Mycophenolic Acid Trough Levels Research Articles

B-329 Comparison Between Trough and AUC Monitoring of MPA in Patients With and Without Organ Transplantation. Influence of the Co-administered Immunosuppressant

Abstract Background Monitoring of mycophenolic acid (MPA) could be performed by measurement of trough concentrations with target therapeutic range of 1.3 to 3.5 mg/L, or by calculation of area under the drug concentration vs time curve (AUC) utilizing 3 or 4 samples within a dosing interval, with a target range of 30 to 60 mg*h/L. AUC is considered more reliable compared to trough levels, and MPA kinetics are dependent on the type of the co-administered calcineurine inhibitor. This study compares trough vs AUC MPA monitoring received alone or in co-administration with Cyclosporine (CsA) or with Tacrolimus (TAC). Methods 77 transplanted patients receiving MPA, 25 of them on CsA, 49 on TAC, and 20 non-transplanted patients on MPA alone, were evaluated more than once, yielding 260 monitoring consults included for assessment: 45 for MPA alone, 108 for MPA combined with CsA, and 117 consults for the MPA combined with TAC. MPA, CsA, and TAC levels were measured by validated LC/MS/MS methods. Validated pharmacokinetic programs for the calculation of MPA AUC were used, adapted to the type of calcineurine inhibitor. Assessment was made by comparison of the distribution and coincidence between trough levels and AUC with respect to the above therapeutic ranges. Results Transplanted patents: when combined with CsA, MPA AUC was in the target range in 61% of cases, under it—in 31%, and in 8%—over it, while trough levels were 52% under, 42.5% within, and 5.5% over the therapeutic range; agreement between trough MPA and MPA AUC was poor—there was coincidence in 37.5% of sub-therapeutic, 63% of therapeutic and 0% of supra-therapeutic ranges, 3 cases were identified with sub-therapeutic trough and supra-therapeutic AUC; when combined with TAC, MPA AUC was in the target range in 63% of cases, under it—in 13%, and in 24%—over it; trough levels being 23% under, 60% within and 17% over the therapeutic range; agreement between trough MPA and MPA AUC was much better, compared to the combination with CsA: there was coincidence in 56% of sub-therapeutic, 84% of therapeutic and 80% of supra-therapeutic ranges. Nevertheless, 1 case was found with sub-therapeutic trough and supra-therapeutic AUC. In non-transplanted patients MPA AUC was in the target range in 47% of cases, under it—in 13%, and in 40%—over it; trough levels being 18% under, 53% within and 29% over the therapeutic range; agreement between trough MPA and MPA AUC showed coincidence in 75% of sub-therapeutic, 75% of therapeutic and 92% of supra-therapeutic ranges. Conclusion This study confirms that MPA AUC is more relevant than trough monitoring for dose individualization. It also shows that MPA trough levels are much more concordant with MPA AUC in non-transplanted patients and in transplanted patients on TAC, while in combination with CsA, discordance remains significant.

Mycophenolic acid therapeutic drug monitoring using area under the curve in pediatric heart transplant recipients.

Pharmacokinetics of mycophenolic acid (MPA) display substantial interpatient variability, with up to 10-fold difference of exposure in individual patients under a fixed-dose regimen. MPA trough level (C0) monitoring is common in clinical practice but has not proven sufficiently informative in predicting MPA exposure or patient outcomes, especially in children. No limited sampling strategies (LSSs) have been generated from pediatric heart transplant (HTx) recipients to estimate MPA AUC. Single-center, observational analysis of 135 de novo pediatric HTx recipients ≤21years old who underwent MPA AUC between 2011 and 2021. Median age was 4years (IQR .6-12.1). Median time from transplant to MPA AUC sampling was 15days (IQR 11-19). MMF doses (mg or mg/day) had low, negative Pearson correlation coefficients (r) while doses adjusted for weight or body surface area had low correlation with Trapezoidal MPA AUC0-24h (r=.3 and .383, respectively). MPA C0 had weak association (r=.451) with Trapezoidal MPA AUC0-24h . LSS with two pharmacokinetic sampling time points at 90 (C3 ) and 360 (C5 )min after MMF administration (estimated AUC0-24h =32.82+4.12×C3 +11.53×C5 ) showed strong correlation with Trapezoidal MPA AUC0-24h (r=.87). MMF at fixed or weight-adjusted doses, as well as MPA trough levels, correlate poorly with MPA AUC0-24h . We developed novel LSSs to estimate Trapezoidal MPA AUC from a large cohort of pediatric HTx recipients. Validation of our LSSs should be completed in a separate cohort of pediatric HTx recipients.

Individualization of Mycophenolic Acid Therapy through Pharmacogenetic, Pharmacokinetic and Pharmacodynamic Testing.

Mycophenolic acid (MPA) is a widely used immunosuppressive agent and exerts its effect by inhibiting inosine 5'-monophosphate dehydrogenase (IMPDH), the main regulating enzyme of purine metabolism. However, significant unexplained differences in the efficacy and tolerability of MPA therapy pose a clinical challenge. Therefore, broad pharmacogenetic, pharmacokinetic, and pharmacodynamic approaches are needed to individualize MPA therapy. In this prospective cohort study including 277 renal transplant recipients, IMPDH2 rs11706052 SNP status was assessed by genetic sequencing, and plasma MPA trough levels were determined by HPLC and IMPDH enzyme activity in peripheral blood mononuclear cells (PBMCs) by liquid chromatography-mass spectrometry. Among the 277 patients, 84 were identified with episodes of biopsy-proven rejection (BPR). No association was found between rs11706052 SNP status and graft rejection (OR 1.808, and 95% CI, 0.939 to 3.479; p = 0.076). Furthermore, there was no association between MPA plasma levels and BPR (p = 0.69). However, the patients with graft rejection had a significantly higher predose IMPDH activity in PBMCs compared to the controls without rejection at the time of biopsy (110.1 ± 50.2 vs. 95.2 ± 45.4 pmol/h; p = 0.001), and relative to the baseline IMPDH activity before transplantation (p = 0.042). Our results suggest that individualization of MPA therapy, particularly through pharmacodynamic monitoring of IMPDH activity in PBMCs, has the potential to improve the clinical outcomes of transplant patients.

Serum Trough Concentration and Effects of Mycophenolate Mofetil Based on Pathologic Findings in Infants After Liver Transplantation

ObjectivesMycophenolate mofetil (MMF) is mainly used in conjunction with calcineurin inhibitors as an additional immunosuppressive for renal sparing after liver transplantation. However, few reports about MMF use in infants after living donor liver transplantation (LDLT) are available. The purpose of this study was to examine the efficacy and safety of MMF in infants. MethodsThis study enrolled infants younger than 1 year of age who received LDLT at our institution. Patients received oral MMF twice daily. The initial dose was 40 to 50 mg/kg/d, which was increased to a target mycophenolic acid (MPA) trough level of 2 mg/L. Body weight, height, MMF dose, MPA trough level, acute cellular rejection (ACR) episodes, pathologic findings, and adverse effects were analyzed. Allograft fibrosis was graded using the Meta-analysis of Histological Data in Viral Hepatitis score. ResultsPatients received MMF for refractory ACR (n = 2), fulminant hepatitis (n = 2), and pre-existing antibodies (n = 1). Original diseases were biliary atresia (n = 3) and fulminant hepatitis (n = 2). Mean age at transplant was 8 months (range 3-10 months). The last available mean trough level was 2.7 mg/L. The mean dose was 66 mg/kg/d or 1429 mg/m2/d at the time of the last available through level. The regression line for MMF dose and MPA trough level was y = 1.8 × 10-3x. The correlation coefficient was 0.65. All allografts showed F1 to F2 fibrosis. Two patients discontinued MMF because of infection and bone marrow suppression, respectively. Two patients converted to everolimus. One patient continued on MMF. ConclusionsAfter LDLT, infants require a higher MMF dose than older patients based on trough levels, but allograft fibrosis can progress.

Assessment of Mycophenolic Acid Levels on Biopsy Proven Rejection and Adverse Effects in Pediatric Heart Transplant Recipients

Therapeutic ranges of Mycophenolic Acid (MPA) concentrations have not been established in pediatric heart transplant recipients. There are limited data supporting are under the concentration-time curve (AUC) in adult heart transplant on outcomes such as rejection, but AUC monitoring may be not be feasible in clinical practice. The purpose of our study is to evaluate the relationship between mycophenolic acid (MPA) trough levels and incidence of biopsy proven rejection and adverse effects in pediatric heart transplant patients. A single-center retrospective chart review was performed on patients receiving heart transplant between Jan 2011 and Dec 2015. Patients included for analysis were ≤18 years at transplant and received maintenance immunosuppression with tacrolimus, mycophenolate, and a corticosteroid. Endomyocardial biopsy grades up to one-year post transplant and simultaneous MPA levels were recorded. Patients with acute cellular rejection scores of 2R or 3R or immunopathologic evidence of antibody mediated rejection were considered as biopsy proven acute rejection (BPAR). Leukopenia, gastrointestinal side effects, and mycophenolate dose decreases were also recorded. A total of 47 patients were included in the final analysis. There were no significant differences in baseline demographics between patients who had BPAR and those who did not. Overall 24% of patients had at least 1 incidence of BPAR after heart transplant. The mean MPA trough levels between the group of patients with rejection (2.4 ug/mL +/- 1.62) and those without rejection (2.46 ug/mL +/- 1.74) was not significantly different (p=0.38). Mean MPA trough levels also were also not consistent when examining rejection by time from transplant. Only examining by individual MPA trough levels on biopsy days did we observe a significantly lower MPA trough 1.6 ug/mL +/- 1.05 in those with rejection versus those without 2.5 ug/mL +/- 1.69 (p=0.02). The mean MPA level associated with a dose decrease due to an adverse effect between these two groups was not significant. MPA trough levels may have a relationship with incidence of biopsy proven rejection or with incidence of adverse events within one-year post transplant in this population. Controlled prospective studies with are warranted to further evaluate this potential relationship.

SAT-333 MYCOPHENOLIC ACID MONTTORNIC IN RENAL ALIOGRAFT RECIPIENTS; ASSOCIATATION WITH SAFETY AND EFFICACY

Mycophenolic acid (MPA) is one of the cornerstones immunosuppressants in the setting of transplantation. Advances in the pharmacokinetic studies have uncovered the high inter and intra_individual variability of plasma mycophenolic acid level. This variability in drug concentration can cause both supra therapeutic and sub therapeutic drug plasma levels which can have hazardous results in transplant patients. To date, routine therapeutic drug monitoring of MPA has not been established in clinical practice. Aim of the work: Our objective was to monitor the level of MPA in relation to the occurrence of gastrointestinal (GI) complications and renal function in renal allograft recipients. MPA trough level was measured in 51 renal allograft recipients at the entry of the study and 4 weeks after any dose modification. Levels were correlated with the side effects recorded during the study follow up period. GI toxicity, hematological toxicity and biopsy proven acute rejection (BPAR) were diagnosed in 29.4%, 9.8% and 11.7% of the studied population respectively. Higher MPA 12-hr trough levels were associated with hematological side effects, yet, the correlation with GI side effects was largely negative. A significant correlation between low MPA plasma levels and the development of BPAR after kidney transplantation was detected. An MPA level of 3.5 µg/mL best discriminated between patients who developed hematological toxicity from those who didn’t while MPA level of 2.4 µg/mL best discriminated between patients with and without BPAR. Monitoring of MPA trough level should be practiced in renal allograft recipients in order to avoid drug toxicity without compromising efficacy.

Trough Level of Mycophenolic Acid Did Not Affect De Novo DSA Development in Kidney Transplantation

IntroductionMycophenolate mofetil has improved long-term outcomes of kidney transplantation. However, the impact of mycophenolic acid (MPA) trough level on the development of de novo donor-specific anti-HLA antibody (DSA) is unclear. We examined the relation between MPA trough level and de novo DSA development. MethodWe retrospectively studied 617 kidney recipients whose MPA trough level and de novo DSA data were available. All patients underwent primary kidney transplant from living donors from 2008 to 2014, and were chronically treated with a calcineurin inhibitor, mycophenolate mofetil, and +/- steroids. They were equally divided into 4 groups according to the mean trough level of MPA (mMPA) at 1 year post-transplantation: Group 1, mMPA < 2.14 ng/mL (n = 152); Group 2, mMPA 2.14-2.83 ng/mL (n = 157); Group 3, mMPA 2.83-3.57 ng/mL (n = 153); and Group 4, mMPA ≥ 3.57 ng/mL (n = 155). The groups were compared by incidence rate of de novo DSA, graft survival rate, and renal function. ResultsThe incidence rates of de novo DSA were 33.3% in Group 1, 23.7% in Group 2, 22.9% in Group 3, and 30.3% in Group 4 (P = .158). Although there was no significant difference in graft survival rates, a significant difference of renal functions was noted: the higher the renal function, the lower the MPA trough level. ConclusionThe mMPA trough level at 1 year post-transplantation was not statistically associated with the incidence rate of de novo DSA after kidney transplantation.

Tablet or capsule form of generic mycophenolate mofetil (My-Rept®) after liver transplantation: a prospective randomized trial.

BackgroundTablet and capsule forms have advantages and disadvantages in the market. Generally, the tablet form (500 mg) of mycophenolate mofetil (MMF) is more convenient for drug ingestion and more cost-effective than the capsule form (250 mg). We examined the efficacy and safety of MMF in its different forms combined with tacrolimus in liver transplant recipients.MethodsA randomized controlled trial was performed to compare the efficacy and safety between the tablet form of MMF (tablet group) and the capsule form of MMF (capsule group) in liver transplant patients. One hundred sixteen patients were enrolled in the present study from 2014 to 2017. Fifty-six patients in the full-analysis set (FAS) population were in the capsule group and 60 were in the tablet group. The primary endpoint was incidence of biopsy-proven acute rejection (BPAR) by 24 weeks after liver transplantation (LT). Secondary endpoints were patient survival, serum creatinine level, and adverse events (AEs).ResultsIn the per-protocol population, 45 patients were in the tablet group and 49 were in the capsule group. There were no statistically significant differences in MMF dose, mycophenolic acid trough level, and tacrolimus trough level between the two groups. The incidence of BPAR at 24 weeks after randomization was 6.7% in the tablet group and 6.1% in the capsule group (P=0.627). All patients with BPAR responded well to steroid pulse therapy and increased tacrolimus. Serum creatine level and eGFR were not different between the two groups. The incidence of serious AEs was 7.2% in the tablet group and 7.6% in the capsule group, and none were related to formulation. There was no significant difference in incidence of discontinuations or serious AEs between the two groups.ConclusionThe present study suggests that the new tablet formulation can be a useful treatment option to maintain a consistent systemic exposure level of MMF, which may help reduce graft failure in liver transplant patients.

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

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

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

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

Developmental changes of MPA exposure in children.

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

What is the intrapatient variability of mycophenolic acid trough levels?

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

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

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

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

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

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

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

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

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

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

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

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

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

Use of limited sampling strategy for estimating area under concentration-versus-time curve of mycophenolate sodium in renal allograft recipients

To establish a formula for estimating area under the concentration-versus-time curve (AUC) of mycophenolate sodium in Chinese renal allograft recipients with a limited sampling model. A total of 35 renal allograft recipients were recruited from 2010 to 2013 to receive enteric-coated mycophenolate sodium (EC-MPS), calcineurin (CNI) and prednisone as immunosuppressive triple therapy. The serum concentration of mycophenolic acid (MPA) was assayed by enzyme multiplied immunoassay technique (EMIT) at pre-dose (C0), 0.5 (C0.5), 1.0 (C1), 1.5 (C1.5), 2.0 (C2), 3.0 (C3), 4.0 (C4), 6.0 (C6), 8.0 (C8) and 12.0 (C12) h post-dose respectively. Pharmacokinetic parameters of MPA (C0, C12, Cmax, Tmax, AUC0-12 h) were calculated by software WINNOLIN. Simplified formulae for estimation of MPA-AUC in tacrolimus (Tac) group or cyclosporin A (CsA) group were established by multiple stepwise regression analysis. There were variable MPA AUC0-12 h levels between 14 and 67 mg×h/L (mean: 37 ± 14). The MPA trough level (C0) had no correlations with MPA AUC0-12 h (r(2) = 0.090) . The simplified MPA AUC formula for Tac group was AUC = 5.678+1.718×C4+2.853×C6+1.812×C8+3.413×C12 with four sampling points (C4, C6, C8, C12). Estimated AUC with the formula had correlations with AUC0-12 h (r(2) = 0.890). The mean absolute predict error (APE) was 3.45% (0.41%-24.71%) and the proportion of APE above 15% stood at 11.1% (2/18) . In CsA group, the simplified MPA AUC formula was AUC = 7.072+1.525×C3+1.558×C4+ 1.573×C6+2.285×C8. The correlation was r(2) = 0.952, mean APE was 6.50% (0.02%-12.91%) and proportion of APE above 15% stood at 0. The above formulae were observed to have agreement with AUC0-12 h by Bland-Altman analysis. The simplified MPA AUC formulae with 4-point sampling provide an effective approach for estimating full MPA AUC0-12 h in Chinese renal recipients on EC-MPS plus tacrolimus or cyclosporin A.

Development and Validation of Limited Sampling Strategies for the Estimation of Mycophenolic Acid Area Under the Curve in Adult Kidney and Liver Transplant Recipients Receiving Concomitant Enteric-Coated Mycophenolate Sodium and Tacrolimus

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.