Drug Monitoring Of Mycophenolic Acid Research Articles

Liquid chromatography-tandem mass spectrometry method for mycophenolic acid and its glucuronide determination in saliva samples from children with nephrotic syndrome.

Saliva sampling is one of the methods of therapeutic drug monitoring for mycophenolic acid (MPA) and its metabolite, mycophenolic acid glucuronide (MPAG). The study describes the liquid chromatography tandem mass spectrometry (LC-MS/MS) method developed for saliva MPA and MPAG determination in children with nephrotic syndrome. The mobile phase consisted of methanol and water at gradient flow, both with 0.1% formic acid. Firstly, 100µL of saliva was evaporated at 45°C for 2h to dryness, secondly, it was reconstituted in the mobile phase, and finally 10µL was injected into the LC-MS/MS system. Saliva from ten children with nephrotic syndrome treated with mycophenolate mofetil was collected with Salivette®. For MPA and MPAG, within the 2-500ng/mL range, the method was selective, specific, accurate and precise within-run and between-run. No carry-over and matrix effects were observed. Stability tests showed that MPA and MPAG were stable in saliva samples if stored for 2h at room temperature, 18h at 4°C, and at least 5months at - 80°C as well as after three freeze-thaw cycles, in a dry extract for 16h at 4°C, and for 8h at 15°C in the autosampler. The analytes were not adsorbed onto Salivette® cotton swabs. For concentrations above 500ng/mL, the samples may be diluted twofold. In children, saliva MPA and MPAG were within the ranges of 4.6-531.8ng/mL and 10.7-183.7ng/mL, respectively. The evaluated LC-MS/MS method has met the validation requirements for saliva MPA and MPAG determination in children with nephrotic syndrome. Further studies are needed to explore plasma-saliva correlations and assess their potential contribution to MPA monitoring.

Therapeutic drug monitoring of mycophenolic acid and clinical outcomes of lupus nephritis: a systematic review and meta-analysis.

Mycophenolic acid (MPA) is a primary immunosuppressive agent used in the treatment of lupus nephritis (LN). While therapeutic drug monitoring (TDM) of MPA is well established in organ transplantation, its role in LN treatment remains uncertain. Our objective was to review and summarise current knowledge on TDM of MPA in the LN treatment. A systematic search was conducted in the online databases, specifically targeted patients diagnosed with LN receiving MPA treatment. The included studies had to report both MPA pharmacokinetic parameters and renal outcomes. A random-effects model meta-analysis was conducted to assess the relationship between clinical responses and MPA pharmacokinetics. A total of 1507 studies were initially screened, resulting in the inclusion of 16 studies for meta-analysis, encompassing 433 patients. The response group exhibited significantly higher MPA area under the concentration-time curve (AUC) compared with the non-response group (51.44±21.73 mg·h/L vs 30.30±16.24 mg·h/L). The weighted mean difference (WMD) of MPA-AUC between responders and non-responders was 16.83 mg·h/L (95% CI 10.59 to 23.06; p<0.001). Similarly, trough concentration (C0) of MPA showed a strong association with renal response, evidenced by C0 values of 2.50±1.73 mg/L in the response group vs 1.51±1.33 mg/L in the non-response group (WMD 1.37 mg/L; 95% CI 0.77 to 1.97; p<0.001). There was no significant relationship identified between MPA-AUC and adverse events. This meta-analysis emphasised the meaningful correlation between MPA AUC and C0 with renal response in LN treatment. Randomised controlled trials are necessary to validate this approach and determine its superiority over fixed dosing in the context of LN treatment.

Therapeutic drug monitoring of mycophenolic acid (MPA) using volumetric absorptive microsampling (VAMS) in pediatric renal transplant recipients: ultra-high-performance liquid chromatography-tandem mass spectrometry analytical method development, cross-validation, and clinical application

BackgroundMycophenolic acid (MPA) is widely used in posttransplant pharmacotherapy for pediatric patients after renal transplantation. Volumetric absorptive microsampling (VAMS) is a recent approach for sample collection, particularly during therapeutic drug monitoring (TDM). The recommended matrix for MPA determination is plasma (PL), and conversion between capillary-blood VAMS samples and PL concentrations is required for the appropriate interpretation of the results.MethodsThis study aimed to validate and develop a UHPLC-MS/MS method for MPA quantification in whole blood (WB), PL, and VAMS samples, with cross and clinical validation based on regression calculations. Methods were validated in the 0.10–15 µg/mL range for trough MPA concentration measurement according to the European Medicines Agency (EMA) guidelines. Fifty pediatric patients treated with MPA after renal transplantation were included in this study. PL and WB samples were obtained via venipuncture, whereas VAMS samples were collected after the fingerstick. The conversion from VAMSMPA to PLMPA concentration was performed using formulas based on hematocrit values and a regression model.ResultsLC–MS/MS methods were successfully developed and validated according to EMA guidelines. The cross-correlation between the methods was evaluated using Passing-Bablok regression, Bland–Altman bias plots, and predictive performance calculations. Clinical validation of the developed method was successfully performed, and the formula based on regression was successfully validated for VAMSMPA to PLMPA concentration and confirmed on an independent group of samples.ConclusionsThis study is the first development of a triple matrix-based LC–MS/MS method for MPA determination in the pediatric population after renal transplantation. For the first time, the developed methods were cross-validated with routinely used HPLC–DAD protocol.Graphical

Therapeutic Drug Monitoring of Mycophenolic Acid as a Precision Medicine Tool for Heart Transplant Patients: Results of an Observational Pharmacokinetic Pilot Study.

In the clinical practice management of heart transplant (HTx), the impact of calcineurin inhibitors co-administration on pharmacokinetics (PKs) of mycophenolic acid (MPA), mycophenolate mofetil (MMF) active drug, is not adequately considered. This retrospective study investigated full MPA-PK profiles by therapeutic drug monitoring (TDM) in 21 HTx recipients treated with MMF combined with cyclosporine (CsA) or tacrolimus (TAC) at a median time of 2.6 months post-transplant. The two treatment groups were compared. We described the main MPA-PK parameters in patients developing acute cellular rejection (ACR) and those who did not. Median dose-adjusted MPA-trough levels and MPA-AUC0–12h were higher in patients co-treated with TAC than with CsA (p = 0.0001 and p = 0.006, respectively). MPA-Cmax and Tmax were similar between the two groups, whereas the enterohepatic recirculation biomarker of MPA (MPA-AUC4–12h) was higher in the MMF and TAC group (p = 0.004). Consistently, MPA clearance was higher in the MMF and CsA group (p = 0.006). In total, 87.5% of ACR patients were treated with MMF and CsA, presenting a lower MPA-AUC0–12h (p = 0.02). This real-world study suggested the CsA interference on MPA-PK in HTx, evidencing the pivotal role of MPA TDM as a precision medicine tool in the early phase after HTx. A prospective study is mandatory to investigate this approach to HTx clinical outcomes.

Comparison of a Point-of-Care Testing with Enzyme-Multiplied Immunoassay Technique and Liquid Chromatography Combined With Tandem Mass Spectrometry Methods for Therapeutic Drug Monitoring of Mycophenolic Acid: A Preliminary Study.

For mycophenolic acid (MPA), therapeutic drug monitoring is an essential tool for dosage optimization in transplant recipients and autoimmune diseases. In China, a new commercial kit using an immunochromatographic assay (FICA) with a point-of-care testing system was approved for therapeutic drug monitoring of MPA. However, corroboration between FICA and clinically used assays remains unknown. The authors evaluated MPA concentrations in heart transplant recipients obtained by FICA, high-performance liquid chromatography combined with tandem mass spectrometry (LC-MS/MS), and enzyme-multiplied immunoassay technique (EMIT). Nine heart transplant recipients administered a single mycophenolate mofetil (MMF) dose, and 4 administered multiple MMF doses were enrolled. MPA samples were collected before administration, and after 0.5, 1, 1.5, 2, 4, 6, 8, 10, and 12 hours, and assessed by 2 immunoassays (EMIT and FICA) and LC-MS/MS. Consistency between methods was evaluated using Passing-Bablok regression and Bland-Altman analysis. For Passing-Bablok regression between FICA and LC-MS/MS, FICA = 0.784 LC-MS/MS + 0.360 (95% CI slope: 0.739 to 0.829, 95% CI intercept: 0.174-0.545). Regardless of a significant observed correlation coefficient (R2 = 0.9126), statistical analyses revealed a significant difference between FICA and the reference LC-MS/MS method. The mean absolute bias was 0.69 mcg/mL between FICA and LC-MS/MS. Bland-Altman plots showed a mean bias of -0.23 mcg/mL (±1.96 SD, -2.19 to 1.72 mcg/mL) and average relative bias of 14.73% (±1.96 SD, -67.91% to 97.37%) between FICA and LC-MS/MS. Unsatisfactory consistency was observed between EMIT and LC-MS/MS, and FICA and EMIT. Differences between pharmacokinetic parameters after a single or 7 days of MMF administration, by LC-MS/MS and FICA, were not statistically significant. The consistency of the new FICA using a point-of-care testing device with LC-MS/MS and EMIT was inadequate, and the accuracy of EMIT and LC-MS/MS was inappropriate. Clinicians should be informed when switching MPA detection methods to avoid misleading results.

Comparison between enzyme-multiplied immunoassay technique (EMIT) and high-performance liquid chromatography with ultraviolet detection (HPLC-UV) for the therapeutic drug monitoring of mycophenolic acid in Mexican pediatric patients with renal transplantation

Introduction. Mycophenolic acid (MPA) is an immunosuppressant; thus, monitoring of plasma levels is recommended. The most popular analytic methods used for the MPA quantification are the enzyme-multiplied immunoassay technique (EMIT) and the high-performance liquid chromatography with ultraviolet detection (HPLC-UV). The purpose of the present study was to compare both methods performances for the therapeutic drug monitoring of MPA in Mexican pediatric patients with renal transplantation. Material and Methods. A prospective cross‐sectional study was carried out, 25 patients with kidney transplantation were included. Mycophenolate mofetil was administered and blood samples were drawn at 0, 0.5, 1, 2, 3, 4, 6, 8, and 12 h after medication. Plasma samples were obtained and divided into two aliquots for further quantification by both methodologies. Each concentration determined by EMIT was compared with the corresponding quantification by HLPC-UV. Bias and precision were estimated as previously described by Sheiner and Beal. Results. EMIT overestimated MPA concentrations with a positive bias of 59.25% and a precision of 54.85%. AUC0-12, the recommended parameter for therapeutic drug monitoring of MPA, was significantly overestimated by EMIT in more than 50%. Discussion. Overestimation derives from metabolite cross-reactivity in EMIT, which does not occur with HPLC-UV. Hence, HPLC-UV appears to be a more suitable method for MPA therapeutic drug monitoring in Mexican pediatric patients with renal transplantation.

Mycophenolic Acid Exposure Prediction Using Machine Learning

Therapeutic drug monitoring of mycophenolic acid (MPA) based on area under the curve (AUC) is well-established and machine learning (ML) approaches could help to estimate AUC. The aim of this work is to estimate the AUC of MPA in organ transplant patients using extreme gradient boosting (Xgboost R package) ML models. A total of 12,877 MPA AUC from 0 to 12 hours (AUC0-12h ) requests from 6,884 patients sent to our Immunosuppressant Bayesian Dose Adjustment expert system (https://abis.chu-limoges.fr) for AUC estimation and dose recommendation based on MPA concentrations measured at least at three sampling times (~20minutes, 1 and 3hours after dosing) were used to develop two ML models based on two or three concentrations. Data were split into a training set (75%) and a test set (25%) and the Xgboost models in the training set with the lowest root mean squared error (RMSE) in a 10-fold cross-validation experiment were evaluated in the test set and in 4 independent full-pharmacokinetic (PK) datasets from renal or heart transplant recipients. ML models based on two or three concentrations, differences between these concentrations, relative deviations from theoretical times of sampling, presence of a delayed absorption peak, and five covariates (dose, type of transplantation, associated immunosuppressant, age, and time between transplantation and sampling) yielded accurate AUC estimation performances in the test datasets (relative bias<5% and relative RMSE<20%) and better performance than MAP Bayesian estimation in the four independent full-PK datasets. The Xgboost ML models described allow accurate estimation of MPA AUC0-12h and can be used for routine exposure estimation and dose adjustment and will soon be implemented in a dedicated web interface.

Plasma mycophenolic acid concentration and the clinical outcome after lung transplantation.

The therapeutic drug monitoring of mycophenolic acid (MPA) has been investigated for renal and heart transplantations; however, its usefulness in lung transplantation is unclear. The MPA area under the plasma concentration-time curve (AUC) was calculated in 59 adult lung transplant recipients. The MPA AUC0-12 s were compared among the three groups determined by the presence of adverse events (no events, infection, and chronic lung allograft dysfunction [CLAD]). Next, MPA AUC0-12 thresholds for the adverse events were identified by receiver operating characteristic analysis. Cumulative occurrence rate of the adverse events was compared between two groups (adequate and inadequate groups) according to the thresholds. The MPA AUC0-12 s in the no event, infection, and CLAD groups were 30.3±6.5, 36.8±10.7, and 20.6±9.6µg·h/mL, respectively (P=.0027), while the tacrolimus trough levels were similarly controlled in the groups. The thresholds of MPA AUC0-12 for the occurrence of infection and CLAD were 40.5 and 22.8µg·h/mL, respectively. The cumulative occurrence rate of adverse events of adequate group (15.3%) was significantly lower than that of inadequate group (56.0%) (P=.0050). The MPA AUC0-12 may affect the occurrence of adverse events in lung transplant recipients.

Drug monitoring for mycophenolic acid in graft-vs-host disease prophylaxis in cord blood transplantation.

We performed the retrospective analysis to clarify the significance of drug monitoring for mycophenolic acid (MPA), the active form of mycophenolate mofetil (MMF), in prophylaxis for graft-vs-host disease (GVHD) in cord blood transplantation. We retrospectively analysed the data of 46 patients who underwent first cord blood transplantation and received GVHD prophylaxis with tacrolimus plus MMF. MPA levels were measured on days 7 and 21, and 24-hour areas under the curve (AUC0-24 ) were estimated. The engraftment and 3-year overall survival rates of all patients were 94% and 78%, respectively. The cumulative incidence of sepsis before engraftment was higher in patients with AUC0-24 on day 7 of >60 μg h/mL than in other patients (33 vs 6%, P = .02). The cumulative incidence of grade II-IV acute GVHD was higher in patients with AUC0-24 on day 21 of ≤30 μg h/mL than in other patients (80 vs 50%, P = .04). The cumulative incidence of human herpesvirus 6 reactivation was higher in patients with AUC0-24 on day 21 of ≤48 μg h/mL (median) than in other patients (50 vs 19%, P = .03). Blood level of MPA was associated with risk of acute GVHD and infection. A prospective trial evaluating the benefit of personalized MMF dosing using MPA levels is needed.

Lack of concordance between EMIT assay and LC-MS/MS for Therapeutic Drug Monitoring of Mycophenolic Acid: Potential increased risk for graft rejection?

Therapeutic drug monitoring (TDM) of immunosuppressive drugs is crucial in organ-transplanted patients to prevent rejection or toxic effects due to inadequate dosage. Mycophenolic acid (MPA) is a commonly used immunosuppressant in this setting.Nowadays, MPA concentrations are monitored by Enzyme Multiplied Immunoassay Technology (EMIT), and Liquid Chromatography (LC)-based techniques, particularly coupled to Tandem Mass Spectrometry (LC–MS/MS).This study evaluates the concordance between TDM results for MPA obtained through CE-IVD EMIT and LC–MS/MS assays in plasma samples. LC–MS/MS quantification was based on a commercial kit and the analytical performance in terms of accuracy was tested through external proficiency tests and inter-laboratory comparison with a home-made HPLC-UV method.Both these evaluations confirmed the reliability of the LC–MS/MS method (1.6 % and 9.0 % of bias, respectively). Conversely, the comparison between EMIT and LC–MS/MS showed overestimation by EMIT of 33.5 %. This bias resulted concentration-dependent, ranging from 46.4 % in the concentration range of 1–2 mg/L, to 21.4 % over 4 mg/L. Considering the theoretical clinical impact of this overestimation, a fraction comprised between 12.4 % and 31.4 % of samples which resulted over three different minimum effective concentration values by EMIT (no indication for dose adjustment) had discordant indications by LC–MS/MS (dose adjustment needed). Concluding, this study highlights a clinically relevant systematic overestimation of MPA concentration by EMIT, supporting the switch to LC–MS/MS techniques for TDM purpose. However, further prospective studies are needed in order to evaluate the clinical impact of switching the TDM activity from EMIT to LC–MS/MS in a larger cohort in a long period.

Limited sampling strategy to predict mycophenolic acid area under the curve in pediatric patients with nephrotic syndrome: a retrospective cohort study

PurposeLimited sampling strategy (LSS) is a precise and relatively convenient therapeutic drug monitoring method. We evaluated LSSs for mycophenolic acid (MPA) in children with nephrotic syndrome treated with mycophenolic mofetil (MMF) and validated the LSSs using two different approaches.MethodsWe measured MPA plasma concentrations in 31 children using HPLC-UV method and received 37 MPA pharmacokinetic profiles (0–12 h). For six children, MPA profiles were estimated twice after two MMF doses. LSSs were developed using multilinear regression with STATISTICA and R software and validated using validation group and bootstrap method, respectively.ResultsThe best three time point equations included C1, C3, C6 (good guess 83%, bias − 2.78%; 95% confidence interval (CI) − 9.85–0.46); C1, C2, C6 (good guess 72%, bias 0.72%; 95% CI − 5.33–7.69); and C1, C2, C4 (good guess 72%, bias 2.05%; 95% CI − 4.92–13.01) for STATISTICA software. For R software, the best equations consisted of C1, C3, C6 (good guess 92%, bias − 2.69%; 95% CI − 27.18–33.75); C0, C1, C3 (good guess 84%, bias − 2.11%; 95% CI − 24.19–22.29); and C0, C1, C2 (good guess 84%, bias − 0.48%; 95% CI − 30.77–54.07). During validation, better results were obtained for R evaluations, i.e., bootstrap method.ConclusionsThe most useful equations included C0, C1, C3 and C0, C1, C2 time points; however, the most precise included C1, C3, C6 time points because of MPA enterohepatic recirculation. Better results were obtained for bootstrap validation due to greater number of patients. Validated LSS should be used only in the population for which it was developed. As there is growing evidence that underexposure of MPA is associated with insufficient treatment response, we recommend the introduction of therapeutic drug monitoring for MPA in children with nephrotic syndrome.

Mycophenolic Acid Pharmacokinetics and Relapse in Children with Steroid-Dependent Idiopathic Nephrotic Syndrome.

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. 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. 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; P=0.01). 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.

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.

Therapeutic drug monitoring of enteric-coated mycophenolate sodium by limited sampling strategies is associated with a high rate of failure.

BackgroundTherapeutic drug monitoring of mycophenolic acid (MPA) is usually performed with a limited sampling strategy (LSS), which relies on a limited number of blood samples and subsequent extrapolation of the global exposure to MPA. LSS is usually performed successfully with mycophenolate mofetil (MMF), but data on enteric-coated mycophenolate sodium (EC-MPS) are scarce. Here, we evaluated the feasibility of 6-h LSS therapeutic drug monitoring with EC-MPS compared with MMF monitoring among kidney transplant recipients.MethodsSixty-two patients who received EC-MPS during the first 6 months of transplantation were compared with a matched group of 64 MMF-treated kidney transplant recipients. The area under the curve (AUC) was computed by LSS using multiple concentration time points (0, 1, 2, 3 and 6 h post-dose) and a trapezoidal rule. Patients had MPA therapeutic drug monitoring performed on two occasions, one within 2 weeks and the second after 3–4 months of transplantation.ResultsEC-MPS monitoring and MMF therapeutic drug monitoring were not interpretable in 34.5% (n = 40/116) and 1.8% (n = 2/112) of patients, respectively {relative risk [RR] 19.3 [95% confidence interval (CI) 4.8–78.0]; P < 0.0001}. The main cause of abnormal EC-MPS therapeutic drug monitoring was delayed absorption of both the previous evening and the morning dose, resulting in MPA plasma levels before the next morning dose being higher than MPA plasma levels measured at 1, 2 and 3 h after taking EC-MPS. Cyclosporin in association with MMF significantly increased the risk of low AUC values (<30 mg h/L) in comparison with tacrolimus [55% (n = 11/20) and 10% (n = 9/88), respectively; RR 5.4 (95% CI 2.6–11.2); P < 0.0001].ConclusionsThe risk of therapeutic drug monitoring failure with EC-MPS is >30% during the first 6 months of renal transplantation. Delayed pharmacokinetics was the main reason. In contrast, the risk of therapeutic drug monitoring failure was substantially lower with MMF.

Therapeutic Drug Monitoring of Mycophenolic Acid.

Mycophenolic acid (MPA) is an immunosuppressant requiring therapeutic drug monitoring. Although immunoassays are commercially available, there is significant positive bias using this approach when compared to high-performance liquid chromatography or LC combined with mass spectrometry (LC/MS) or tandem mass spectrometry (LC/MS/MS). Positive bias is due to variable cross-reactivity of MPA acyl glucuronide with antibodies traditionally used in immunoassay formats. As can be expected, the magnitude of bias varies considerably. MPA strongly binds albumin and, as a result, disproportionate increases in free MPA occur in patients with uremia, hypoalbuminemia, and hepatic dysfunction. As such, monitoring free MPA poses additional challenges. Because MPA inhibits inosine monophosphate dehydrogenase, monitoring this enzyme may provide an alternative approach.

Development and validation of limited sampling strategy equation for mycophenolate mofetil in children with systemic lupus erythematosus.

The aim of this study was to establish a limited sample strategy (LSS) to predict the mycophenolic acid (MPA) area under the curve (AUC)(0-12) in children with systemic lupus erythematosus (SLE). Three months after initiation of mycophenolate mofetil (MMF) 26 children with SLE presented for therapeutic drug monitoring of MPA. On the day of the test, 10 specimens were collected, analyzed, and MPA AUC(0-12) was calculated. Using step-wise regression analysis, LSS equations were developed. Using bootstrap validation, the predictive performance was calculated. The measured mean (standard deviation) for the trough concentration and AUC(0-12) were 2.55 (1.57) μg/ml and 62.6 (21.67) mg.h/L, respectively. The range of trough concentrations and AUC(0-12) were 0.7–5.54 μg/ml and 22.1–104.8 mg.h/L, respectively. The interindividual variability (%CV) for dose normalized AUC(0-12) and dose normalized Ctrough was 46.5% and 61.1%, respectively. The correlation between the concentrations at the different time points and MPA AUC(0-12) ranged from 0.05 (1.5 h) to 0.56 (4 h). Two LSS equations that included 4 or 5 time points up to 3 h were developed and validated. The 4 point LSS had a correlation (R2) of 0.88 and the 5 point LSS an R2 of 0.87. With respect to the 4 point and 5 point MPA LSS AUC(0-12), the bias was 1.92% and 1.96%, respectively, and the imprecision was 11.24% and 11.28%, respectively. A 4 point LSS which concludes within 3 h after the administration of the MMF dose was developed and validated, to determine the MPA AUC(0-12) in children with SLE.

Therapeutic Drug Monitoring of Mycophenolic Acid in Lupus Nephritis: A Review of Current Literature.

In recent years, mycophenolate mofetil (MMF)-based immunosuppressive regimen was recommended in induction and in maintenance therapy in lupus nephritis (LN), one of the most severe and common manifestations of systemic lupus erythematosus. However, no recommendations were made so far regarding monitoring of mycophenolic acid (MPA) plasma concentrations. Therapeutic drug monitoring (TDM) constitutes a practical tool to ensure optimal posology. In renal transplantation, it was proved that acute allograft rejection incidences decreased when the recommended MPA target exposure has been maintained (30-60 mg·h·L). The results obtained in the field of transplant medicine indicate the potential benefit of carrying out TDM in LN. To date, the correlation of MPA exposure and clinical outcomes in the population of LN patients was the objective of just a few studies. The aim of this review was therefore to present TDM studies in LN patients on MMF therapy and to compare their results. Based on the conclusions drawn from TDM studies in LN, it can be suggested that the area under the concentration-time curve threshold values of 30-45 mg·h·L can potentially be associated with favorable treatment outcome. Moreover, the majority of the analyzed studies indicate relatively good correlation between trough concentration and the area under the concentration-time curve in patients treated with MMF that constitutes an important implication for TDM approach in routine setting. The threshold of 3 mg/L can potentially be recommended as a target trough value.

Short-term therapeutic drug monitoring of mycophenolic acid reduces infection: a prospective, single-center cohort study in Chinese living-related kidney transplantation.

The role of therapeutic drug monitoring (TDM) of mycophenolic acid (MPA) in kidney transplant recipients (KTRs) is not clear. We performed a prospective cohort study to evaluate the efficiency of MPA TDM in the Chinese population. A total of 183 living-related KTRs were studied; 101 KTRs received controlled-dose mycophenolate mofetil (MMF) (the CD group), and 82 patients received fixed-dose MMF (the FD group). MPA exposure was measured at days 3, 7, 14, and 30 in the CD group, and at day 30 in the FD group. The primary endpoint was treatment failure (a composite of acute rejection, graft loss, death, or MMF discontinuation) at 12 months post transplantation. In the CD group, with a starting MMF dose of 2 g/day, approximately 35% of patients had high MPA levels, which were >60 mg × h/L, and mean MPA levels were 59.17 mg × h/L and 61.38 mg × h/L for the CD and FD groups, respectively (P = 0.588). After adjusting MMF dose, MPA exposures in the CD group at day 30 were lower than those in the FD group at day 30 (54.06 vs. 61.38, P = 0.004). At month 12, the CD group had fewer infections (16.8% vs. 31.7%, P = 0.018) with no difference in treatment failure, acute rejection, diarrhea, or anemia. KTRs can benefit from short-term TDM of MPA in reducing infection, without increasing acute rejection.

The Optimal MMF Dose in Tacrolimus Treated Patients

To the Editor: We appreciate the opportunity to respond to the Letter to the Editor of Knotek et al (1Knotek M Galešić Ljubanović D Mihovilović K Maksimović B Tacrolimus or mycophenolate in kidney transplantation—Less, or more?.Am J Transplant. 2014; 14: 1220Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar). In their letter they propose a novel immunosuppressive strategy, aimed at treating de novo kidney transplant recipients with (very) low-dose tacrolimus and a higher mycophenolate mofetil (MMF) dose. The hypothesis of their prospective study is that reduced exposure to tacrolimus will result in an improved histology in 1-year protocol biopsies (less interstitial fibrosis and tubular atrophy), while the higher MMF dose (3 g daily) compensates for the lower tacrolimus exposure and will maintain efficacy. We feel that the observations in our analysis of three large, randomized-controlled trials (2Bouamar R Shuker N Hesselink DA et al.Tacrolimus predose concentrations do not predict the risk of acute rejection after renal transplantation: A pooled analysis from three randomized-controlled clinical trials.Am J Transplant. 2013; 13: 1253-1261Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar) suggest that the currently targeted tacrolimus predose concentrations may be too high and that a further reduction of the target levels is possible without compromising efficacy. We agree that optimizing MMF exposure is likely to further improve the outcome. What the optimal MMF dose would be has been a matter of debate for some time. In the registration trials, MMF doses of 2 or 3 g per day were compared with placebo or azathioprine treatment. Patients in these studies were on full-dose cyclosporine (CsA) treatment. It may well be that in a setting of low-dose tacrolimus treatment (say target predose concentrations in the range of 3 ng/mL) higher MMF doses would offer a benefit. It is known that in tacrolimus-treated patients an MMF dose of 2 g/day will result in mycophenolic acid (MPA) exposure below the target in 25% of patients in the first month after transplantation (and in CsA co-treated patients this occurs in no less than 50%). Temporary intensified dosing has been suggested to avoid reduced MPA exposure in the early posttransplant phase (3Gourishankar S Houde I Keown PA et al.The CLEAR study: A 5-day, 3-g loading dose of mycophenolate mofetil versus standard 2-g dosing in renal transplantation.Clin J Am Soc Nephrol. 2010; 5: 1282-1289Crossref PubMed Scopus (48) Google Scholar). Knotek et al (1Knotek M Galešić Ljubanović D Mihovilović K Maksimović B Tacrolimus or mycophenolate in kidney transplantation—Less, or more?.Am J Transplant. 2014; 14: 1220Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar) propose a 3 g MMF dose in the first week, and in half of the patients this dose is maintained thereafter. Whether or not a prolonged duration of higher MMF dosing would offer a benefit when very low tacrolimus concentrations are targeted remains to be seen. One could expect more MMF-related toxicity in a substantial proportion of patients, as observed in an older MMF dose finding study in tacrolimus-treated patients (4Squifflet JP Bäckman L Claesson K et al.Dose optimization of mycophenolate mofetil when administered with a low dose of tacrolimus in cadaveric renal transplant recipients.Transplantation. 2001; 72: 63-69Crossref PubMed Scopus (122) Google Scholar). Therapeutic drug monitoring for MPA may identify patients with over-exposure, and in such patients, dose reductions may improve tolerability to the proposed regimen (5van Gelder T Therapeutic drug monitoring for mycophenolic acid is value for (little) money.Clin Pharmacol Ther. 2011; 90: 203-204Crossref PubMed Scopus (15) Google Scholar). The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. Dr. Hesselink has received lecture fees from Astellas Pharma. Dr. van Gelder has received lecture fees from Astellas Pharma, and Roche. Dr. Bernasconi has received consulting fees from F. Hoffmann-La Roche Ltd, Basel, Switzerland. All other authors have no conflicts to declare.

Clinical mycophenolic acid monitoring in liver transplant recipients.

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.