Drug Monitoring Of Mycophenolic Acid Research Articles

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.

Higher Mycophenolic Acid (MPA) Trough Levels Result In Lower Day 100 Severe Acute GVHD Without Increased Toxicity In Double-Unit Cord Blood Transplantation (CBT) Recipients

BackgroundMycophenolate mofetil (MMF) is frequently combined with cyclosporine-A (CSA) as immunosuppression in unrelated donor CBT. Recent evidence suggests that therapeutic drug monitoring of mycophenolic acid (MPA), the active metabolite of MMF, is advisable based on intra- and inter-patient variability of MMF pharmacokinetics. Moreover, an increased incidence of acute graft-versus-host disease (aGVHD) has been associated with low unbound MPA AUCs in hematopoietic stem cell transplantation. This is highly relevant in cord blood transplantation (CBT) as aGVHD is a leading cause of transplant-related morbidity and mortality. However, as AUCs are cumbersome, a limited pharmacokinetic parameter such as MPA troughs would be ideal. Additionally, the toxicity associated with MPA trough levels is not established and is of concern in CBT especially due to the theoretical risk of myelosuppression from high MPA levels. MethodsWe evaluated the association between serial (weeks 1-6) total MPA serum trough levels and transplant outcomes in pediatric and adult recipients of double-unit CB grafts. Patients were transplanted between 8/2009 and 11/2012 for hematologic malignancies with 4-6/6 HLA-A,-B antigen, -DRB1 allele donor-recipient matched units and intravenous CSA/MMF was commenced on day -3. To evaluate the association between trough levels and outcomes, the trough levels were dichotomized into < 2 mcg/mL and ≥ 2 mcg/mL for toxicity (neutrophil and platelet engraftment, gastro-intestinal toxicity as measured by TPN duration, and CMV infection) at each time point. For the efficacy (aGVHD prevention) analysis, mean week 1 and 2 trough levels were split at < 0.5 versus ≥ 0.5 mcg/mL. ResultsEighty-three patients (median age 44 years, range 1-71) had MPA serum trough levels drawn weekly for the first 6 weeks after CBT. Sixty-nine (83%) received myeloablative (MA) conditioning and 45 (54%) were CMV seropositive. Diagnoses included acute leukemia (n = 51), myeloproliferative disorders/MDS (n = 7), or lymphoma (n = 25). Median trough levels by week were 0.9, 0.9, 0.6, 0.6, 0.9 and 1.3 mcg/mL. The increase in trough levels over time reached significance (p = 0.03). Recipients of MA conditioning had lower MPA troughs than those who received non-myeloablative conditioning (p = 0.02). Younger age (0-15 years old) was associated with lower trough levels (p = 0.002). By time dependent Cox regression analysis, there was no association between trough levels and toxicity as measured by speed and success of neutrophil engraftment, duration of TPN in myeloablative CBT recipients, or time to CMV viremia in seropositive patients. However, MA CBT recipients with a MPA trough ≥ 2 mcg/mL had enhanced platelet recovery (p = 0.005). In a competing risk 2-week landmark efficacy analysis, there were no differences in rates of grade II-IV aGVHD (61% vs 57%, p = 0.52) according to trough level. However, patients with a low MPA trough early post-CBT had nearly triple the incidence of severe (grade III-IV) aGVHD (27.8% vs 9.5%, p = 0.06, Figure 1). ConclusionsThis analysis suggests that higher total MPA serum trough levels are safe from the standpoint of toxicity and may protect against severe aGVHD. The beneficial effect on platelet engraftment was unexpected but may be explained by a lower incidence of severe aGVHD. Prospective investigation of the utility of MPA trough measurements, and ultimately intervention based on drug monitoring in a larger CBT series is warranted.▪ Disclosures:No relevant conflicts of interest to declare.

Mathematical Equations to Calculate True Mycophenolic Acid Concentration in Human Plasma by Using Two Immunoassays With Different Cross‐Reactivities With Acyl Glucuronide Metabolite: Comparison of Calculated Values With Values Obtained by Using an HPLC‐UV Method

Both immunoassays and chromatographic methods are available for therapeutic drug monitoring of mycophenolic acid (MPA). Although chromatographic methods are more precise, immunoassays are widely used in clinical laboratories due to ease of adopting such assays on automated analyzers. We studied the possibility of using mathematical equations to calculate true MPA concentration by accounting for acyl glucuronide cross-reactivities with immunoassays by using two immunoassays with widely different cross-reactivities with the metabolite. We determined MPA concentrations in 20 specimens obtained from transplant recipients using cloned enzyme donor immunoassay (CEDIA) assay and a new particle enhanced turbidimetric inhibition immunoassay (PETINIA) assay. Then we developed mathematical equations to calculate true MPA concentration using values obtained by both immunoassays and reported cross-reactivity of acyl glucuronide with respective immunoassays. Calculated concentrations were compared with values obtained by using a high-performance liquid chromatography combined with ultraviolet detection (HPLC-UV) method. We obtained good correlation between calculated MPA concentrations and corresponding MPA level obtained by using HPLC-UV method. Using x-axis as the MPA concentrations determined by the HPLC-UV method and y-axis as the calculated MPA level, we observed the following regression equation: y = 1.083x - 0.0995 (r = 0.99, n = 20). Mathematical equations can be used to calculate true MPA concentrations using two immunoassays with different cross-reactivities with acyl glucuronide metabolite.

Positive Bias in Mycophenolic Acid Concentrations Determined by the CEDIA Assay Compared to HPLC‐UV Method: Is CEDIA Assay Suitable for Therapeutic Drug Monitoring of Mycophenolic Acid?

Both immunoassays and chromatographic methods are available for therapeutic drug monitoring of mycophenolic acid (MPA), an immunosuppressant. We studied the suitability of cloned enzyme donor immunoassay (CEDIA) assay for routine monitoring of MPA by comparing values obtained by the CEDIA assay with corresponding values obtained by using a high-performance liquid chromatography combined with ultraviolet detection (HPLC-UV) method. We compared MPA concentrations obtained by a reference HPLC-UV method and CEDIA assay on Hitachi 917 analyzer (Roche Diagnostics, Indianapolis, IN) using 60 patient specimens (18 liver transplant recipient and 42 kidney transplant recipients). When MPA concentrations in all 60 transplant recipients obtained by the HPLC-UV (x-axis) method were compared with corresponding values obtained by the CEDIA method (y-axis), the following regression equation was obtained: y = 1.1558x + 0.2876 (r = 0.97). Interestingly, much lower bias was observed in 42 renal transplant recipients as revealed by the following regression equation; y = 1.1181x + 0.2745 (r = 0.98). However, more significant positive bias was observed in 18 liver transplant recipients as following regression equation as observed: y = 1.3337x + 0.1493 (r = 0.94). We conclude that MPA concentrations determined by the CEDIA assay showed significant positive bias compared to HPLC-UV method. Therefore, caution must be exercised in interpreting therapeutic drug monitoring result of MPA if CEDIA assay is used.

Comparison of mycophenolic acid concentrations determined by a new PETINIA assay on the Dimension EXL analyzer and a HPLC-UV method

ObjectiveMycophenolic acid requires routine therapeutic drug monitoring. We evaluated the suitability of a new PETINIA (particle enhanced turbidimetric inhibition immunoassay) assay on the Dimension EXL analyzer for monitoring of mycophenolic acid by comparing values obtained by this assay with a HPLC-UV method. Design and methodsMycophenolic acid concentrations determined in sera of 60 organ transplant recipients using high performance liquid chromatography combined with ultraviolet detection (HPLC-UV, reference method) and the new immunoassay on the Dimension RxL analyzer. ResultsThe within and between run precision of the new PETINIA assay was <10%. The assay was linear for a mycophenolic acid concentration up to 30μg/mL. When mycophenolic acid concentrations in 60 transplant recipients obtained by the HPLC-UV (x-axis) method were compared with corresponding values obtained by the PETINIA assay (y-axis), the following regression equation was obtained: y=1.1204 x+0.0881 (r=0.983, n=60). ConclusionsIf PETINIA assay is used for therapeutic drug monitoring of mycophenolic acid, caution must be exercised in interpreting serum mycophenolic acid level due to observed positive bias.

Therapeutic Drug Monitoring for Mycophenolic Acid Is Value for (Little) Money

Therapeutic Drug Monitoring for Mycophenolic Acid Is Value for (Little) Money

Monitoring of Mycophenolic Acid Predose Concentrations in the Maintenance Phase More Than One Year After Renal Transplantation

Routine therapeutic drug monitoring of mycophenolic acid (MPA) is generally performed using the area under the concentration-time curve from 0 to 12 hours (AUC0-12) with recommended values between 30 and 60 μg·h/mL. The aim of this study was to examine whether the monitoring of the MPA predose concentration (C0) in patients who are stable for >1 year after renal transplantation was practical and to determine factors that cause MPA C0 variability among patients. Eighty-six Japanese patients who had undergone renal transplantation and were taking tacrolimus and who had their MPA C0 analyzed >6 times by high-performance liquid chromatography for >1 year posttransplantation were enrolled. Recipients with MPA AUC0-12 levels<30 μg·h/mL on day 28 and 1 year after transplantation had an MPA C0 of <2.0 μg/mL, with a sensitivity of 90.9% and a specificity of 70.7%. There was no significant difference in the mean dose-adjusted MPA C0>1 year after transplantation between subjects with either the UGT (1A1, 1A9, and 2B7) or drug transporter (SLCO1B3, ABCC2, and ABCG2) genotypes. However, in a multiple regression analysis, the dose-adjusted mean MPA C0>1 year after transplantation was significantly associated with age (P=0.0035), creatinine clearance (P=0.0001), and the dose-adjusted MPA AUC0-12 at 1 year (P=0.0147). To keep the MPA AUC0-12>30 μg·h/mL, the plasma threshold for maintaining the MPA C0 with tacrolimus should be set >2.0 μg/mL as determined by high-performance liquid chromatography. For patients who are stable for >1 year after transplantation, continued monitoring of the MPA C0 using the same samples used to monitor the tacrolimus C0 and the additional assessment of the MPA AUC0-12 at the 1-year time point seem to be a viable option. If a change of the mycophenolate mofetil dose seems necessary based on the routine MPA C0 information, the determination of MPA AUC0-12 using a limited sampling strategy is recommended.

Pediatric aspects of therapeutic drug monitoring of mycophenolic acid in renal transplantation

Mycophenolate mofetil (MMF) is widely used for maintenance immunosuppressive therapy in pediatric renal and heart transplant recipients. Children undergo developmental changes (ontogeny) of drug disposition, which may affect drug metabolism of the active compound mycophenolic acid (MPA). Therefore, a detailed characterization of MPA pharmacokinetics and pharmacodynamics in this patient population is required. In general, the overall efficacy and tolerability of MMF in pediatric patients appear to be comparable with those in adults, except for a higher prevalence of gastrointestinal adverse effects in children younger than 6 years. The currently recommended dose in pediatric patients with concomitant cyclosporine is 1200 mg/m(2) per day in 2 divided doses; the recommended MMF dose with concomitant tacrolimus or without a concurrent calcineurin inhibitor is 900 mg/m(2) per day in 2 divided doses. Recent data suggest that fixed MMF dosing results in MPA underexposure (MPA-area under the concentration-time curve (AUC(0-12)), <30 mg × h/L) early posttransplant in approximately 60% of patients. To achieve adequate MPA exposure in most patients, an initial MMF dose of 1800 mg/m(2) per day with concomitant cyclosporine and 1200 mg/m(2) per day with concomitant tacrolimus for the first 2 to 4 weeks posttransplant has been suggested. As in adults, there is an approximately 10-fold variability in dose-normalized MPA-AUC(0-12) values between pediatric patients after renal transplantation, strengthening the argument for concentration-controlled dosing of the drug. Although the clinical utility of therapeutic drug monitoring of MPA for graft outcome and patient survival is still controversial, potential indications are the avoidance of underimmunosuppression, particularly in patients with high immunologic risk in the initial period posttransplant, in patients who are treated with protocols that explore the possibilities of calcineurin inhibitor minimization, withdrawal or even complete avoidance, and steroid withdrawal or avoidance regimens that might also benefit from intensified therapeutic drug monitoring of MPA. An additional indication especially in adolescent patients is the monitoring of drug adherence. Therapeutic drug monitoring of MPA in pediatric solid organ transplantation using limited sampling strategies is preferable over drug dosing based on trough level monitoring only. Several validated pediatric limited sampling strategies are available. Clearly, more research is required to determine whether pediatric patients will benefit from therapeutic drug monitoring of MPA for long-term maintenance immunosuppression with MMF.

Therapeutic Drug Monitoring of Mycophenolic Acid After Lung Transplantation—Is It Clinically Relevant?

Mycophenolate mofetil (MMF) is a purine synthesis antagonist frequently used after solid organ transplantation including lung transplantation (LTx) (1). MMF is an inactive prodrug that is converted to its active metabolite mycophenolic acid (MPA) by intestinal, liver, and plasma esterases (2). MMF is normally administered at a fixed dose, and the role of therapeutic drug monitoring (TDM) for MPA in solid organ transplantation remains controversial (3). The aim of this study was to evaluate the role of MPA-TDM in lung transplant recipients. A retrospective analysis in a single center was performed in outpatient stable lung transplant patients receiving triple calcineurin inhibitor (CNI)-based immunosuppression during routine follow-up visits from January 2007 to May 2009. Inclusion criteria for MPA-TDM were clinical suspicion of over- or underdosing or fluctuating drug levels of CNIs. To evaluate clinical outcome, events occurring within 6 months before and after TDM were compared. Blood samples were collected before (C0), and 30 and 120 min (C30 and C120) after the morning dose. A target range of 30 to 60 mg/hr L according to recommended values in renal transplant patients was used (4). Serum concentrations of MPA were measured using reserve-phase high performance liquid chromatography (5, 6). MPA exposure (area under the curve [AUC]) was estimated by 3-point equation according to validated algorithms using the MPA concentration data from predose and at 30- and 120-min levels (7, 8). One hundred twenty-six patients were included. Indications for inclusion centered on recurrent acute rejection episodes (6%) or infections (10%), unexplained leucopenia or anemia (36%), gastrointestinal complaints (12%), and fluctuating CNI (13%). Patient demographics and results are listed in Table 1.TABLE 1: Baseline characteristics of patientsFifty-three patients (42%) had a MPA-AUC outside of 30 to 60 mg/hr L: subtherapeutic AUCs were found in 27% and supratherapeutic AUCs in 15%. Patients taking tacrolimus (44.6 [interquartile range: 35.5–59.4] mg/hr L) demonstrated significantly higher MPA AUCs in comparison with those receiving cyclosporine (vs. 35.4 [26.6–45.8] mg/hr L, P=0.001). C0 levels moderately correlated with AUC (see Figure, Supplemental Digital Content 1,https://links.lww.com/TP/A347). C0 levels were more predictive for MPA AUC in long-term LTx. In the first 6 postoperative months, significantly lower MPA exposure was observed. No significant differences between abnormal MPA-AUCs and incidence of acute rejections, infections, gastrointestinal side effects, or anemia were observed. Leukocytes and hemoglobin increased significantly by median 1.8 Tsd/μL (47 vs. 6.5 Tsd/μL) and 0.1 g/dL (12.3 vs. 12.4 g/dL) 6 months after dose reduction (P=0.035 and P=0.012) in 21 patients. No significant relationships between subtherapeutic MPA AUC and incidence of rejection episodes, cytomegalovirus, respiratory viral, or bacterial infections during the preceding 6 months were observed. In patients with cystic fibrosis (CF), subtherapeutic MPA-AUCs occurred more frequently (38% vs. 24% in non-CF patients, respectively) despite receiving significantly higher doses (29.9 [21.2–39.6] mg/kg/day vs. 21.7 [15.5– 29.0] mg/kg/day, P=0.002). No significant decrease in MPA exposure in patients with proton pump inhibitor (PPI) comedication (40 [29–52] mg/hr L) was observed, when compared with those without PPIs (42 [29–60] mg/hr L). Our results of MMF pharmacokinetics in a large lung transplant population indicate that subtherapeutic MPA levels are frequent in CF patients and early after transplantation. The cause for observed lowered MPA AUCs in the early posttransplant period seems multifactorial. Low serum albumin or increased urea may result in increased plasma clearance along with malabsorption or gastroparesis may explain the pharmacokinetic variation (9). Analysis of genetic polymorphisms in enzymes may also account for supratherapeutic MPA levels. The pharmacokinetics of drugs are altered in CF patients, and the plasma concentrations of many drugs are found to be lower than in individuals without CF (10). Our results regarding drug deposition of MMF in recipients with CF are consistent with those reported by Gerbase et al. (11). The majority of studies in other forms of transplantation similarly demonstrated no significant relationship between clinical outcomes and TDM of MPA (12, 13). In general, MPA monitoring correlated poorly with clinical suspicion of abnormal MMF dosing in our study. Rupprecht et al. (14) have recently shown that concomitant treatment with the PPI pantoprazole significantly decreased MPA in healthy volunteers. In our analysis, there was no significant decrease in MPA exposure in patients with long-term PPI comedication. In conclusion, a substantial clinical benefit of MMF TDM needs to be established. We suggest MPA monitoring in LTx only when dose reduction does not ameliorate side effects. Prospective trials to assess the potential risk of long-term MPA overexposure in LTx are needed. Claudia de Wall Thomas Fuehner Patricia Wehmeier Tobias Welte Jens Gottlieb Department of Respiratory Medicine Medical School Hanover Hanover, Germany

Therapeutic drug monitoring of mycophenolic acid: a potential treatment for lupus nephritis

Mycophenolate mofetil, an immunosuppressant approved for the prevention of transplant rejection, has been used in patients with lupus nephritis. Lertdumrongluk et al. suggest that mycophenolic acid exposure may predict therapeutic responses in severe lupus nephritis, and their initial results confirm that hypothesis. However, it seems that enteric-coated mycophenolate sodium should not be administered to patients provided with therapeutic drug monitoring.

Pharmacokinetics of mycophenolic acid in severe lupus nephritis

Mycophenolic acid (MPA) is an effective treatment for active lupus nephritis despite its variable efficacy in different ethnic groups. Here we tested whether pharmacokinetic monitoring may help to optimize dosing of MPA in an Asian population. Patients with biopsy-proven class III or IV lupus nephritis (ISN/RPS category) were treated with mycophenolate mofetil or enteric-coated mycophenolate sodium. One month after initiating treatment we measured plasma MPA levels in eight samples taken over a 12-h period after drug administration. The mean area under the time-dependent curve for MPA of responding patients was significantly higher than those not responding. Successful treatment was seen in patients with areas >45 mg h/l. The dosage of the drug was not related to MPA pharmacokinetics. In the mycophenolate mofetil group, however, MPA-area under the curve was positively, and significantly, correlated with trough or 1 h after dose concentrations and associated with a therapeutic response. Thus, our study shows that MPA pharmacokinetics were positively correlated with therapeutic responses of mycophenolate, suggesting that controlling the concentrations may improve its therapeutic efficacy in lupus nephritis. As the absorption and pharmacokinetic peak of enteric-coated tablets is slower, it is important to take different formulations into account when determining optimal MPA concentrations.

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

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

Defining algorithms for efficient therapeutic drug monitoring of mycophenolic acid in heart transplant recipients

Defining algorithms for efficient therapeutic drug monitoring of mycophenolic acid in heart transplant recipients

Stability issues of mycophenolic acid in plasma: From patient to laboratory

Although mycophenolate is widely prescribed in India, therapeutic drug monitoring of mycophenolic acid is not performed in most centers. This could be due to many factors such as the large investment and expertise required for high performance liquid chromatography, or the high costs involved as specialized refrigeration is required when transporting patient specimens to the laboratories with the facility to analyze MPA. The Clinical Pharmacology unit of the Christian Medical College Hospital routinely monitors the area under the curve of MPA. In order to determine if this unit could act as a central laboratory for MPA monitoring, the stability of MPA in plasma under a series of storage and transport conditions was assessed. The procedures involved the analysis of plasma specimens from patients on mycophenolate mofetil and blank plasma spiked with MPA reference standard. A range of low and high concentrations were separately analyzed to confirm long term and short term stability. The measured concentrations of MPA showed no significant change over 5 months when stored at −20° or over five days under conditions encountered during transport.

Comparison of a new enzymatic assay with a high-performance liquid chromatography/ ultraviolet detection method for therapeutic drug monitoring of mycophenolic acid in adult liver transplant recipients

Mycophenolic acid (MPA) is used to prevent graft rejection. The methods used for determining the plasma MPA concentration in liver transplant recipients are the enzyme-multiplied immunoassay technique (EMIT), high-performance liquid chromatography with ultraviolet detection (HPLC-UV), and most recently mass spectrometry. EMIT has been reported to overestimate the MPA concentration by 30% to 35% in comparison with HPLC-UV. Recently, a new automated enzymatic assay based on inosine monophosphate dehydrogenase inhibition has been designed. The aim of the present investigation was to compare this technique with validated HPLC-UV in adult liver transplant recipients treated with tacrolimus or cyclosporine. One hundred seventy-six samples from 50 adult liver transplant recipients were analyzed with both techniques. Patients received mycophenolate mofetil (2 or 3 times daily) coadministered with cyclosporine microemulsion (n = 18) or tacrolimus (n = 32). Samples were drawn over an interdose interval during the early or late posttransplantation period. The Passing-Bablok regression and Bland-Altman plot were used to compare the 2 techniques. The Passing-Bablock regression, calculated from 166 samples, showed very good agreement between the enzymatic assay and the HPLC-UV method: enzymatic assay = 1.0204 (95% confidence interval, 0.9942, 1.0478) x HPLC-UV + 0.0201 (-0.0442, 0.0882). No significant bias was found between the techniques (Bland-Altman plot), and the median relative difference was 2.7% (95% confidence interval, -0.4, 6.6). In conclusion, the enzymatic assay showed an excellent correlation with HPLC-UV. Therefore, this method was proved valid and reliable for the monitoring of the plasma MPA concentration in adult liver transplant recipients treated with cyclosporine microemulsion or tacrolimus.

Therapeutic drug monitoring for mycophenolic acid in patients with autoimmune diseases

)hasbecomethemost frequently used immunosuppressive drug in kidneytransplant recipients [1]. Since its approval for the preven-tionofacuterejectionafterkidneytransplantationin1995intheUSAandin1996inEurope,theuseofazathioprinehasbeenrapidlydiminishing,givingwaytotheuseofMMF.Asecondformulationofmycophenolicacid(MPA),theactivemetaboliteofMMF,hasbecomeavailableasenteric-coatedmycophenolate sodium (EC-MPS, Myfortic

Association between mycophenolic acid 12-h trough levels and clinical endpoints in patients with autoimmune disease on mycophenolate mofetil

Triggered by heightened interest in mycophenolate mofetil (MMF) for the treatment of autoimmune diseases (AID) and encouraged by the results from a previous study, we hypothesized that therapeutic drug monitoring of mycophenolic acid (MPA) based on troughs may be useful for effective MMF dosing in patients with AID. A two-step approach was pursued. First, we confirmed in 38 AID patients (26 with antineutrophil cytoplasmic antibody-associated vasculitis; 12 with systemic lupus erythematosus) a significant correlation (r = 0.545, P < 0.001) between MPA C(12 h) and MPA exposure (AUC). Second, we performed an analysis of 294 MPA 12-h trough levels serially collected from 39 patients (same indications) receiving MMF for remission maintenance therapy to elucidate possible associations with disease activity and MMF toxicity. Higher MPA trough levels were associated with better protection from recurrence of active disease. While at levels <3 mg/L 29% of collected samples (43/147) were from patients with active disease, this was only the case in 2% of samples (3/147) with an MPA concentration of >or=3 mg/L. Remission persisted in all patients with MPA troughs >or=3.5 mg/L. Upon combined analysis of efficacy and safety data, most favourable results were obtained with MPA troughs between 3.5 and 4.5 mg/L. There was no discernable relationship between MMF dose and clinical endpoints. The target range proposed by this explorative study may serve as an initial guidance for MPA monitoring in the context of further prospective controlled trials in patients with AID.

Evaluation of MPA and MPAG Removal by Continuous Venovenous Hemodiafiltration and Continuous Venovenous Hemofiltration

The study assessed the removal of mycophenolic acid (MPA) and its major glucuronide metabolite (MPAG) during continuous venovenous hemofiltration (CVVHF) and continuous venovenous hemodiafiltration (CVVHDF) in 4 heart transplant recipients treated for at least 6 days with mycophenolate mofetil (MMF) in addition to cyclosporine and corticosteroids. The sieving coefficient ranged from 0.02 to 0.04 for MPA and from 0.15 to 0.33 for MPAG. The clearance of MPAG by CVVHDF or CVVHF ranged from 7.52 mL/min to 19.45 mL/min, and that of MPA was lower than 2.28 mL/min, with no significant difference between the two continuous replacement therapies. Whereas MPA percentage recovered by hour following CVVHDF or CVVHF was negligible, the percentage of MPAG represents up to 12.9% of the administered dose. A relevant decrease in the free fraction of MPA and MPAG was observed after continuous renal replacement therapy (CRRT). These preliminary results demonstrate that MPAG is able to permeate the filter. In light of the alteration in protein binding following CRRT and the competition between MPA and MPAG to albumin site, drug monitoring of MPA and MPAG in patients undergoing CVVHDF or CVVHF may be suggested. Moreover, monitoring of free MPA may be of interest for these patients.

Stability of mycophenolic acid and glucuronide metabolites in human plasma and the impact of deproteinization methodology

In recent years there is growing interest in therapeutic drug monitoring of mycophenolic acid (MPA) and its glucuronide metabolites MPAG and AcMPAG. Like other acyl glucuronide metabolites, AcMPAG has a limited stability, but this aspect has received little attention. Plasma sample deproteinization with perchloric acid 2 M (method A) was compared to metaphosphoric acid 15% (method B). Stability of MPA, MPAG and AcMPAG in acidified and non-acidified plasma stored at room temperature, 4 degrees C, -20 degrees C and -80 degrees C was assessed over short and long time intervals using HPLC-UV methodology. The area ratio of AcMPAG/IS on spiked plasma at pH 2.5 with method A was 63% of the respective ratio in water, in contrast to 102% with method B, suggesting partial deconjugation and/or incomplete release of AcMPAG from proteins with method A. At room temperature, AcMPAG concentrations in both whole blood and non-acidified plasma decreased significantly after 2-5 h. MPA, MPAG and AcMPAG concentrations remained stable in acidified plasma stored at -20 degrees C and -80 degrees C, but not longer than 5 months after collection. It is concluded that adequate sample collection, storage measures and deproteinization methods should be applied in order to avoid deconjugation and hence underestimation of MPA, MPAG and AcMPAG concentrations.