Search

Mycophenolate mofetil (MMF) or enteric coated mycophenolate sodium (EC-MPS) and steroids are used for induction and maintenance therapy in severe lupus nephritis (LN). Blood concentrations of mycophenolic acid (MPA), the active metabolite of these drugs varies among LN patients. The objective of this study was to examine whether concentration controlled (CC) dosing (via therapeutic drug monitoring) of EC-MPS result in a higher proportion of participants achieving target exposure of MPA compared to fixed dosing (FD). An additional aim of the study was to evaluate the influence of CC dosing on clinical outcomes. Nineteen participants were randomly assigned either to FD or CC group. All the participants were eligible to have free and total measurements of MPA over a period of 8-12 hours on three different occasions. Area under the concentration-time curve between 0 and 12 hours (AUC0-12) was calculated using non-compartmental method. Dose of EC-MPS was titrated according to AUC0-12 in the CC group. Thirty-two AUC0-12 measurements were obtained from 9 FD and 9 CC participants. Large interpatient variability was observed in both groups but was more pronounced in FD group. There were no significant differences between FD and CC participants in any pharmacokinetic parameters across the study visits except for total C0 (FD 2.0 ± 0.3 mg/L vs. CC 1.1 ± 0.3; p = 0.01) and dose-normalised C0 (FD 2.9 ± 0.2 mg/L/g vs. CC 2.1 ± 0.7 mg/L/g; p = 0.04) at the second visit and total AUC0-12 (FD 66.6 ± 6.0 mg[BULLET OPERATOR]h/L vs. CC 35.2 ± 11.4 mg[BULLET OPERATOR]h/L; p = 0.03) at the third visit. At the first study visit, 33.3% of the FD and 11.1% of the CC participants achieved the target AUC (p = 0.58). From the second visit, none of the FD participants, compared to all the CC participants, achieved target AUC0-12 (p = 0.01). More CC participants achieved remission compared to FD participants (absolute difference of -22.2, 95% confidence interval -0.19-0.55; p = 0.62). The mean free MPA AUC0-12 was significantly lower in those who had complete remission. CC participants reached target AUC0-12 quicker. Larger studies are required to test clinical efficacy.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

The aim of this study was to characterize the pharmacokinetics of mycophenolic acid (MPA) and MPA glucuronide (MPAG) in Chinese renal transplant patients taking enteric-coated mycophenolate sodium (EC-MPS). Limited sampling strategies (LSSs) were developed to estimate the area under the concentration curve from 0 to 12 hours (AUC0-12h) of total and free MPA. Another objective was to investigate the correlation between high-performance liquid chromatography (HPLC) and enzyme-multiplied immunoassay technology (EMIT) for total MPA determination.Serial blood samples were collected over 12 hours from 15 patients who were administered multiple doses of EC-MPS. LSS was developed by multiple stepwise regression analysis. Measurement by HPLC and EMIT was compared using Passing-Bablok regression and Bland-Altman analysis.Normalized to 720 mg twice daily, the AUC0-12h of total MPA and MPAG was 43.0 ± 17.4 and 653 ± 329 mg·h/L, respectively, whereas the free MPA AUC0-12h was 1.368 ± 0.988 mg·h/L. The free fraction of MPA was 3.01% ± 3.15%. The combination of C2h-C4h-C6h and C2h-C4h-C6h-C8h was found to be superior to estimate total and free MPA simultaneously. The EMIT showed an acceptable correlation with HPLC, with an AUC0-12h overestimation of 11.32% ± 15.77%.The pharmacokinetic profile of total and free MPA and its main metabolite MPAG was examined in Chinese adult renal transplant patients receiving EC-MPS. The use of LSS to estimate individual free and total MPA exposure could be useful in optimizing patient care.

BACKGROUND Enteric-coated mycophenolate sodium is frequently used in renal transplantation. The pharmacokinetic profile of mycophenolic acid (MPA) shows a broad range of time-to-maximum concentration (Tmax) that limits the use of a single MPA concentration to calculate the area under the time-concentration curve (AUC). For both research and clinical MPA monitoring, measuring a complete AUC is troublesome to the center and patients. METHODS We obtained 171 complete MPA-AUC12h (0, 20, 40, 60, 90, 120, 180, 240, 360, 480, 600, and 720 minutes) from 59 adult (54 ± 16 years) patients (29 men and 43 whites) who have been receiving stable doses of tacrolimus/enteric-coated mycophenolate sodium and steroids. We used the 59 curves drawn at 31 ± 4 days after transplantation to develop the abbreviated equations, and the remaining 112 curves drawn at 109 ± 59 days were used to validate them. We used 5 other proposed equations to estimate MPA-AUC (eAUC) (4 with enzyme-multiplied immunoassay technique assay and one with high-performance liquid chromatography [HPLC]) and then used these results to compare with our measured AUC, the bias, and the 10% and 30% accuracy. MPA was measured by ultraperformance liquid chromatography coupled to a tandem mass spectrometry, and AUC was calculated by the trapezoidal rule. RESULTS For both MPA-measuring methods, enzyme-multiplied immunoassay technique and ultraperformance liquid chromatography coupled to a tandem mass spectrometry, the Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (HCFMUSP) equations, and others that measure MPA up to 6 hours after the dose had an acceptable low bias with more results in the 10%-30% range than those using data collected until 4 hours. A highly adequate eAUC is obtained using blood collected at 8 hours. CONCLUSIONS This analysis offers blood-sampling alternatives for MPA monitoring depending on the precision needed.

Background Mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (MPS) is now commonly used in pediatric intestinal transplantation (Tx), but to date, no clear recommendations regarding the dosing regimen have been made in this population. The aim of this study was to determine the MMF/MPS dosage required to achieve an area under the plasma concentration-time curve from 0 to 12 hours (AUC0-12) for mycophenolic acid (MPA) greater than 30 mg·h·L in children after intestinal transplantation. Methods A pharmacokinetic study was conducted in 8 children (median, 9.4 years; range, 0.75-15.8 years) at a median time of 113 months (range, 1.5-160 months) after intestinal transplantation. Results MMF was initially introduced at a low median starting dose of 687 mg·m·d (range, 310-1414 mg·m·d). One of the 3 patients who received MPS and 2 of the 6 patients who received MMF had an MPA AUC0-12 value below 30 mg.h.L. The median MMF dosage had to be increased by 91% (1319 mg·m·d versus 687 mg·m·d) to reach AUC0-12 values above the defined target level of 30 mg·h·L. Conclusions When used in combination with tacrolimus and steroids, an initial MMF dose of 600 mg/m twice a day would be recommended to children after intestinal transplantation to achieve MPA exposure similar to those observed in adults and children after the transplantation of other organs. Further studies are required to recommend a suitable dosage for pediatric intestinal transplant recipients who receive MPA.

Background: The enteric-coated mycophenolate sodium (EC-MPS), whose active constituent is mycophenolic acid (MPA), has been widely clinically used for organ transplant recipients. However, its absorption is delayed due to its special designed dosage form, which results in difficulty to monitor the exposure of the MPA in patients receiving the EC-MPS. This study was aimed at developing a relatively practical and precise model with limited sampling strategy to estimate the 12-hour area under the concentration–time curve (AUC0–12 h) of MPA for Chinese renal transplant recipients receiving EC-MPS. Methods: A total of 36 Chinese renal transplant recipients receiving the EC-MPS and tacrolimus were recruited in this study. The time point was 2 weeks after the transplantation for all the patients. The MPA concentrations were measured with enzyme-multiplied immunoassay technique for 11 blood specimens collected predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours after the morning dose of EC-MPS. The measured AUC was calculated with these 11 points of MPA concentrations with the linear trapezoidal rule. Limited sampling strategy was used to develop models for estimated AUC in the model group (n = 18). The bias and precision of different models were evaluated in the validation group (n = 18). Results: C4 showed the strongest correlation with the measured AUC. The best 3 time point equation was 6.629 + 8.029 × C0 + 0.592 × C3 + 1.786 × C4 (R2 = 0.910; P < 0.001), whereas the best 4 time point equation was 3.132 + 5.337 × C0 + 0.735 × C3 + 1.783 × C4 + 3.065 × C8 (R2 = 0.959; P < 0.001). When evaluated in the validation group, the 4 time point model had a much better performance than the 3 time point model: for the 4 time point model: R2 = 0.873, bias = 0.505 [95% confidence interval (CI), −10.159 to 11.170], precision = 13.370 (95% CI, 5.186–21.555), and 77.8% of estimated AUCs was within 85%–115% of the measured AUCs; for the 3 time point model: R2 = 0.573, bias = 6.196 (95% CI, −10.627 to 23.018), precision = 21.286 (95% CI, 8.079–34.492), and 50.0% of estimated AUCs was within 85%–115% of the measured AUCs. Conclusions: It demanded at least 4 time points to develop a relatively reliable model to estimate the exposure of MPA in renal transplant recipients receiving the EC-MPS. The long time span needed restricted its application, especially for the outpatients, but it could be a useful tool to guide the personalized prescription for the inpatients.

Background Considerable interest exists in identifying calcineurin inhibitor (CNI)-free and thus, less-toxic immunosuppressive regimens, with mycophenolic acid (MPA)-based treatments being a suitable approach. Because pharmacokinetic analyses of MPA treatments in stable CNI-free renal transplant recipients are lacking, the authors aimed at comparing the steady-state pharmacokinetic characteristics of MPA in patients on stable treatment with mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS) plus prednisone (≤5 mg/d). Methods In the prospective, nonrandomized, open-label study, patients with stable transplant function since ≥6 months received their routine single dose of either MMF (n = 12) or EC-MPS (n = 11). The MPA plasma concentration was recorded over 12 hours. Parameters assessed were predose MPA concentration (C0), postdose minimum and maximum concentration (Cmin and Cmax), time to maximum concentration (Tmax), and area under the concentration-time curve (AUC) for the 12-hours of exposure (AUC0-12). Results Baseline characteristics were comparable between both the groups. Consistent with enteric coating, the mean Tmax was significantly longer after the intake of EC-MPS compared with MMF (2.2 versus 0.8 hours; P = 0.0002). The exposure measures Cmin, Cmax, and AUC0-12 were not significantly different despite the higher mean MPA equivalent dose in patients receiving MMF compared with those receiving EC-MPS (85% versus 64% of the recommended single dose, respectively). Exposures as reflected by the median AUC0-12 values were 50.7 and 58.7 mg·h·L with MMF and EC-MPS, respectively (P = 0.340). All patients achieved a target AUC of >30 mg·h·L, and 61% had an AUC of >50 mg·h·L. Conclusions The study provides first results on the steady-state pharmacokinetics of the 2 MPA drugs in CNI-free immunosuppressant regimens. Pharmacokinetic parameters measured in this study under real-life conditions were comparable in patients receiving MMF or EC-MPS.

Although multiple linear regression-based limited sampling strategies (LSSs) have been published for enteric-coated mycophenolate sodium, none have been evaluated for the prediction of subsequent mycophenolic acid (MPA) exposure. This study aimed to examine the predictive performance of the published LSS for the estimation of future MPA area under the concentration-time curve from 0 to 12 hours (AUC0-12) in renal transplant recipients.Total MPA plasma concentrations were measured in 20 adult renal transplant patients on 2 occasions a week apart. All subjects received concomitant tacrolimus and were approximately 1 month after transplant. Samples were taken at 0, 0.33, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours and 0, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 9, and 12 hours after dose on the first and second sampling occasion, respectively. Predicted MPA AUC0-12 was calculated using 19 published LSSs and data from the first or second sampling occasion for each patient and compared with the second occasion full MPA AUC0-12 calculated using the linear trapezoidal rule. Bias (median percentage prediction error) and imprecision (median absolute prediction error) were determined.Median percentage prediction error and median absolute prediction error for the prediction of full MPA AUC0-12 were15% for 4 LSSs, using the data from the same (second) occasion. One equation (1.583C1 + 0.765C2 + 0.369C2.5 + 0.748C3 + 1.518C4 + 2.158C6 + 3.292C8 + 3.6690) showed bias and imprecision15% for the prediction of future MPA AUC0-12, where the predicted AUC0-12 from the first occasion was compared with the full AUC0-12 from the second. All LSSs with an acceptable predictive performance included concentrations taken at least 6 hours after the dose.Only one LSS had an acceptable bias and precision for future estimation. Accurate dosage prediction using a multiple linear regression-based LSS was not possible without concentrations up to at least 8 hours after the dose.

Background Mycophenolic acid (MPA), a potent immunosuppressant, is widely used in solid organ transplantations. This study aimed to investigate the pharmacokinetics of enteric-coated mycophenolate sodium (EC-MPS) in Chinese adult renal allograft recipients and to generate optimal model equations for estimation of the MPA area under the concentration-time curve from 0 to 12 hours (AUC0-12 h), using a limited sampling strategy (LSS). Methods Serial blood samples were collected over 12 hours from 38 recipients of a primary living-related donor kidney graft treated with EC-MPS, tacrolimus, and corticosteroid. MPA concentrations were evaluated using an enzyme-multiplied immunoassay technique. The LSSs were developed and validated by multiple regression analysis using a 2-group method (test group, n = 19; validation group, n = 19). Results The best algorithms obtained from the test group were the following: 15.09 + 1.05 × C1.5 + 1.8 × C4 + 4.18 × C6 (for 3 time points, r = 0.902) and 10.44 + 0.7 × C1 + 1.22 × C2 + 1.75 × C4 + 4.36 × C6 (for 4 time points, r = 0.941). When these algorithms were tested in the validation group, there were no significant differences in prediction errors. Conclusions LSSs using time points of 1.5, 4, and 6 hours or 1, 2, 4, and 6 hours after dose provide effective and reliable estimations of the MPA AUC0-12 h in Chinese renal allograft recipients treated concomitantly with EC-MPS and tacrolimus during the early posttransplantation phase.

Background Two oral mycophenolic acid (MPA) formulations, immediate-release mycophenolate mofetil and enteric-coated mycophenolate sodium, have been shown to differ regarding some drug-drug interactions. The aim was to assess whether the effects of cyclosporine (CsA) on steady-state pharmacokinetics (PK) of MPA in renal transplant patients were affected by MPA formulation. Methods A prospective, stratified observational study based on therapeutic drug monitoring of MPA (6 total plasma concentrations over a 12-hour dosing interval, τ) in consecutive stable adult renal transplant recipients (n = 68). Results Patients treated with enteric-coated mycophenolate sodium (n = 45) or mycophenolate mofetil (n = 23) and with either CsA (microemulsion, n = 43) or tacrolimus (Tac) (immediate release, n = 25) were comparable regarding demographics, comorbidity, renal and liver functions, comedication, corticosteroid dose, CsA or Tac dose, and trough concentrations. Based on dose-normalized MPA concentrations and with adjustment for age, sex, body mass index, estimated glomerular filtration rate, and corticosteroid dose, CsA (as compared with Tac) consistently reduced MPA area under the concentration-time curve during the dosing interval at steady state overall [geometric mean ratio (GMR), 0.78; 95% confidence interval, 0.62-0.99] and by MPA formulation (by 22% and 21%, respectively), increased CLT/F,ss overall (1.31; 1.00-1.70) and by formulation (by 25% and 36%, respectively), reduced morning predose MPA concentration overall (0.59; 0.38-0.92) and by formulation (by 34% and 47%, respectively), increased peak-trough fluctuation overall (1.51; 1.06-2.17) and by formulation (by 58% and 45%, respectively), and prolonged tmax,ss overall (adjusted median difference 0.58, 0.04-1.12 hours) and by formulation (by 0.6 and 0.5 hours, respectively). Conclusions Qualitatively and quantitatively, the effect of CsA on steady-state PK of MPA is not conditional on MPA formulation.

Background Substantial research has been conducted to develop limited-sampling strategies (LSS) to estimate the area under the curve (AUC(0-12h)) in patients treated with mycophenolate mofetil. However, no LSS has been validated for enteric-coated mycophenolate sodium (EC-MPS). Our aim was to develop an LSS to measure the AUC(0-12h) of mycophenolic acid in kidney recipients treated with tacrolimus and EC-MPS. Study design Thirteen serial blood samples were collected over 12 hours from 71 patients treated with tacrolimus and EC-MPS. Mycophenolic acid was measured in plasma using the enzyme-multiplied immunoassay. LSSs were developed and validated by multiple regression analysis using a 2-group method (test, n = 47; validation, n = 24). Results The best LSS obtained in the test group were for 3 and 4 time points AUC(0-12h) (mg·h(-1)·L(-1)) = 15.99 + 0.87C1 h + 0.68C2 h + 7.85C4 h and AUC(0-12h) (mg·h(-1)·L(-1)) =11.15 + 0.68C1 h + 0.45C1.5 h + 0.57C2 h + 8.16C4 h, respectively. When these LSS were tested in the validation group, the results were acceptable (adjusted r(2) = 0.71, bias =-0.214 [95% confidence interval (CI): -7.91 to 7.48], precision = 7.48 (95% CI: 3.69-19.39) for 3 time points and adjusted r(2) = 0.76, bias = -1.48 (95% CI: -8.23 to 5.27), precision = 7.68 (95% CI: 4.23-13.50) for 4 time points). Conclusions : An LSS using time points at C(1h)-C(2h)-C(4h) or C(1h)-C(1.5h)-C(2h)-C(4h) provides the most reliable and accurate estimation of the AUC(0-12h) of mycophenolic acid in stable renal transplant recipients treated with EC-MPS and tacrolimus.

The aim of the study is to characterize the pharmacokinetics and the gastrointestinal side effect profiles of enteric-coated mycophenolate sodium (EC-MPS) in de novo kidney transplant patients of Hispanic ethnicity.The pharmacokinetic study of EC-MPS was conducted in 11 de novo kidney transplant patients of Hispanic ethnicity. Eight blood samples were obtained after EC-MPS was given at the steady state. Blood concentrations of mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) were measured.The mean age (± standard deviation) was 39.4 (± 12.3) years. The mean daily dose of EC-MPS at the time of the pharmacokinetic study was 1408 ± 108 mg. For MPA and MPAG, the time to peak concentration was 2.5 ± 1.3 hours and 4.6 ± 3.1 hours, respectively; the peak concentration (Cmax) was 19.3 ± 17.2 mg/L and 109.4 ± 49.2 mg/L; and the area under the curve from 6 to 12 hours (AUC6-12) was 32.2 ± 19.3 mg·hr/L and 373.7 ± 235.8 mg·hr/L, respectively, which represents 41.3% and 43.0% of AUC0-12. The AUC0-12 for MPA measured 77.8 ± 53.1 mg·hr/L and for MPAG 869.2 ± 388.8 mg·hr/L. Seven patients (64%) exhibited a second peak at approximately 8.3 hours after the dose at a mean concentration (± standard deviation) of 10.3 ± 7.6 mg/L. The Cmax or AUC of MPA does not correlate with overall Gastrointestinal Symptom Rating Scale scores or subscale scores, but the Cmax of MPAG correlates with indigestion subscale (P = 0.022), diarrhea (P = 0.032), and overall scores (P = 0.028). The AUC of MPAG also correlates with acid reflux (P = 0.024) and indigestion (P = 0.032).The pharmacokinetics of EC-MPS has a high variability in de novo kidney transplant patients of the Hispanic ethnicity, which was similar to other ethnic groups. The MPA exposure expressed by the AUC appears to be higher in Hispanic patients than those reported in other ethnic groups, which may be the result of various factors such as difference of the uridine diphosphate glucuronosyltransferase enzyme genotypes, but gastrointestinal side effects were acceptable and the Cmax or AUC of MPAG showed correlations with gastrointestinal symptoms.

The delayed release of mycophenolic acid (MPA) from enteric-coated mycophenolate sodium (EC-MPS) may lead to different MPA predose (C0) levels compared with mycophenolate mofetil (MMF). A post hoc analysis was performed on MPA morning predose values assessed in 88 maintenance renal transplant patients from three studies converted from MMF (1000 mg twice a day) to equimolar EC-MPS (720 mg twice a day) or vice versa, both in combination with cyclosporine. The median MPA predose level was approximately 30% higher when patients received EC-MPS (2.40 microg/mL; range, 0.49-39.30 microg/mL) compared with MMF (1.83 microg/mL; range

Mycophenolic acid (MPA) is widely used in solid organ transplantation. MPA absorption from enteric-coated mycophenolate sodium (EC-MPS) is delayed, which results in a delayed enterohepatic recirculation and subsequently higher and more variable MPA 12-hour trough concentration and tmax values. Therefore, MPA trough level monitoring cannot be used to monitor MPA exposure in patients who are given EC-MPS. The aim of the study was to develop and validate a limited sampling strategy (LSS) for accurate prediction of the 12-hour area under the concentration-time curve (AUC0-12h) for MPA in patients who receive concomitant EC-MPS and Tacrolimus (Prograf or Advagraf) within 196 months posttransplantation. According to our knowledge, the LSS for MPA AUC estimation using high-performance liquid chromatography to determine MPA concentrations in plasma samples of kidney and liver transplant patients receiving EC-MPS and Tacrolimus (Advagraf) has not been previously evaluated.Seventy-four renal and liver transplant patients receiving EC-MPS and concomitant tacrolimus (either Prograf or Advagraf) provided a total of 74 pharmacokinetic profiles. MPA concentrations were measured using a validated high-performance liquid chromatography method for 9 plasma samples collected at predose and at 0.5, 1, 2, 3, 4, 6, 9, and 12 hours after the morning dose of EC-MPS after an overnight fast. LSS were developed and validated by stepwise multiple regression analysis with the use of a 2-group method (test, n = 37; and validation, n = 37).The 3 and 4 time point equations using C1h, C3h, C9h and C1h, C2h, C3h, C6h, respectively, were found to be superior to all other models tested. When these LSS models were tested in the validation group, the results were acceptable [for 3 time points equation: r = 0.824, percentage of prediction error: 6.32 ± 25.75, 95% confidence interval (CI): -40.71 to 79.76; percentage of absolute prediction error: 27.45 ± 29.89, 95% CI: 0.04-199.92, predictive performance, 71% of estimated AUCs comprised within 85%-115% of the measured full MPA AUC, natural logarithmic residuals (ln) mean ± SD: -0.03 ± 0.24; for 4 time points equation: r = 0.898, percentage of prediction error: 3.32 ± 18.26, 95% CI: -49.35 to 51.06; percentage of absolute prediction error: 14.05 ± 11.89, 95% CI 0.13-49.86, percentage of predictive performance, 83% of estimated AUCs comprised within 85%-115% of the measured full MPA AUC, natural logarithmic residuals (ln) mean ± SD: -0.01 ± 0.19].LSS equations using concentrations at 1, 3, and 9 hours or 1, 2, 3, and 6 hours time points provided the most reliable and accurate estimations of the MPA AUC in stable renal and liver transplant recipients treated with EC-MPS and tacrolimus. Further studies on independent groups of patients are required to confirm clinical utility of the presented LSS models.

BACKGROUND The influence of the conversion from cyclosporine (CsA) to everolimus (EVR) on the chronopharmacokinetics of mycophenolic acid (MPA) and its glucuronide (MPAG) and acyl glucuronide (acyl-MPAG) metabolites in patients receiving enteric-coated mycophenolate sodium (EC-MPS) has not been studied. METHODS We evaluated daytime and nighttime steady-state MPA, MPAG, and acyl-MPAG pharmacokinetics in 24 stable kidney transplant recipients while receiving cyclosporine and 28 days after conversion from CsA to EVR. The effect of concomitant treatment and the circadian difference on AUC(t,ss) and C(max,ss) were assessed using a linear mixed model. RESULTS After conversion from CsA to EVR, MPA AUC(t,ss) was 43% higher (29% daytime and 58% during nighttime), whereas MPAG AUC(t,ss) was 33% lower (35% daytime and 30% during nighttime) and acyl-MPAG AUC(t,ss) was 31% lower (36% during daytime and 26% nighttime). Compared with daytime, MPA AUC(t,ss) was 25% lower (32% with CsA and 17% with EVR), MPAG AUC(t,ss) was 24% lower (26% with CsA and 21% with EVR), and acyl-MPAG AUC(t,ss) was 26% lower (32% with CsA and 21% with EVR) during nighttime. After conversion from CsA to EVR, MPAG:MPA and acyl-MPAG:MPA AUC(t,ss) ratios were 50% lower but were not different during daytime compared with nighttime EC-MPS administration. There was no correlation between CsA or EVR concentrations with MPA, MPAG, and acyl-MPAG exposures during daytime and nighttime. At least 1 adverse event was reported in 70.8% of patients receiving EC-MPS and CsA and in 91.7% receiving EC-MPS and EVR. CONCLUSION In stable kidney transplant recipients receiving EC-MPS and steroids, exposures to MPA, MPAG, and acyl-MPAG were lower during nighttime compared with daytime, both with CsA or EVR. This circadian effect on MPA exposure did not correlate with CsA or EVR concentrations or with altered MPAG and acyl-MPAG formation.

Introduction: Strategies based on monitoring pharmacodynamic effects are increasingly evaluated to individualize immunosuppressive therapy. In the present investigation, both drug-specific and general pharmacodynamic biomarkers were assessed and their association with clinical events early after kidney transplantation was examined. Methods: Thirty-five de novo kidney transplant patients receiving basiliximab, enteric-coated mycophenolate sodium (2 × 720 mg/day), steroids, and tacrolimus (target: 6-8 μg/L) were included. Blood was drawn on days 7(± 1) and 21(± 2) after transplantation. Mononuclear leucocytes were isolated and the following parameters were investigated: inosine monophosphate dehydrogenase activity (high-performance liquid chromatography-diode array detection), cell proliferation (bromodeoxyuridine test), and CD marker cell surface expression (CD25, CD71, CD26) on stimulated (phytohemagglutinin 2.5 μg/10 6 cells) and nonstimulated CD3 + cells. Acute rejection, gastrointestinal adverse effects, leucopenia, and infections were monitored over 3 months. Results: There was no association between clinical events and inosine monophosphate dehydrogenase activity apart from patients with diarrhea showing a significantly higher inosine monophosphate dehydrogenase activity 2 hours after the enteric-coated mycophenolate sodium dose (P < 0.05). Cell proliferation was significantly reduced in patients with leucopenia (P < 0.05). CD71 expression was less inducible in patients with infections (P < 0.05). A lower CD26 expression on non stimulated CD3 + cells predicted freedom from rejection (Day 7; negative predictive value 100%). No associations were found between CD25 expression and events. Conclusions: A potential benefit of pharmacodynamic monitoring to optimize immunosuppressive combination therapy has been demonstrated. In particular, CD26 and CD71 may be promising biomarkers to assess adequate immunosuppression in the early phase after kidney transplantation. The results of this pilot study require verification in further trials with more patients and events as well as with different graft types.