Mycophenolic Acid Trough Levels Research Articles

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.

Intensified Mycophenolate Mofetil (MMF) Dosing Every 8 Hours Is Safe From The Standpoint Of Engraftment and May Ameliorate Severe Acute Graft-Versus-Host Disease (GVHD) After Double-Unit Cord Blood Transplantation (CBT)

Background Acute graft-versus-host disease (aGVHD) is common after double-unit cord blood transplantation (CBT) with an incidence of grade II-IV aGVHD as high as 55% by day 180 in patients transplanted without ATG. aGVHD is associated with increased morbidity and transplant-related mortality (TRM). Mycophenolate mofetil (MMF) combined with a calcineurin-inhibitor is commonly used to prevent GVHD after CBT. However, unlike the 1 gram (gm) every 8 hours dosing that is now standard in adult donor allografts, MMF dosing in CBT has traditionally been every 12 hours. Our center has increased MMF dose from 1 gm every 12 (q12) to 1 gm every 8 (q8) hours in an effort to reduce severe aGVHD after double-unit CBT. However, the efficacy of this intervention is not established and a theoretical concern is that intensified MMF dosing could result in an increased risk of delayed engraftment or graft failure. Methods We evaluated 171 double-unit CBT recipients (median age 39 years, range 0.9-71) transplanted with either myeloablative (MA, n = 133) or non-myeloablative (NMA, n = 38) conditioning for high-risk hematologic malignancies between 10/2005 and 4/2013. CB units were 4-6/6 HLA-A, -B antigen, -DRB1 allele matched to the recipient (16 6/6, 171 5/6, 155 4/6). All patients received GVHD prophylaxis with intravenous calcineurin-inhibitor (predominantly CSA) and MMF from day -3 without ATG. Prior to 9/2009, 80 patients (47%) received MMF 1 gm IV q12 (and those &lt;12 years received 15 mg/kg/dose). From 9/2009, 91 patients (53%) received MMF at 1 gm IV q8 for patients both &gt;12 years and ≥50 kg (or 15 mg/kg/dose if &gt;12 years but &lt;50 kg, or 20 mg/kg/dose if &lt;12 years). The Gray's test compared the incidence of GVHD across the q12 and q8 dosing while the log-rank test was used to compare progression-free survival (PFS). Results Patient characteristics and infused viable CD34+ cell doses were similar in the q12 and q8 MMF groups. A comparison of transplant outcomes by MMF dosing is shown (Table). There were no differences in the time to neutrophil or platelet engraftment and the median time to count recovery was also similar. The incidences of grade II-IV aGVHD at day 100 were similar in the groups (46% vs 52%). However, there was a suggestion of decreased grade III-IV aGVHD at day 100 in the q8 MMF group (12%) versus the q12 group (21%), although this comparison did not reach significance. With a median follow-up of 41 months (range 3-94), the PFS in each dosing group was not significantly different. Conclusions We demonstrated that intensified q8 MMF dosing is safe from the standpoint of engraftment and toxicity. There was a suggestion of decreased severe grade III-IV aGVHD in recipients of 1 gm IV every 8 hours. While a larger analysis is needed to further investigate these findings, the results are encouraging. They suggest that, as with adult donor allografts, intensified q8 hour MMF dosing should be the dose investigated for the prevention of aGVHD in CBT recipients transplanted with CSA/ MMF prophylaxis without ATG. Finally, aGVHD prophylaxis could be further optimized in CSA/ MMF-based CBT by mycophenolic acid trough level drug monitoring, early post-transplant biomarker measurements such as ST2, and delayed taper post-transplant. Disclosures: No relevant conflicts of interest to declare.

Mycophenolate Mofetil versus Cyclosporin A in Children with Frequently Relapsing Nephrotic Syndrome

The severe side effects of long-term corticosteroid or cyclosporin A (CsA) therapy complicate the treatment of children with frequently relapsing steroid-sensitive nephrotic syndrome (FR-SSNS). We conducted a randomized, multicenter, open-label, crossover study comparing the efficacy and safety of a 1-year treatment with mycophenolate mofetil (MMF; target plasma mycophenolic acid trough level of 1.5-2.5 µg/ml) or CsA (target trough level of 80-100 ng/ml) in 60 pediatric patients with FR-SSNS. We assessed the frequency of relapse as the primary endpoint and evaluated pharmacokinetic profiles (area under the curve [AUC]) after 3 and 6 months of treatment. More relapses per patient per year occurred with MMF than with CsA during the first year (P=0.03), but not during the second year (P=0.14). No relapses occurred in 85% of patients during CsA therapy and in 64% of patients during MMF therapy (P=0.06). However, the time without relapse was significantly longer with CsA than with MMF during the first year (P<0.05), but not during the second year (P=0.36). In post hoc analysis, patients with low mycophenolic acid exposure (AUC <50 µg⋅h/ml) experienced 1.4 relapses per year compared with 0.27 relapses per year in those with high exposure (AUC>50 µg⋅h/ml; P<0.05). There were no significant differences between groups with respect to BP, growth, lipid levels, or adverse events. However, cystatin clearance, estimated GFR, and hemoglobin levels increased significantly with MMF compared with CsA. These results indicate that MMF is inferior to CsA in preventing relapses in pediatric patients with FR-SSNS, but may be a less nephrotoxic treatment option.

Therapeutic dose monitoring of mycophenolate mofetil in dermatologic diseases

Mycophenolate mofetil (MMF) is used for prevention of allograft rejection in transplantation medicine. In dermatology it is used as a corticosteroid-sparing agent. The pharmacokinetics of MMF are known to vary by individual. Therapeutic dose monitoring of mycophenolic acid (MPA), the active metabolite of MMF, is used as a guide in transplantation medicine, but limited data exist on the benefit of measuring MPA levels in the management of dermatologic disease. We sought to describe the use of MPA level monitoring in the management of dermatologic disease. We retrospectively searched for cases of patients who were treated with MMF for a dermatologic condition at our tertiary care center, and who had at least 1 trough level measurement of MPA from January 1, 2003, through November 30, 2009. Our search identified 24 patients treated with MMF for autoimmune bullous diseases, connective tissue diseases, erythema multiforme, atopic dermatitis, or pyoderma gangrenosum who had at least 1 MPA trough level measured. The range of MPA levels in patients who responded to therapy was 1.2 to 8 μg/mL at a dose range of 1 to 3.5 g/d of MMF. Four cases were analyzed in detail to highlight the use of therapeutic dose monitoring in the management of dermatologic disease. This was a retrospective study. We recommend monitoring MPA levels only in patients not responding to the standard 2-g/d dosage of MMF. MPA levels can help the dermatologist to increase the dose in patients who have poor absorption or to detect therapeutic noncompliance.

Pharmacokinetic monitoring of mycophenolic acid in heart transplant patients: Correlation the side-effects and rejections with pharmacokinetic parameters

Mycophenolate mofetil is a commonly used immunosuppressant in heart transplantation but pharmacokinetic monitoring is not routinely done. We performed a prospective pilot multi-center trial in de-novo heart transplant recipients to evaluate the pharmacokinetics (PK) of mycophenolic acid (MPA) at multiple time points in the first year following transplant.<br /> MPA trough and estimated area-under-the-curve (AUC) values were obtained at multiple visits from 21 enrolled patients. We attempted to correlate the side-effects and rejections with PK parameters.<br /> MPA AUC and trough levels increased modestly over 12 months with substantial inter and intra patient variability. Cardiac rejection was associated with low MPA AUC values with a threshold of <36.2 mg×h/L during the first two post-transplant weeks. A threshold of 2-weeks average MPA trough level of 1.43 mg/L provided a sensitivity 82% and a specificity of 60%.<br /> Adequate MPA levels are associated with decreased risk of allograft rejection. For patients with Cyclosporine co-immunosuppression, we propose an MPA trough of 1.4 mg/L and an MPA AUC of 36 mg × h/L as threshold values for dose adjustments. We recommend monitoring MPA levels at 1, 2 and 4 weeks, 6 months, 1 year and whenever an unexplained side-effect or allograft rejection occurs. Additional MPA AUC measurements are recommended when trough levels do not explain the clinical picture.<br />

Mycophenolic acid trough level monitoring: relevance in acute and chronic graft versus host disease and its relation with albumin

Mycophenolate mofetil (MMF) is used to treat acute and chronic graft versus host disease (GvHD). There is scant evidence in the literature about mycophenolic acid (MPA) trough level monitoring in GvHD. We therefore reviewed 32 patients treated with MMF for acute (n = 19) or chronic GvHD (n = 13). Twelve (63%) of 19 patients with acute GvHD and nine (69%) of 13 with chronic GvHD showed a good response. In all 21 patients who responded to MMF, their mean total MPA levels were therapeutic (1-3.5 mg/L), whereas five of 11 patients who did not respond had sub-therapeutic mean MPA levels (p = 0.002). Sixteen (66%) of 24 steroid refractory or dependent patients responded to MMF. Associations between the mean total MPA level for each patient and the corresponding mean serum albumin concentration showed therapeutic mean total MPA levels for all 23 patients with mean albumin ≥ 31 g/L but sub-therapeutic mean total MPA levels in five of nine patients with mean albumin <31 g/L (p = 0.0006). In conclusion, MMF is efficacious in steroid refractory and dependent acute or chronic GvHD with statistically significant correlation between therapeutic plasma total MPA trough levels and clinical response. Serum albumin levels should be taken into account when considering MMF dose adjustments.

A limited sampling strategy for estimation of the area under the curve (0 to 8 hours) of mycophenolic acid administered three times daily to liver transplant recipients

Objectives. Gastrointestinal side-effects caused by mycophenolic acid (MPA) are frequent in liver transplant recipients, and in these cases a switch from two to three daily doses is usually recommended. However, a limited sampling strategy for the estimation of MPA area under the curve from 0 to 8 hours (AUC(0–8h)) has not been made.Design and methods. In 22 liver transplant patients who were administered MPA three times daily, the trapezoidal extrapolated MPA AUC(0–8h) values using a sampling time from 0 to 2 hours were calculated.Results. A tentative therapeutic range for MPA AUC(0–8h) of about 20–40 μg.h/mL is proposed, and in the 13 patients with supratherapeutic values the total leukocyte blood count was significantly lower than in the 9 patients with AUC(0–8h) ≤ 40 μg.h/mL (P < 0.001). Significant negative correlations were found between the total leukocyte blood count and the MPA trough levels (r = −0.458; P < 0.05), AUC(0–8h) (r = −0.479; P < 0.05), and AUC(0–2h) (r = −0.437; P < 0.05). A significant correlation was found between the trapezoidal extrapolated AUC(0–8h) and trapezoidal AUC(0–2h) results (r = 0.850; P < 0.001).Conclusions. The trapezoidal extrapolated AUC(0–8h), and possibly trapezoidal AUC(0–2h), may be useful for routine therapeutic MPA monitoring in liver transplant recipients in which the dosing frequency is increased from twice to three times a day.

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.

Randomized crossover study to assess the inter‐ and intrasubject variability of morning mycophenolic acid concentrations from enteric‐coated mycophenolate sodium and mycophenolate mofetil in stable renal transplant recipients

The delayed release of mycophenolic acid (MPA) from enteric-coated mycophenolate sodium (EC-MPS, myfortic®) may have an impact on the variability of MPA trough (C0 h) levels. A randomized, two-period crossover study was performed in 24 maintenance renal transplants to evaluate the inter- and intrasubject variability of MPA predose levels from EC-MPS and mycophenolate mofetil (MMF, CellCept®), both in combination with cyclosporine. Patients received EC-MPS (720 mg b.i.d.) and MMF (1000 mg b.i.d.) for a period of 21 d each. MPA plasma levels were measured over the final seven consecutive days at -1, 0, 1, 2, and 3 h after the morning MPA dose. Intersubject coefficients of variation (%CV) for MPA troughs were 47.5% (95% CI, 34.1-80.3) and 54.4% (40.0-86.8) for EC-MPS and MMF, respectively; intrasubject %CVs were 62.7% (55.1-72.9) and 42.8% (37.9-49.2). High MPA C0 h levels>10 μg/mL were rarely observed with both EC-MPS (1.8%) and MMF (0.6%). Mean MPA area under the curve (AUC)0-3 h was comparable between treatments, while MPA C0 h was on average 46% higher with EC-MPS. In conclusion, predose MPA trough level monitoring appears of limited value during EC-MPS and MMF therapy given the large intrasubject variability in MPA C0 h levels with both treatments.

Authors' Reply to Maintenance Immunosuppressive Agents as Risk Factors for BK Virus Nephropathy

We appreciate the comments by Kuypers et al. regarding our study on the association of maintenance immunosuppressive agents and BK nephropathy (BKN) (1). We are in an agreement with the authors that mycophenolate mofetil (MMF) dose is not a reliable surrogate for drug exposure, and multiple factors, such as renal dysfunction, serum albumin level, and concomitant medications, could significantly affect the concentration of its metabolites (2–6). However, the clinical value of mycophenolic acid (MPA) therapeutic drug monitoring remains a controversial and supportive evidence regarding its added benefit is conflicting (7). Although, many retrospective studies found an association between the risk of acute rejection and total MPA area under the curve (AUC0–12 h) (7–9), the relationship between adverse effects of MMF, such as anemia, leukopenia, gastrointestinal symptoms, and infection, and the AUC0–12 h is less well established (7, 9, 10). Some studies have found better correlation between the incidence of infection or leucopenia with free rather than total MPA level (2–4). Others have suggested that adverse events are better predicted by MMF dose, rather than blood concentration (8, 11). We agree with the authors that the wide interindividual and intraindividual variability in MMF pharmacokinetics makes its dose a less than optimal indicator of its effect at the cellular level. For the same reason, a single MPA trough level suffers from similar shortcomings and is the reason that there is no consensus on its use for drug monitoring or its optimal target level. Therefore, acknowledging the pitfall of using the drug dose, we are not sure that MPA trough level is a better surrogate for drug exposure and effect. Moreover, the use of complete or abbreviated AUC for comparing the drug exposure between the cases and controls in this setting is not practically feasible, because a single testing after the diagnosis may not reflect the exposure over time, and retrospective AUC measurements at different time points would not be possible. To better study this matter, a prospective cohort study would be a much better design, but the relatively low incidence of the disease would require enrolment of a large cohort, which would make it an expensive study and impair its feasibility. Published guidelines advocate reduction in immunosuppression as the first step after a diagnosis of BKN (12). However, no specific approach has been established regarding whether calcineurin inhibitors (CNI) or antiproliferative agents should be reduced first. Clinical trials to validate different strategies are lacking and published reports on different immunosuppression reduction protocols contain mixed results (13). Therefore, the question on how to manage immunosuppressive agents in this patient population remains uncertain. In our study, we suggested reduction in tacrolimus level as the first step, while maintaining the MMF dose, based on our observation of a significant association between BKN and tacrolimus level (1). Even though, similar to other strategies, there is no clinical trial to support this recommendation, evidence continue to accumulate supporting the benefit of significant reduction in CNI. Recently, Egli et al. (14) explored BK virus-specific T-cell response as a marker of antiviral immune protection. The study found that BK virus-specific T-cell response in vitro inversely correlated with tacrolimus concentration, although there was no relationship with MMF concentration. This further supports the idea that reduction in CNI level would be a better first step for the management of BKN. The risk of rejection after reduction in immunosuppression remains a valid concern, as acute rejection rates as high as 75% have been reported after reduction in immunosuppression with various protocols (13). However, we believe that with our suggested strategy, this risk will not be higher than the traditional reduction in MPA and maintenance of CNI as the first step. In this setting, we agree that the therapeutic drug monitoring for MPA level might have a role in the prevention of acute rejection (7–9). In conclusion, we admit that well-designed clinical trials would be the best way of studying the role of differential reduction in immunosuppressive agents in patients with BKN and use of standard pharmacokinetic methods to examine the drug exposure provides more accurate data; however, in the absence of such studies, the use of observational clinical data such as ours and in vitro studies would provide a better rationale for a therapeutic approach than following practices that are not based on tangible evidence. Wana Manitpisitkul1 Abdolreza Haririan2 1Department of Pharmacy, University of Maryland Medical Center Baltimore, Maryland 2 Division of Nephrology University of Maryland Medical Center Baltimore, Maryland

Mycophenolic Acid Trough Level Measurements and Clinical Outcomes in Kidney Transplantation Recipients on a Fixed Dose (1.5 g/d) of Mycophenolate Mofetil in Korea

BackgroundMycophenolate mofetil (MMF) is routinely used at a fixed dose, but several factors interact to alter the blood level of mycophenolic acid (MPA), resulting in toxicity or treatment failure. MethodsFrom January 2007 to December 2008, 85 kidney transplantation patients were given a fixed dose of 1.5 g/d of MMF in 12-hour intervals. MPA trough levels were measured on postoperative 1 week, 1 month, 3 months, 6 months, and 12 months. ResultsMean age of patients was 41 years. Thirty five cases were deceased donor kidney transplantations and 50 were living donor kidney transplantations. Mean trough levels of MPA were 1.04 μg/mL, 1.09 μg/mL, 1.28 μg/mL, 1.83 μg/mL, and 1.69 μg/mL at postoperative 1 week, 1 month, 3 months, 6 months, and 12 months, respectively. Mean trough levels of the subgroup of patients taking cyclosporine were 0.82 μg/mL, 0.94 μg/mL, 1.01 μg/mL, 1.56 μg/mL, and 1.46 μg/mL (n = 36). Mean trough levels of the subgroup of patients taking tacrolimus were 1.19 μg/mL, 1.21 μg/mL, 1.56 μg/mL, 2.13 μg/mL, and 2.20 μg/mL (n = 49). At 12 months, 31% of all patients experienced one or more opportunistic infections. Eight patients (9.4%) had cytomegalovirus infections, 14 patients (16.5%) had polyomavirus infections, and four patients (4.7%) had parvovirus infections. Ten patients (11.8%) experienced biopsy-proven acute rejection during the follow-up period. ConclusionMean MPA trough levels of patients on 1.5 g/d of MMF reached 1.0 μg/mL within 1 week. Thirty one percent of patients experienced opportunistic infections, and 11.8% of patients had biopsy-proven acute rejections.

肝移植患者における血中ミコフェノール酸トラフ値測定の臨床意義に関する検討

Mycophenolate mofetil,an important immunosuppressant drug,is widely used for the prevention of rejection in organ transplants.Although there have been several studies on the effectiveness of therapeutic drug monitoring (TDM) for kidney and heart transplants,there have been few on TDM for MMF in liver transplants.In the present study,blood concentrations of mycophenolic acid (MPA),an active metabolite of MMF,were measured in 56 liver transplant patients treated with the drug at Kumamoto University Hospital since June,2004.Furthermore,a correlation between trough levels and the efficacy and/or adverse effects of MPA was investigated.MPA trough levels tended to be high in patients exhibiting clinical efficacy but intra- and inter-individual variations in trough levels appeared to be very large.The average MPA trough levels for each patient ranged from 0.2-5.8μg/mL.The coefficient of variation in trough levels among individuals was found to be 19-144%.We also investigated a relationship between cytomegalovirus (CMV) infection,a secondary adverse effect of MMF,and MPA trough levels.The anti-virus drug,ganciclovir (GCV) had been given to 19 patients but we found no significant relationship between trough levels and whether patients had been treated with this drug or not.As the present study did not properly clarify the clinical implications of MPA trough level measurements,detailed investigation of the pharmacokinetics of MMF/MPA in liver transplants and the determinants for intra-/inter-individual variations will be necessary.

Validation of Limited Sampling Strategy for Estimation of Mycophenolic Acid Exposure During the First Year After Heart Transplantation

Background Individualization of mycophenolate mofetil (MMF) dosing based on mycophenolic acid (MPA) therapeutic drug monitoring may minimize the risk of organ transplant rejection. The MPA area under the 12-hour concentration–time curve (MPA-AUC 0–12h) is a more powerful predictor of rejection than are MPA trough levels. Measurement of MPA-AUC 0–12h, however, is difficult and clinically impractical. The limited sampling strategy (LLS) has been proposed to overcome this problem. Objective To validate the predictive performance of MPA LSS algorithms previously published for heart transplant (HTx) recipients (initial group) when applied to a new independent group of 29 HTx recipients (validation group) during the first year after transplantation. Patients and Methods In a previous study, we established 2 algorithms using a LSS in HTx recipients: (1) 5.568 + 0.902 × C 1.25 + 2.022 × C 2 + 4.594 × C 6 and (2) 3.8 + 1.025 · C 1.25 + 1.819 × C 2 + 1.566 × C 4 + 3.479 × C 6. Agreement between abbreviated AUC and the full AUC 0–12h was tested using the Bland-Altman method. The validation group was used to test and assess bias and precision. Results The 2 LSS algorithms used predicted the corresponding MPA-AUC 0–12h with a mean bias of −4.85% and −3.6% and mean precision of 15.9% and 14%, respectively. Conclusions The MPA-AUC 0–12h obtained using the LSS may be useful to guide clinical management and dosing. This study prospectively validates 2 algorithms for calculation of MPA-AUC 0–12h using an LSS calculated in HTx recipients. Bias and precision values suggest that our algorithms could be used for MPA therapeutic drug monitoring predictions in HTx recipients who share the same characteristics.

Use of Mycophenolate Sodium in Stable Renal Transplant Recipients in Spain: Preliminary Results of the MIDATA Study

The use of mycophenolate mofetil (MMF) is limited by gastrointestinal adverse events (GI-AEs). Enteric-coated mycophenolate sodium (EC-MPS) was developed to avoid these effects. This multicenter prospective study sought to analyze the clinical benefit of EC-MPS among 726 stable renal transplant recipients in Spain. The data collection included: doses and trough levels of mycophenolic acid (MPA) and calcineurin inhibitors (CNI), renal function, routine biochemical parameters (3-6 months preconversion, baseline, and 1, 3, 6, and 12 months of EC-MPS initiation), as well as graft and patient survivals and adverse events. The main indication for EC-MPS introduction was GI-AEs associated with MMF (44.1%). Preliminary data showed that before introduction of EC-MPs there was a progressive deterioration of renal function, as demonstrated by a negative slope of the creatinine clearance (P < .005). However, after EC-MPS conversion, the slope became positive (P < .05), suggesting an improvement in renal function. Only in 4.8%, EC-MPS was stopped due to GI-AEs. There was an increase in MPA serum levels (P < .01) and a reduction in CNI doses. Interestingly, 80% of 85 patients without MMF treatment because of severe GI-AEs tolerated EC-MPS, including 43% who could be treated with adequate doses of EC-MPS (>or=720 mg/d). There was a significant improvement in GI-AEs after conversion from MMF to EC-MPS. The use of lower doses of CNI and the better tolerability of EC-MPS could be the underlying causes of improvement in renal function.

Graft Outcome and Mycophenolic Acid Trough Level Monitoring in Kidney Transplantation

Large inter- and intrapatient variabilities have been observed in the pharmacokinetics of mycophenolic acid (MPA). As a consequence, the efficacy and safety of mycophenolate mofetil (MMF) may be optimized with individualized doses based on therapeutic drug monitoring. In this retrospective study we analyzed; 7536 12-hour trough MPA samples obtained during the first year posttransplantation among 314 kidney recipients treated with tacrolimus, MMF, and corticosteroids. Despite taking similar MMF doses, patients with delayed graft function (DGF) showed lower 12-hour trough MPA levels than patients without DGF 1.4 +/- 0.1 vs 2.1 +/- 0.1 microg/mL; P = .001). There was a significant correlation between 12-hour trough MPA levels and creatinine clearance (r = .32; P < .001). Logistic regression analysis showed that creatinine clearance was a predictive factor of adequate 12-hour trough MPA levels (>1.6 microg/mL) at 7 days posttransplantation. Twelve-hour trough MPA levels at 7 days posttransplantation were lower among patients who developed an acute rejecton episode (1.5 +/- 0.1 vs 2.1 +/- 0.1 microg/mL; P < .001), whereas those with gastrointestinal side effects showed high levels (4.1 +/- 0.5 microg/mL). In patients with delayed or poor graft function, MMF doses greater than 2 g/d may be necessary to achieve adequate MPA levels. Therapeutic drug monitoring of MPA may be useful to prevent acute rejection episodes or toxicity.

Mycophenolate mofetil in patients with systemic lupus erythematosus: a prospective pharmacokinetic study

Few studies have assessed the pharmacokinetics of mycophenolic acid (MPA) in non-transplanted patients treated with mycophenolate mofetil (MMF), and little information is available concerning a concentration-effect relationship between the MPA area under the curve (AUC) and the immunological parameters in patients treated for systemic lupus erythematosus (SLE). We evaluated the variations in pharmacokinetics for MPA in patients with SLE and the relationship between MPA-AUC and markers of disease activity. MPA blood concentrations were measured through enzyme-multiplied immunotechnique (T(0), T(30'), T(1h), T(2h), T(3h) and T(4h)) to determine the MPA AUC(0-4h) in patients treated with MMF since at least 4 weeks for SLE. Clinical examination, biochemical analyses and immunological analyses were performed on the same day. The relationship between MPA exposure and disease activity markers was assessed. A total of 20 patients were included in the study. The diagnosis of SLE had been made 87 +/- 72 months before and patients had been treated with MMF for 31 +/- 30 months. Mean dose of MMF on the day of the study was 1600 +/- 447 mg/day. Mean MPA AUC(0-4h) was 28.4 +/- 13.6 mg h/L, mean dose-normalised AUC(0-4h) was 35.5 +/- 13.8 mg h/L and mean MPA C(0) was 3.1 +/- 2.2 mg/L. There was a high correlation between MPA AUC(0-4h) and MPA C(0), (r = 0.80; P < 0.001). AUC(0-4h) tended to be lower in patients who had low complement C3 concentration (<0.67 g/L) and low complement C4 concentration (<0.14 g/L). Moreover, there was a significant relationship between MPA trough levels and complement C4 concentrations (P = 0.043). We confirmed high inter-individual variability of MPA AUC in patients treated with MMF for SLE. This suggests that MPA exposure may be unpredictable with a fixed MMF dose. There was a concentration-effect relationship between MPA exposure (C(0)) and immunological disease activity parameters.

Role of mycophenolate mofetil in remission maintenance after a successful response to rituximab

Sirs, We read with great interest the article about the largest series on rituximab use in childhood nephrotic syndrome by Guigonis et al. [1], published in the August 2008 issue of Pediatric Nephrology. The authors reported a therapeutic benefit from rituximab use in 21 nephrotic patients whose condition was initially steroid-responsive but subsequently became steroid-dependent. In these patients, rituximab was administered while the disease was in remission, concomitantly with a steroid and/or calcineurin inhibitor. Eighteen of the 21 treated patients responded to rituximab. Three non-responders had an underlying diagnosis of focal segmental glomerulosclerosis (FSGS) and received rituximab during one of the relapses. To complement these observations in non-responders, we recently reported a successful response to rituximab in a 12-month-old child with primary nephrotic syndrome, which was initially steroid resistant, who had biopsy confirmed FSGS and was receiving no concomitant immunosuppressive medication [2]. Recently, Nakayama et al. also reported a similar benefit from rituximab use in two children with steroid-resistant nephrotic syndrome [3]. To expand on this subject, we report a benefit from mycophenolate mofetil (MMF) use in the maintenance of remission in the same patient after the initial successful response to rituximab. As in the observation by Guigonis et al., the condition of our patient relapsed at 6 months after the fourth rituximab dose, and the relapse coincided with the re-emergence of peripheral CD19 cells. A single rituximab administration, at a dose of 375 mg/m, again induced remission and suppressed the CD19 cells [1]. To prevent another relapse, we opted to use MMF at a dose of 900 mg/m per day in two divided doses [4], with a target mycophenolic acid trough level of 3–5 mg/l (actual levels 3.7±1.8 ng/ml, n=6). Use of MMF was prompted by a newly speculated role of B-cell immunity in the pathogenesis of nephrotic syndrome, based on the reported therapeutic response to rituximab [1]. Although through different mechanisms, as rituximab acts through CD20+ cells whereas MMF inhibits inosine monophosphate dehydroxygenase (IMPDH) in activated human T and B lymphocytes, B-cell inhibition is a common end-result with the two medications [5]. Three months after the last rituximab administration, peripheral CD19 cells again reemerged in our patient; however, this reappearance did not result in a clinical relapse. At his last clinic visit 9 months after the last rituximab dose, the patient’s serum albumin level was 41 g/l, his CD19 count was 14%, and there was not even microalbuminuria. To date, the remission has continued for 9 months, despite normal peripheral CD19 counts. A therapeutic benefit from MMF use was also suggested by the induction of remission in one of the three rituximab-nonresponders in the series by Guigonis et al. [1]. A potential role of MMF therapy in remission maintenance after a successful response to prior rituximab administration could be an interesting subject for future studies. Pediatr Nephrol (2009) 24:423–424 DOI 10.1007/s00467-008-1030-8

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.

Pharmacokinetics of enteric-coated mycophenolate sodium: comparative study in patients with autoimmune disease and renal allograft

Background: Recently, mycophenolic acid drugs have gained interest in the treatment of autoimmune diseases. However, only limited pharmacokinetic data are available on enteric-coated mycophenolate sodium in non-transplant indications. Objective: This study compared the pharmacokinetics of mycophenolic acid from enteric-coated mycophenolate sodium in patients with autoimmune disease and renal transplant recipients. Methods: Twelve autoimmune disease patients (mainly with antineutrophil cytoplasmic antibody-associated vasculitis) and 11 stable renal transplant patients, all of whom had been on enteric-coated mycophenolate sodium for ≥ 10 weeks, received an oral dose of enteric-coated mycophenolate sodium of 720 mg under fasting conditions. Blood samples for the determination of mycophenolic acid in the plasma were collected over 24 h. Results. Overall, no significant difference was found between both groups for their 0 – 12 h and 0 – 24 h areas under the concentration–time curve, Cmax, Tmax, C0 h, C12 h and C24 h, although the mean Cmax was numerically higher by 39% in the autoimmune disease patients (autoimmune disease 27.3 ± 17.4 mg/l and renal transplant 19.6 ± 15.7 mg/l). Patients on concomitant ciclosporin tended to have a lower mycophenolic acid exposure than patients on a non-ciclosporin regimen. The intersubject variabilities in the mycophenolic acid pharmacokinetics were high in both patient populations (around 40% for the area under the curve values). Both groups exhibited a weak and non-significant correlation between their mycophenolic acid trough (C12 h) levels and mycophenolic acid 0 – 12 h area under the curve (autoimmune disease r = 0.482 and renal transplant r = 0.138), whereas in the autoimmune disease group the mean C1.5 h and C2 h concentrations provided a satisfactory association with the 0 – 12 h area under the curve (for both r > 0.7 and p < 0.001). Conclusion: These data suggest that mycophenolic acid exposure (in terms of the area under the curve) from enteric-coated mycophenolate sodium is comparable in autoimmune disease and renal transplant patients. The mycophenolic acid trough levels did not reflect the systemic exposure to mycophenolic acid adequately; a limited sampling strategy for estimating mycophenolic acid exposure in autoimmune disease patients should include times around C1.5 h and/or C2 h reflecting Tmax if further studies confirm its usefulness.

Targeting mycophenolate mofetil for graft-versus-host disease prophylaxis after allogeneic blood stem cell transplantation

As low trough levels of mycophenolic acid (MPA) have been measured in recipients of allo-SCTs, we performed a pilot study targeting mycophenolate mofetil (MMF) doses according to the MPA area under the concentration (AUC) levels. Twenty-nine patients were transplanted from matched sibling (n=7) and unrelated donors (n=22). Tacrolimus was given orally from day -1 to achieve trough blood levels of 5-10 ng/ml. MMF was started on day 0 at 1500 mg intravenously b.i.d. AUC measurements of MPA by HPLC were scheduled on days 3, 7 and 11 after transplantation. The MMF dose was modified to achieve an MPA AUC of 35-60 microg/ml/h. With the respective adjustments 66 and 75% surpassed the lower AUC target on days 7 and 11, respectively. The cumulative incidence of grade III-IV acute GVHD was 28% (8/29). Eight out of 24 evaluable patients (33%) suffer from limited (n=3) or extensive (n=5) chronic GVHD. Overall, the results of this study suggest that targeting of MPA exposure is feasible early after transplantation. A simplified MMF targeting strategy based on MPA C(max) or C(2h) levels seems to be warranted in future trials involving more patients at later time points in the outpatient setting.