) Levels &amp; Mycophenolic Acid (MMF) Dose With BK Viremia Post Kidney Transplantation (KT).

The utility of routine monitoring of MPA serum trough levels to adjust MMF dosing in patients status post KT is poorly established. There is little real-world data to demonstrate a correlation between routine MPA level monitoring and clinical outcomes. We performed a retrospective analysis on our center database to evaluate whether routine MPA monitoring would correlate with opportunistic infection such as BK viremia. Our retrospective analysis included all adult solitary KT recipients at our center on MMF who had MPA trough levels measured during the 1st year of follow up. BK virus was detected in blood samples using the quantitative real time PCR technique with positive range of ≥200 copies/mL. MPA trough level and MMF dose were compared between the patients with and without BK viremia. Multivariate analysis was conducted to identify the association of MMF dose and BK viremia after controlling for other potential risk factors. MPA levels drawn after development of BK viremia were excluded. Results: A total of 244 patients were included, age 52.4±14.2 years, 34% African American, 37% female, 75% deceased donor KT, and 16.8% sensitized (CPRA >0%). There was no significant difference in MPA levels between the patients who were BK viremic or not (2.73±0.21 vs 2.35±0.14 mcg/mL,P=0.1138). However, the MMF dose was significantly different between the two groups (1808.5±34.1 vs 1612.7±29.4 mg/day total dose, P<.0001). The significant difference for MMF dose still holds after adjusting for covariant risk factors including recipient age, gender, race, dialysis length, HLA mismatch, previous KT, diabetes, tacrolimus trough level, cytomegalovirus, donor type, and induction medicine (HR: 1.18, 95%CI: 1.10-1.27, P<.0001).Figure: No Caption available.In our retrospective analysis, we did not find any significant correlation between MPA trough levels and BK viremia, whereas we did find a correlation between total daily MMF dose and BK viremia. These results suggest doubtful efficacy of MPA trough levels in determining overimmunosuppression and resulting BK viremia.

Impact of Omeprazole On Mycophenolic Acid Pharmacokinetics in Adult Renal Transplant Patients.

Background:Published studies have shown that proton pump inhibitors(PPIs) reduce the mycophenolic acid(MPA) area-under-the-curve(AUC0-12) in patients treated with mycophenolate mofetil(MMF), but not with enteric-coated mycophenolate sodium(EC-MPS). Aim:To analyse the impact of omeprazole(OME) coadministration on MPA pharmacokinetics in adult renal transplant patients treated with MMF(Cellcept®) or EC-MPS(Myfortic®). Patients and methods:Crossover study of 20 patients who underwent a cadaveric renal transplantation, in a stable clinical situation (6th month post-transplant), with tacrolimus, prednisone and MPA equivalent doses (500 mg MMF˜360 mg EC-MPS) and a 20-mg OME daily dose administered in the morning around 30 minutes before immunosuppressive therapy. For each patient, two pharmacokinetic profiles were obtained with OME treatment (1st) and without OME treatment (2nd), with a 7-10-day washout period between each. Samples were extracted before and at 1,2,3,4,6 and 8h after the oral MMF or EC-MPS morning dose. Plasma levels were measured using EMIT on Dimension™analyser. AUC0-12 was calculated using linear trapezoidal rule. MPA trough levels (Ctrough) and AUC0-12 valueswere compared during and after OME discontinuation. Statistical analysis: SPSS version 19.0. Wilcoxon Signed Rank Test was used for studying Ctrough and AUC0-12 variations. P<0.05: statistically significant. Results:The study included 20 patients (9:MMF, 11:EC-MPS), mean age: 50 years, mean weight: 69 kg.In patients treated with MMF, pharmacokinetic variables for those receiving OME or not were respectively: Ctrough (3.12±1.58 vs. 1.96±0.85 ng/mL,p=0.021, median 2.50 vs. 1.80) and AUC0-12 (49.34±10.47 vs. 37.37±7.68 ng.h/mL, p=0.008, median 50.25 vs. 38.85). When the patients were treated with EC-MPS, these parameters were:Ctrough (4.54±4.03 vs. 4.12±2.78 ng/mL,p=0.878, median 2.80 vs. 3.10) and AUC0-12 (52.04±39.78 vs. 71.87±43.03 ng.h/mL, p=0.003,median 41.55 vs.54.25). Conclusions: As omeprazole is an inhibitor, this study performed on renal transplant patients showed a significantly higher exposure (AUC0-12)with OME comedication during MMF and EC-MPS therapy. With respect to Ctrough, OME increased the obtained value for patients treated with MMF but not with EC-MPS.

Correlation Between Mycophenolic Acid Blood Level and Renal Dysfunction in Stable Liver Transplant Recipients Receiving Mycophenolate Monotherapy

PurposeMycophenolate mofetil (MMF) is frequently used after liver transplantation (OLT). Mycophenolic acid (MPA) metabolites are eliminated primarily via the kidneys. If renal function declines, clearance is significantly impaired. The aim of this study was to reveal the renal function-dependent changes of MPA level in stable adult OLT recipients receiving MMF monotherapy. MethodsSixty-five OLT recipients were selected from our OLT database of >3500 cases. All had undergone MMF monotherapy with a daily MMF dose of 1000 mg or 1500 mg for more than 2 years, primarily because they could not tolerate calcineurin inhibitors. Their clinical profiles, including MPA therapeutic drug monitoring (TDM) and renal function, were analyzed as a cross-sectional study. ResultsFor the group treated with 1000 mg MMF (n = 40), the 12-hour MPA trough level was 1.20 ± 0.35 μg/mL with serum creatinine (Cr) level ≤1.4 mg/dL in 13 patients; it was 2.78 ± 1.19 μg/mL with Cr >1.4 mg/dL in 16 patients not undergoing hemodialysis and 3.83 ± 0.87 μg/mL in 11 patients undergoing hemodialysis (P < .001). For the group treated with 1500 mg MMF (n = 25), the MPA trough level was 2.23 ± 0.99 μg/mL with Cr ≤1.4 mg/dL in 6 patients; it was 2.81 ± 0.99 μg/mL with Cr >1.4 mg/dL in 18 patients not undergoing hemodialysis and 3.5 μg/mL in 1 patient undergoing hemodialysis (P = .21). ConclusionsConsidering the potential therapeutic range of MPA, the suggested MMF dosage for Korean adult OLT recipients requiring hemodialysis may be set around 1000 mg per day. We suggest adjusting the MMF dosage on an individualized basis according to the results of MPA TDM, particularly for patients with markedly impaired renal function.

How Accurate and Precise Are Limited Sampling Strategies in Estimating Exposure to Mycophenolic Acid in People with Autoimmune Disease?

Mycophenolic acid (MPA) is a potent immunosuppressant agent, which is increasingly being used in the treatment of patients with various autoimmune diseases. Dosing to achieve a specific target MPA area under the concentration-time curve from 0 to 12 h post-dose (AUC12) is likely to lead to better treatment outcomes in patients with autoimmune disease than a standard fixed-dose strategy. This review summarizes the available published data around concentration monitoring strategies for MPA in patients with autoimmune disease and examines the accuracy and precision of methods reported to date using limited concentration-time points to estimate MPA AUC12. A total of 13 studies were identified that assessed the correlation between single time points and MPA AUC12 and/or examined the predictive performance of limited sampling strategies in estimating MPA AUC12. The majority of studies investigated mycophenolate mofetil (MMF) rather than the enteric-coated mycophenolate sodium (EC-MPS) formulation of MPA. Correlations between MPA trough concentrations and MPA AUC12 estimated by full concentration-time profiling ranged from 0.13 to 0.94 across ten studies, with the highest associations (r (2) = 0.90-0.94) observed in lupus nephritis patients. Correlations were generally higher in autoimmune disease patients compared with renal allograft recipients and higher after MMF compared with EC-MPS intake. Four studies investigated use of a limited sampling strategy to predict MPA AUC12 determined by full concentration-time profiling. Three studies used a limited sampling strategy consisting of a maximum combination of three sampling time points with the latest sample drawn 3-6 h after MMF intake, whereas the remaining study tested all combinations of sampling times. MPA AUC12 was best predicted when three samples were taken at pre-dose and at 1 and 3 h post-dose with a mean bias and imprecision of 0.8 and 22.6 % for multiple linear regression analysis and of -5.5 and 23.0 % for maximum a posteriori (MAP) Bayesian analysis. Although mean bias was less when data were analysed using multiple linear regression, MAP Bayesian analysis is preferable because of its flexibility with respect to sample timing. Estimation of MPA AUC12 following EC-MPS administration using a limited sampling strategy with samples drawn within 3 h post-dose resulted in biased and imprecise results, likely due to a longer time to reach a peak MPA concentration (t max) with this formulation and more variable pharmacokinetic profiles. Inclusion of later sampling time points that capture enterohepatic recirculation and t max improved the predictive performance of strategies to predict EC-MPS exposure. Given the considerable pharmacokinetic variability associated with mycophenolate therapy, limited sampling strategies may potentially help in individualizing patient dosing. However, a compromise needs to be made between the predictive performance of the strategy and its clinical feasibility. An opportunity exists to combine research efforts globally to create an open-source database for MPA (AUC, concentrations and outcomes) that can be used and prospectively evaluated for AUC target-controlled dosing of MPA in autoimmune diseases.

Higher Mycophenolic Acid (MPA) Trough Levels Result in Lower Day 100 Severe Acute Graft-Versus-Host Disease (aGVHD) without Increased Toxicity in Double-Unit Cord Blood Transplantation (CBT) Recipients

Higher Mycophenolic Acid (MPA) Trough Levels Result in Lower Day 100 Severe Acute Graft-Versus-Host Disease (aGVHD) without Increased Toxicity in Double-Unit Cord Blood Transplantation (CBT) Recipients

Safety and Efficacy of Once-Daily Administration of Mycophenolate Mofetil in Kidney Transplant Patients—A New Treatment Option for Non-Adherence

Non-adherence to immunosuppressive therapy is associated with reduced graft survival. Fifteen long-term follow up kidney transplant patients with stable post-transplant clinical courses were enrolled in the study. All patients were prescribed to tacrolimus prolonged release, mycophenolate mofetil (MMF) and corticosteroid at the time of enrolment. Twice-daily administration of MMF was then converted to a single daily dose. As a result, all immunosuppressive agents were administered simultaneously at one time in the morning. The daily total doses of the three immunosuppressants were identical during the study period. No acute rejection or adverse event was observed during the study period. Blood urea nitrogen and estimated glomerular filtration rate did not change significantly after conversion to once-daily administration. The blood tacrolimus trough level and the Mycophenolic acid (MPA) trough level also did not change significantly after conversion to once-daily administration. Interestingly, the meanmedian MPA trough level remained >3 μg/ml even after conversion to once-daily administration. A sufficient plasma MPA level was maintained after conversion to once-daily administration, and no acute rejection was observed during the study period. To our knowledge, this study is the first to report that the plasma MPA concentration can be maintained after once-daily administration of MMF in long-term kidney transplant patients. Once-daily administration of immunosuppressive agents may improve long-term graft survival because of better treatment adherence due to the reduced dosing frequency. The safety or efficacy of conversion to once-daily administration of MMF should be evaluated in a future randomized controlled large-scale clinical study.