Mycophenolic Acid Trough Research Articles

Mycophenolate Metabolite Trough Concentrations Are Not Well Correlated With Dosing or Adverse Outcomes in Pediatric Heart Transplant Recipients.

Although mycophenolate metabolite trough concentrations in serum are routinely obtained for pediatric orthotopic heart transplant (OHT) recipients, limited data support this practice. We sought to investigate the relationship of mycophenolic acid (MPA) and MPA glucuronide (MPAG) serum concentrations to dosing and adverse outcomes among pediatric OHT patients. This retrospective study included OHT recipients ages 0 to 21 years who received mycophenolate mofetil (MMF) with MPA and MPAG serum trough concentration monitoring. The primary outcome was the relationship between MPA and MPAG serum concentrations and dosing. Secondary outcomes included the relationship of adverse outcomes to either MPA and MPAG concentrations or dosing. A total of 98 patients with 1287 MPA and MPAG trough serum concentrations (each) were included. The median initial MMF dose was 40.3 mg/kg/day (IQR, 35.12-51.83) and 1164.4 mg/m2/day (IQR, 1080.77-1206.86). There was no correlation between either MPA or MPAG serum concentrations and mg/kg dosing, or mg/m2 dosing. When comparing the adverse effect of bone marrow suppression with no adverse effect, the median MPA serum trough concentration was 2 (IQR, 1.1-3.2) versus 1.6 (IQR, 0.8-2.5), p = 0.003. When comparing the adverse effect of infection with no adverse effect, median MPA serum trough concentration was 0.9 (IQR, 0.49-1.7) versus 1.6 (IQR, 0.8-2.5), p < 0.001. The clinical utility of this finding is of uncertain benefit. There was no association between MPAG serum concentrations and any adverse outcome (p = 0.053). We did not identify a correlation between mycophenolate serum trough concentrations and either adverse outcomes or dosing. Based on these results, we discourage routine monitoring of mycophenolate trough concentrations.

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.

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

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

Age associations with tacrolimus and mycophenolic acid pharmacokinetics in stable Black and White kidney transplant recipients: Implications for health inequities.

Tacrolimus (TAC) and mycophenolic acid (MPA) provide maintenance immunosuppression and is dosed empirically in elderly kidney transplant recipients (KTRs) resulting in health inequities. Limited immunosuppressive pharmacokinetics are available comparing adult ages. This secondary analysis compared TAC and MPA pharmacokinetics and adverse effects (AEs) among young, middle-aged, and elderly Black and White KTRs. The 12-h TAC and MPA pharmacokinetics with AE evaluation were conducted in 67 stableKTRs greater than or equal to 6 months post-transplant. TAC regimens were adjusted to target troughs. MPA regimens were adjusted using clinical response. Participants were: young: less than or equal to 40 years; middle age: greater than 40 to 60 years, and elderly greater than 60 years. Noncompartmental pharmacokinetic analysis determined area under the concentration-time curve 0-12 h (AUC0-12h ), clearance (CL), and CL/body mass index (BMI) with 0-h troughs. MPA enterohepatic recirculation (EHR), MPA-AUC6-12h /MPA-AUC0-12h , and MPA glucuronide (MPAG)-AUC0-12h /MPA-AUC0-12h were determined. Univariate analysis of variance (ANOVA) was conducted using SAS version 9.4. No group differences were noted for estimated glomerular filtration rate, MPA, and TAC doses. EHR was reduced in elderly with decreased MPA-AUC6-12h /MPA-AUC0-12h (p=0.049) and increased MPAG-AUC0-12h /MPA-AUC0-12h (p=0.036). MPA troughs (p=0.045) were reduced in the elderly. TAC CL/BMI (p=0.043) was reduced in the elderly. For therapeutic MPA AUC0-12h : 30-60 mg·h/L, 34.3% KTRs achieved this target with 55.2% greater than the therapeutic range. 77.6% KTR were in the TAC AUC0-12h target: 100-190 ng·h/mL and 19.4% were below this range with no age relationship. In 44% young, 26% middle-age and 7.8% elderly subjects achieved target AUC0-12h for both medications (p=0.036). Neurologic AEs were manifested in the elderly (p=0.014). Immunosuppressive pharmacokinetics demonstrated age-related differences with reduced TAC CL/BMI and MPA EHR and increased neurologic AE in the elderly. This immunosuppressive regimen may require age-adjusted individualization to optimize allograft function.

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.

Reduced Enterohepatic Recirculation of Mycophenolate and Lower Blood Concentrations Are Associated with the Stool Bacterial Microbiome after Hematopoietic Cell Transplantation

Mycophenolate mofetil (MMF) is an important immunosuppressant used after allogeneic hematopoietic cell transplantation (HCT). MMF has a narrow therapeutic index, and blood concentrations of mycophenolic acid (MPA), the active component of MMF, are highly variable. Low MPA concentrations are associated with the risk of graft-versus-host disease (GVHD), whereas high concentrations are associated with toxicity. Reasons for variability are not well known and may include the presence of β-glucuronidase-producing bacteria in the gastrointestinal tract, which enhance MPA enterohepatic recirculation (EHR) by transforming MPA metabolites formed in the liver back to MPA. This study was conducted to determine whether individuals with high MPA EHR have a greater abundance of β-glucuronidase-producing bacteria in their stool and higher MPA concentrations compared with those with low EHR. We conducted a pharmacomicrobiomics study in 20 adult HCT recipients receiving a myeloablative or reduced-intensity preparative regimen. Participants received MMF 1 g i.v. every 8 hours with tacrolimus. Intensive pharmacokinetic sampling of MMF was conducted before hospital discharge; total MPA, MPA glucuronide (MPAG), and acyl-glucuronide metabolite (acylMPAG) were measured. EHR was defined as the ratio of MPA area under the concentration-versus-time curve (AUC)4-8 to MPA AUC0-8. Differences in stool microbiome diversity and composition, determined by shotgun metagenomic sequencing, were compared above and below the median EHR (22%; range, 5% to 44%). The median EHR was 12% in the low EHR group and 29% in the high EHR group. MPA troughs, MPA AUC4-8, and acyl-glucuronide metabolite (acylMPAG) AUC4-8/AUC0-8 ratio were greater in the high EHR group compared with the low EHR group (1.53 μg/mL versus .28 μg/mL [P=.0001], 7.33 hour·μg/mL versus 1.79 hour·μg/mL [P=.0003], and .33 hour·μg/mL versus .24 hour·μg/mL [P=.0007], respectively). MPA AUC0-8 was greater in the high EHR group than in the low EHR group, and the difference trended toward significance (22.8 hour·μg/mL versus 15.3 hour·μg/mL; P=.06). Bacteroides vulgatus, Bacteroides stercoris, and Bacteroides thetaiotaomicron were 1.2- to 2.4-fold more abundant (P=.039, .024, and .046, respectively) in the high EHR group. MPA EHR was positively correlated with B. vulgatus (⍴=.58; P ≤ .01) and B. thetaiotaomicron (⍴=.46; P < .05) and negatively correlated with Blautia hydrogenotrophica (⍴=-.53; P < .05). Therapeutic MPA troughs were achieved in 80% of patients in the high EHR group but in no patients in the low EHR group. There was a trend toward differences in MPA AUC0-8 and MPA concentration at steady-state (μg/mL) between the high EHR group versus the low EHR group (P=.06). MPA EHR was variable. Patients with high MPA EHR had greater abundance of Bacteroides species in stool and higher MPA exposure compared with patients with low MPA EHR. Therefore, Bacteroides may be protective against poor outcomes, such as graft-versus-host disease, in some patients but may increase the risk of MPA adverse effects in others. These data need to be confirmed and studied after oral MMF therapy.

Significant Correlations between p-Cresol Sulfate and Mycophenolic Acid Plasma Concentrations in Adult Kidney Transplant Recipients.

Mycophenolic acid (MPA) is a commonly prescribed life-long immunosuppressant for kidney transplant recipients. The frequently observed large variations in MPA plasma exposure may lead to severe adverse outcomes; therefore, characterizations of contributing factors can potentially improve the precision dosing of MPA. Our group recently reported the potent inhibitory effects of p-cresol (a protein-bound uremic toxin that can be accumulated in kidney transplant patients) on the hepatic metabolism of MPA in human in vitro models. Based on these data, the hypothesis for this clinical investigation was that a direct correlation between p-cresol and MPA plasma exposure should be evident in adult kidney transplant recipients. Using a prospective and observational approach, adult kidney transplant recipients within the first year after transplant on oral mycophenolate mofetil (with tacrolimus ± prednisone) were screened for recruitment. The exclusion criteria were cold ischemia time >30 h, malignancy, pregnancy, severe renal dysfunction (i.e., estimated glomerular filtration rate, eGFR, <10 mL/min/1.73 m2), active graft rejection, or MPA intolerance. Patients' demographic and biochemistry data were collected. Total and free plasma concentrations of MPA, MPA glucuronide (MPAG), and total p-cresol sulfate (the predominant, quantifiable form of p-cresol in the plasma) were quantified using validated assays. Correlational and categorical analyses were performed using GraphPad Prism. Forty patients (11 females) were included: donor type (living/deceased: 20/20), induction regimen (basiliximab/thymoglobulin/basiliximab followed by thymoglobulin: 35/3/2), post-transplant time (74 ± 60 days, mean ± standard deviation), age (53.7 ± 12.4 years), bodyweight (79.8 ± 18.5 kg), eGFR (51.9 ± 18.0 mL/min/1.73 m2), serum albumin (3.6 ± 0.5 g/dL), prednisone dose (18.5 ± 13.2 mg, n = 33), and tacrolimus trough concentration (9.4 ± 2.4 µg/L). Based on Spearman analysis, significant control correlations supporting the validity of our dataset were observed between total MPA trough concentration (C0) and total MPAG C0 (correlation coefficient [R] = 0.39), ratio of total MPAG C0-to-total MPA C0 and post-transplant time (R = -0.56), total MPAG C0 and eGFR (R = -0.35), and p-cresol sulfate concentration and eGFR (R = -0.70). Our primary analysis indicated the novel observation that total MPA C0 (R = 0.39), daily dose-normalized total MPA C0 (R = 0.32), and bodyweight-normalized total MPA C0 (R = 0.32) were significantly correlated with plasma p-cresol sulfate concentrations. Consistently, patients categorized with elevated p-cresol sulfate concentrations (i.e., ≥ median of 3.2 µg/mL) also exhibited increased total MPA C0 (by 57 % vs those below median), daily dose-normalized total MPA C0 (by 89 %), and bodyweight-normalized total MPA C0 (by 62 %). Our secondary analyses with MPA metabolites, unbound concentrations, free fractions, and MPA metabolite ratios supported additional potential interacting mechanisms. We have identified a novel, positive association between p-cresol sulfate exposure and total MPA C0 in adult kidney transplant recipients, which is supported by published mechanistic in vitro data. Our findings confirm a potential role of p-cresol as a significant clinical variable affecting the pharmacokinetics of MPA. These data also provide the justifications for conducting subsequent full-scale pharmacokinetic-pharmacodynamic studies to further characterize the cause-effect relationships of this interaction, which could also rule out potential confounding variables not adequately controlled in this correlational study.

Influence of SLCO1B1 521T&gt;C, UGT2B7 802C&gt;T and IMPDH1 −106G&gt;A Genetic Polymorphisms on Mycophenolic Acid Levels and Adverse Reactions in Chinese Autoimmune Disease Patients

IntroductionMycophenolate mofetil (MMF), a new type of immunosuppressant, has emerged as a frontline agent for treating autoimmune diseases. Mycophenolic acid (MPA) is an active metabolite of MMF. MPA exposure varies greatly among individuals, which may lead to adverse drug reactions such as gastrointestinal side effects, infection, and leukopenia. Genetic factors play an important role in the variation of MPA levels and its side effects. Although many published studies have focused on MMF use in patients after organ transplant, studies that examine the use of MMF in patients with autoimmune diseases are still lacking.MethodsThis study will not only explore the genetic factors affecting MPA levels and adverse reactions but also investigate the relationships between UGT1A9 −118(dT)9/10, UGT1A9 - 1818T>C, UGT2B7 802C>T, SLCO1B1 521T>C, SLCO1B3 334T>G, IMPDH1 −106G>A and MPA trough concentration (MPA C0), along with adverse reactions among Chinese patients with autoimmune diseases. A total of 120 patients with autoimmune diseases were recruited. The MPA trough concentration was detected using the enzyme multiplied immunoassay technique (EMIT). Genotyping was performed using a real-time polymerase chain reaction (PCR) system and validated allelic discrimination assays. Clinical data were collected for the determination of side effects.ResultsSLCO1B1 521T>C demonstrated a significant association with MPA C0/d (p=0.003), in which patients with the CC type showed a higher MPA C0/d than patients with the TT type (p=0.001) or the CT type (p=0.000). No significant differences were found in MPA C0/d among the other SNPs. IMPDH1 −106G>A was found to be significantly related to infections (p=0.006). Subgroup analysis revealed that UGT2B7 802C>T was significantly related to Pneumocystis carinii pneumonia infection (p=0.036), while SLCO1B1 521T>C was associated with anemia (p=0.029).ConclusionFor Chinese autoimmune disease patients, SLCO1B1 521T>C was correlated with MPA C0/d and anemia. IMPDH1 −106G>A was significantly related to infections. UGT2B7 802C>T was significantly related to Pneumocystis carinii pneumonia infection.

Only Modest Effect of Lipids and Albumin on Apparent Mycophenolic Acid Clearance in Pediatric Transplant Recipients – a Retrospective Cohort Study

Background: There is growing evidence for the need of therapeutic drug monitoring (TDM) of the active compound Mycophenolic Acid (MPA) of mycophenolate mofetil therapy for the management of antirejection therapy after pediatric renal transplantation. While there is substantial inter- and intra-patient variability of MPA exposure, the factors affecting its apparent clearance (CL/F) are understudied. The objective of this study was to determine the relationship between MPA CL/F, eGFR, creatinine, Cystatin C, triglycerides, cholesterol and albumin. Material and Methods: We calculated 1004 estimated mass-spectrometry-determined MPA CL/F using trough concentrations from 35 pediatric renal transplant patients. Results: Mean age was 8.7±4.6 years at transplant with a median follow-up of 5.8 years. Each patient had a median of 30 MPA trough concentrations. The median MPA AUC was 53.21 mg*h/L, the median CL/F was 8.66 L/h. Univariate and multivariate analysis revealed significant correlations of CL/F with creatinine, triglycerides, cholesterol and albumin, and very weakly with hemoglobin, whereas cystatin C was unrelated. Especially higher lipid levels and weekly, but significantly, lower albumin augmented CL/F. However, the correlations were not strong enough to predict CL/F. Conclusion: The data presented indicate the necessity for MPA TDM and suggest that dose modifications may apply in the face of low serum albumin and hyperlipidemia.

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.

P1798MYCOPHENOLIC ACID TROUGH CONCENTRATION AND DOSE ARE ASSOCIATED WITH HEMATOLOGIC ABNORMALITIES BUT NOT REJECTION IN KIDNEY TRANSPLANT RECIPIENTS

Abstract Background and Aims Little is known regarding the safe fixed dose of mycophenolic acid (MPA) for preventing biopsy-proven acute rejection (BPAR) in kidney transplant recipients (KTRs). We investigated the correlation of MPA trough concentration (MPA C0) and dose with renal transplant outcomes and adverse events. Method This study included 79 consecutive KTRs who received MPA with tacrolimus (TAC) and corticosteroids. The MPA C0 of all the enrolled KTRs was measured, which was determined monthly by using particle-enhanced turbidimetric inhibition immunoassay for 12 months, and clinical data were collected at each time point. The clinical endpoints included BPAR, any cytopenia, and BK or cytomegalovirus infections. Results No differences in MPA C0 and dose were observed between KTRs with or without BPAR or viral infections under statistically comparable TAC concentrations. MPA C0 was significantly higher in patients with leukopenia (P = 0.021) and anemia (P = 0.002) compared with those without cytopenia. The MPA dose was significantly higher in patients with thrombocytopenia (P = 0.002) compared with those without thrombocytopenia. MPA C0 ≥ 3.5 µg/mL was an independent risk factor for leukopenia (adjusted odds ratio [AOR] 3.80, 95% confidence interval [CI] 1.24–11.64, P = 0.019) and anemia (AOR 5.90, 95% CI 1.27–27.51, P = 0.024). An MPA dose greater than the mean value of 1188.8 mg/day was an independent risk factor for thrombocytopenia (AOR 3.83, 95% CI 1.15–12.78, P = 0.029). However, an MPA dose less than the mean value of 1137.3 mg/day did not increase the risk of BPAR. Conclusion Either a higher MPA C0 or dose was associated with an increased risk of cytopenia, but neither a lower MPA C0 nor dose was associated with BPAR within the first year of transplantation. Hence, a reduced MPA dose with TAC and corticosteroids might be safe in terms of reducing hematologic abnormalities without causing rejection.

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.

Mycophenolic Acid Trough Concentration and Dose Are Associated with Hematologic Abnormalities but Not Rejection in Kidney Transplant Recipients.

BackgroundLittle is known regarding the safe fixed dose of mycophenolic acid (MPA) for preventing biopsy-proven acute rejection (BPAR) in kidney transplant recipients (KTRs). We investigated the correlation of MPA trough concentration (MPA C0) and dose with renal transplant outcomes and adverse events.MethodsThis study included 79 consecutive KTRs who received MPA with tacrolimus (TAC) and corticosteroids. The MPA C0 of all the enrolled KTRs was measured, which was determined monthly by using particle-enhanced turbidimetric inhibition immunoassay for 12 months, and clinical data were collected at each time point. The clinical endpoints included BPAR, any cytopenia, and BK or cytomegalovirus infections.ResultsNo differences in MPA C0 and dose were observed between KTRs with or without BPAR or viral infections under statistically comparable TAC concentrations. MPA C0 was significantly higher in patients with leukopenia (P = 0.021) and anemia (P = 0.002) compared with those without cytopenia. The MPA dose was significantly higher in patients with thrombocytopenia (P = 0.002) compared with those without thrombocytopenia. MPA C0 ≥ 3.5 µg/mL was an independent risk factor for leukopenia (adjusted odds ratio [AOR], 3.80; 95% confidence interval [CI], 1.24–11.64; P = 0.019) and anemia (AOR, 5.90; 95% CI, 1.27–27.51; P = 0.024). An MPA dose greater than the mean value of 1,188.8 mg/day was an independent risk factor for thrombocytopenia (AOR, 3.83; 95% CI, 1.15–12.78; P = 0.029). However, an MPA dose less than the mean value of 1,137.3 mg/day did not increase the risk of BPAR.ConclusionEither a higher MPA C0 or dose is associated with an increased risk of cytopenia, but neither a lower MPA C0 nor dose is associated with BPAR within the first year of transplantation. Hence, a reduced MPA dose with TAC and corticosteroids might be safe in terms of reducing hematologic abnormalities without causing rejection.

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.

Optimizing Mycophenolic Acid Exposure in Kidney Transplant Recipients: Time for Target Concentration Intervention.

The immunosuppressive agent mycophenolate is used extensively in kidney transplantation, yet dosing strategy applied varies markedly from fixed dosing (“one-dose-fits-all”), to mycophenolic acid (MPA) trough concentration monitoring, to dose optimization to an MPA exposure target (as area under the concentration-time curve [MPA AUC0-12]). This relates in part to inconsistent results in prospective trials of concentration-controlled dosing (CCD). In this review, the totality of evidence supporting mycophenolate CCD is examined: pharmacological characteristics, observational data linking exposure to efficacy and toxicities, and randomized controlled trials of CCD, with attention to dose optimization method and exposure achieved. Fixed dosing of mycophenolate consistently leads to underexposure associated with rejection, as well as overexposure associated with toxicities. When CCD is driven by pharmacokinetic calculation to a target concentration (target concentration intervention), MPA exposure is successfully controlled and clinical benefits are seen. There remains a need for consensus on practical aspects of mycophenolate target concentration intervention in contemporary tacrolimus-containing regimens and future research to define maintenance phase exposure targets. However, given ongoing consequences of both overimmunosuppression and underimmunosuppression in kidney transplantation, impacting short- and long-term outcomes, these should be a priority. The imprecise “one-dose-fits-all” approach should be replaced by the clinically proven MPA target concentration strategy.

Investigation of the Association Between Total and Free Plasma and Saliva Mycophenolic Acid Concentrations Following Administration of Enteric-Coated Mycophenolate Sodium in Adult Kidney Transplant Recipients.

Mycophenolic acid (MPA) is commonly used following renal transplant. Saliva MPA concentrations may reflect the pharmacologically active form of MPA in plasma. Therapeutic drug monitoring using saliva is convenient and non-invasive. This study examined the correlation between total and free plasma and saliva MPA concentrations following enteric-coated mycophenolate sodium (EC-MS) administration in renal transplant recipients. Total and free plasma and saliva MPA concentrations were measured simultaneously in 20 adult renal transplant recipients 1-2months' post-transplant. Thirteen samples were taken pre-dose and at specified time points up until 12h post-dose. When considering all time points, correlation between total plasma and saliva MPA was r2 = 0.51 and between free plasma and saliva MPA concentrations r2 = 0.41. The correlation between total plasma MPA area under the concentration-time curve (AUC) or free plasma AUC and saliva MPA AUC was r2 = 0.25 and r2 = 0.13, respectively. The correlation between total plasma MPA AUC and total plasma MPA trough (C0) concentrations was r2 = 0.51, and between total plasma MPA AUC and saliva MPA trough concentrations, r2 = 0.03. Measurement of MPA concentration in saliva cannot currently replace plasma measurement for therapeutic drug monitoring of MPA following EC-MS administration. Additional studies are required to examine the relationship between MPA saliva concentrations and patient outcomes.

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.

Monitoring of Mycophenolic Acid Trough Concentration in Kidney Transplant under Cyclosporine Is Beneficial in Reducing Acute Rejection within 1 Year

Monitoring of Mycophenolic Acid Trough Concentration in Kidney Transplant under Cyclosporine Is Beneficial in Reducing Acute Rejection within 1 Year