Mycophenolic Acid Trough Concentrations Research Articles

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.

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.

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.

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.

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

Development of a Formula to Correct Particle-Enhanced Turbidimetric Inhibition Immunoassay Values so That it More Precisely Reflects High-Performance Liquid Chromatography Values for Mycophenolic Acid.

BackgroundMycophenolic acid (MPA) concentration measured by homogeneous particle-enhanced turbidimetric inhibition immunoassay (PETINA) may be overestimated due to its cross-reactivity with pharmacologically inactive MPA glucuronide (MPAG), as well as other minor metabolites, accumulated with renal function impairment or co-administered cyclosporine A. In contrast, high-performance liquid chromatography (HPLC) is precise because it can exclude the cross-reactivity. In this study, we assumed HPLC values for MPA (HPLC-MPA) as a reference and aimed to develop a formula correcting PETINA values for MPA (PETINA-MPA) to more precisely reflect HPLC-MPA.MethodsMPA trough concentrations were measured both by HPLC-UV and PETINA in 39 samples issued from 39 solid-organ transplant recipients. MPAG concentrations were also measured using HPLC UV assay. We determined the impacts of renal function and coadministered calcineurin inhibitor on concentrations of MPA and MPAG measured by HPLC. Then, we evaluated the difference between PETINA-MPA and HPLC-MPA. Finally, we develop a formula to reflect HPLC-MPA by using multilinear regression analysis.ResultsMPAG concentration was negatively correlated with estimated glomerular filtration rate (eGFR) (R2 = 0.376, P < 0.001), although MPA was not correlated with eGFR. There were no significant differences in MPA or MPAG concentrations per dose between the patients who were co-administered tacrolimus versus cyclosporine A. Finally, we developed the formulas to reflect HPLC-MPA:Formula 1: Estimated MPA concentration = 0.048 + 0.798 × PETINA‐MPAFormula 2: Estimated MPA concentration = − 0.059 + 0.800 × PETINA‐MPA + 0.002 × eGFRHowever, there was no significant improvement in the coefficient of determination with addition of eGFR in the formula, suggesting that HPLC-MPA can be well predicted by only 1 variable, PETINA-MPA.ConclusionsThis study developed a formula so that PETINA-MPA can be corrected to more precisely reflect HPLC-MPA.

Clinical Implication of Mycophenolic Acid Trough Concentration Monitoring in Kidney Transplant Patients on a Tacrolimus Triple Maintenance Regimen: A Single-Center Experience.

BackgroundThis study was designed to analyze the clinical implications of mycophenolic acid trough concentration monitoring.Material/MethodsWe collected data of patients with mycophenolic acid trough concentration monitoring after their first kidney transplant between November 2006 and March 2015 who were prescribed tacrolimus, mycophenolate, and methylprednisolone. Analyses were performed on 3 periods: 1 month, 1 month to 1 year, and after 1 year post-transplantation. To analyze factors related to acute cellular rejection, logistic regression was used for 1 month, while Cox analysis was used during 1 month to 1 year and after 1 year post-transplantation.ResultsIn the 145 patients receiving mycophenolate mofetil, mean tacrolimus trough ≥7.0 ng/mL (OR=0.177, CI=0.060–0.524, p=0.002) and mean mycophenolic acid trough ≥1.7 mg/L (OR=0.190, CI=0.040–0.896, p=0.036) were protective for rejection during 1 month. Mean mycophenolic acid trough ≥1.7 mg/L (HR=0.179, CI=0.040–0.806, p=0.025) and ≥0.7 mg/L (HR=0.142, CI=0.028–0.729, p=0.019) were related to better rejection-free survival during 1 month to 1 year and after 1 year, respectively. In 399 patients receiving enteric-coated mycophenolate sodium, mean tacrolimus trough ≥7.0 ng/mL (OR=0.258, CI=0.131–0.507, p<0.001) and mean mycophenolic acid trough ≥2.1 mg/L (OR=0.507, CI=0.264–0.973, p=0.041) were protective for rejection during 1 month. Mean mycophenolic acid trough ≥1.7 mg/L (HR=0.519, CI=0.289–0.932, p=0.028) and ≥0.7 mg/L (HR=0.208, CI=0.072–0.602, p=0.004) were related to better rejection-free survival during 1 month to 1 year and after 1 year, respectively.ConclusionsMycophenolic acid trough concentration monitoring can be useful in preventing acute cellular rejection in patients receiving tacrolimus, mycophenolate, and methylprednisolone.

A Retrospective Study on Mycophenolic Acid Drug Interactions: Effect of Prednisone, Sirolimus, and Tacrolimus With MPA.

Mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is widely used as an antirejection drug after renal transplantation. There is growing evidence supporting the notion that there is substantial variability in the intra- and interpatient exposure to MPA. Drug interactions involving MPA with tacrolimus, steroids, and sirolimus have been understudied. The objective of this study was to determine the relationship between MPA, steroids, tacrolimus, and sirolimus. MPA trough concentrations from 37 pediatric renal transplant recipients (mean age 7.6 years at transplant) followed for a median follow-up of 7.8 years were analyzed retrospectively and 2131 dose-normalized MPA trough concentrations were evaluated against all known covariates including all concomitant immunosuppressant drug doses and exposure, age, albumin, hematocrit, and estimated glomerular filtration rate (eGFR). Age, hematocrit, and estimated glomerular filtration rate affected the dose-normalized MPA trough concentrations. The authors used appropriate linear regression univariate models and created 5 different multivariate models to examine individual drug-drug interactions (DDIs). Although the authors' findings support the notion that there is a DDI between MMF and both sirolimus and steroids, the sample size was small, and these findings should be confirmed in future studies. The authors found no DDIs between tacrolimus and MMF, the prodrug of MPA. These findings are important because there is a tendency to under-dose MMF early and to overdose late after transplantation. The DDI between sirolimus and MMF has not been described. Although therapeutic drug monitoring of MMF therapy is often not performed, the data presented here indicate a necessity for therapeutic drug monitoring. This is especially true when converting from tacrolimus to sirolimus, as a way to avoid MPA underexposure and organ rejection.

Exposure to Mycophenolate and Fatherhood

BackgroundMycophenolic acid (MPA) is the active immunosuppressive substance in both mycophenolate mofetil and mycophenolate sodium, and it is widely used after organ transplantation. In women, taking MPA is teratogenic and may also influence spermatogenesis. There is a lack of knowledge regarding outcome of pregnancies fathered by men exposed to MPA.MethodsWe compared outcomes in pregnancies fathered by renal transplant men per whether they had been exposed to MPA or not at time of conception. A nationwide population-based retrospective cohort study was performed. Data from the Norwegian Renal Registry with all renal transplanted men alive between January 1, 1995 and December 31, 2015 were included, and relevant outcome data were extracted from the Medical Birth Registry of Norway.ResultsDuring the given time, 230 immunosuppressed renal transplanted men fathered 350 children (155 on MPA/195 not on MPA). There were no significant increased risks of malformation (3.9% vs. 2.6%, P = 0.49) in MPA exposed versus unexposed cohorts of children. The average dose (±SD) of mycophenolate was 1.42 ± 0.3 g/day and the individual median MPA trough concentration in the time period of anticipated conception and pregnancy was 2.8 ± 1.6 mg/L. Birth weight was similar in exposed and unexposed cohorts of children; 3381 ± 681 g vs. 3429 ± 714 g (P = 0.53).ConclusionsPaternal exposure to MPA did not increase the risk of adverse birth outcomes in children fathered by male kidney transplanted patients. These results are reassuring and support the continuation of paternal MPA treatment before, during, and after conception.

Mycophenolic Acid Metabolites Acyl-Glucuronide and Glucoside Affect the Occurrence of Infectious Complications and Bone Marrow Dysfunction in Liver Transplant Recipients.

BACKGROUND Mycophenolic acid (MPA) prodrugs are anti-proliferative immunosuppressive agents commonly used after organ transplantation. Although they are generally well tolerated by patients, adverse effects may occur. It is postulated that MPA metabolites could also contribute to these adverse effects. MATERIAL AND METHODS The objective of this study was the assessment of concentrations of total MPA and its metabolites, phenyl glucuronide (MPAG), acyl glucuronide (AcMPAG) and glucoside (GluMPA), using liquid chromatography combined with mass spectrometry (LC/MS/MS) in two groups: kidney transplant recipients and liver transplant patients. Associations of MPA and its metabolites with adverse effects were analyzed. RESULTS The study group consisted of 211 recipients of liver or kidney transplants who received immunosuppressive therapy, including MPA prodrugs. Multivariant analysis showed a positive influence of MPA on gastroenterotoxicity in kidney transplant recipients. In liver patients, gastroenterotoxicity was associated with lower MPAG concentrations. A positive influence of AcMPAG on bacterial infections in liver transplant patients was observed. In liver transplant recipients, a positive influence of MPA and a negative influence of GluMPA levels on the PLT count were revealed. MPA and its metabolites did not influence the hemoglobin levels in both groups. There were no significant relationships among MPA, its metabolites and WBC counts. CONCLUSIONS In kidney transplant recipients, total MPA trough concentration is associated with gastroenterotoxicity and its monitoring could have important role in management of gastrointestinal complications. The quantification of AcMPAG in liver recipients receiving MPA may be helpful in avoiding bacterial infections. GluMPA seems to have a toxic effect on thrombopoiesis.

Short-term Pharmacokinetic Study of Mycophenolate Mofetil in Neonatal Swine

BackgroundMycophenolate mofetil (MMF) is an effective immunosuppressive agent that has been frequently used in laboratory animals including swine; however, the pharmacokinetic properties of MMF in swine have not been studied. This short-term study was designed to evaluate the feasibility and the pharmacokinetic profiles of MMF therapy in neonatal swine. Materials and MethodsTwelve neonatal pigs were randomized into four groups including one control and three treated groups with oral MMF administered at 0.5, 1, and 2 g/m2/d for 4 days, divided by 2 half-doses at 9:00 and 17:00 (except day 4 during which MMF was not administered at 17:00). Blood samples were collected at 9:00 on days 0, 2, 3 and 4 for complete blood count and hepatic/renal function examination; the trough concentration of plasma mycophenolic acid (MPA) was also determined. On days 2 and 4, blood was collected to determine the area under the curve (AUC) of plasma MPA concentration. Animal body-weight growth and manifestations of MMF side-effects such as anorexia, vomiting, and diarrhea were also observed. ResultsMMF has no acute hepatic/renal toxicity in newborn pigs; however, less body-weight growth was observed in treated groups. In the control group, a spontaneous increase of lymphocyte count was observed; in contrast, MMF therapy with doses of 1 and 2 g/m2/d reduced both lymphocyte and monocyte counts of piglets. Oral MMF had high bioavailability in neonatal swine. MPA-AUC0-12h of doses 0.5, 1, and 2 g/m2/d was 22.00 ± 3.32, 57.57 ± 34.30, and 140.00 ± 19.70 μg × h/mL, respectively. Neither MPA trough concentration (MPA-C0), nor MPA maximum concentration (MPA-Cmax) or MPA-AUC0-6h had high correlation with MMF-dose. For surveillance of MPA exposure, MPA-C0 had significant correlation with MPA-AUC0-12h (Spearman's ρ = 0.933, AUC0-12h = 17.882 × C0 + 14.479, r2 = 0.966). ConclusionTo reach adequate drug exposure and to reduce dose-dependent side effects, an MMF dose of 1 g/m2/d is recommended to be used as an initial dose for immunosuppressive therapy in piglets, and MPA-C0 monitoring is the most practical strategy for experimental transplantation study.

How Accurate and Precise Are Limited Sampling Strategies in Estimating Exposure to Mycophenolic Acid in People with Autoimmune Disease?

Mycophenolic acid (MPA) is a potent immunosuppressant agent, which is increasingly being used in the treatment of patients with various autoimmune diseases. Dosing to achieve a specific target MPA area under the concentration-time curve from 0 to 12 h post-dose (AUC12) is likely to lead to better treatment outcomes in patients with autoimmune disease than a standard fixed-dose strategy. This review summarizes the available published data around concentration monitoring strategies for MPA in patients with autoimmune disease and examines the accuracy and precision of methods reported to date using limited concentration-time points to estimate MPA AUC12. A total of 13 studies were identified that assessed the correlation between single time points and MPA AUC12 and/or examined the predictive performance of limited sampling strategies in estimating MPA AUC12. The majority of studies investigated mycophenolate mofetil (MMF) rather than the enteric-coated mycophenolate sodium (EC-MPS) formulation of MPA. Correlations between MPA trough concentrations and MPA AUC12 estimated by full concentration-time profiling ranged from 0.13 to 0.94 across ten studies, with the highest associations (r (2) = 0.90-0.94) observed in lupus nephritis patients. Correlations were generally higher in autoimmune disease patients compared with renal allograft recipients and higher after MMF compared with EC-MPS intake. Four studies investigated use of a limited sampling strategy to predict MPA AUC12 determined by full concentration-time profiling. Three studies used a limited sampling strategy consisting of a maximum combination of three sampling time points with the latest sample drawn 3-6 h after MMF intake, whereas the remaining study tested all combinations of sampling times. MPA AUC12 was best predicted when three samples were taken at pre-dose and at 1 and 3 h post-dose with a mean bias and imprecision of 0.8 and 22.6 % for multiple linear regression analysis and of -5.5 and 23.0 % for maximum a posteriori (MAP) Bayesian analysis. Although mean bias was less when data were analysed using multiple linear regression, MAP Bayesian analysis is preferable because of its flexibility with respect to sample timing. Estimation of MPA AUC12 following EC-MPS administration using a limited sampling strategy with samples drawn within 3 h post-dose resulted in biased and imprecise results, likely due to a longer time to reach a peak MPA concentration (t max) with this formulation and more variable pharmacokinetic profiles. Inclusion of later sampling time points that capture enterohepatic recirculation and t max improved the predictive performance of strategies to predict EC-MPS exposure. Given the considerable pharmacokinetic variability associated with mycophenolate therapy, limited sampling strategies may potentially help in individualizing patient dosing. However, a compromise needs to be made between the predictive performance of the strategy and its clinical feasibility. An opportunity exists to combine research efforts globally to create an open-source database for MPA (AUC, concentrations and outcomes) that can be used and prospectively evaluated for AUC target-controlled dosing of MPA in autoimmune diseases.

A Pilot Study Of Continuous Infusion Mycophenolate Mofetil For Graft Versus Host Disease Prophylaxis

Mycophenolate mofetil (MMF), an ester prodrug of mycophenolic acid (MPA) has been used successfully for graft-versus-host disease (GVHD) prophylaxis. Most MMF dosing regimens and pharmacokinetic (PK) parameters have been established in solid organ transplant recipients. Empiric fixed-dose-escalation strategies have failed to achieve target MPA exposure, especially in the early period following conditioning therapy. We hypothesized that a PK-based dosing approach using a novel continuous infusion (CI) method of MMF will be able to achieve and maintain target MPA exposure. The objective of this study was to evaluate the safety and feasibility of this MMF dosing approach in pediatric BMT recipients. Fifteen patients were enrolled in the study. The median age at transplant was 8.4 years (0.9 – 21.5); eight were female and seven were male. Thirteen patients were transplanted for hematologic malignancies and two patients for nonmalignant diseases. Stem cell sources included matched-sibling bone marrow in seven, 10/10 allele matched donor bone marrow in four, and unrelated cord blood in four cases. All patients received a myeloablative conditioning regimen with either cyclophosphamide-TBI (n=8) or busulfan-cyclophosphamide (n=7). In addition, of eight unrelated donor transplants, six patients received equine ATG and two received fludarabine. All patients received cyclosporine A and MMF for GVHD prophylaxis. Intravenous (IV) cyclosporine was initiated on day -2 as a continuous infusion (target blood level: 160 to 250 ng/mL). IV MMF was started on day “0” in a dose of 15 mg/kg every 8 hours. After a minimum of five doses, serial blood samples were collected within one dosing interval for the 1st PK analysis. Using these results, MMF was converted from intermittent IV to CI administration to target total MPA AUC0-24 of 40-80 mcg/mL/hr. MMF dose was adjusted to maintain a total MPA steady-state concentration (Css) of 1.7-3.3 mcg/mL. CI MMF was converted to every-8-hour oral dosing when patients were tolerating oral medications. A 2nd PK study was performed after a minimum of five oral doses, and dose adjustments were made to maintain a total MPA trough concentration (Ctrough) of 1-3.5 mcg/mL. MMF was continued until day 42, and in the absence of acute GVHD, tapered off over 8 weeks. On the initial 15 mg/kg q8 IV MMF dose schedule, MPA half-life was 1.3±1.3 hrs and AUC0-24 was 44.3±60.3 mg* hr/L. During the CI schedule, MMF dose was 44±16 mg/kg/day and MPA AUC0-24 38.4±20.7 mg* hr/L, and thirteen of fifteen (87%) patients achieved MPA Css within target of 1.7–3.3 mcg/mL. On conversion to oral route, median MMF dose was 45±19mg/kg/day, MPA half-life 1.95±2.3 hrs and AUC0-24 38.3±16.0 mg* hr/L. MPA clearance was 17±14 ml/min/kg. Higher steady state MPA concentrations were achieved with CI method (Css 1.6 ±0.9 mcg/mL) compared with intermittent IV or oral dosing (Ctrough 0.7±0.9 mcg/mL). All patients achieved neutrophil engraftment at 13 ± 11 days post-transplant, and platelet engraftment at 45 ± 72 days post-transplant. Seven out of 15 patients (47%) developed stage I-IV acute GVHD. Three patients had stage III-IV aGVHD (20%); they were steroid-refractory but went into remission with additional therapy. For 11 patients with a minimum of one year follow-up post-transplant, one (9%) developed “overlap” chronic GVHD. MMF was discontinued without weaning in four patients: in three of them due to concern of delay in blood count recovery and all of them achieved hematopoietic engraftment, and in one patient with severe aGVHD due to potential concern for MMF gut toxicity. One patient with severe congenital neutropenia developed autologous hematopoietic recovery by day 52. One patient with ALL died of relapse 150 days after transplant. With a median follow-up of 23 months (range 100 days to 3.6 y), 14 out of 15 patients are alive, and one-year event-free survival and overall survival are 83% and 92% respectively. In conclusion, we show that continuous infusion of MMF is feasible and well-tolerated. In this pilot PK study, we observed no toxic deaths, excellent engraftment, and low rates of grade III-IV aGVHD and cGVHD. The PK studies showed significantly lower half-life and higher drug clearance in pediatric BMT recipients compared to stable pediatric renal transplant patients. This regimen deserves further validation in a larger cohort of pediatric patients undergoing myeloablative transplantation. Disclosures: Off Label Use: Use of Mycophenolate Mofetil for Graft versus Host Disease Prophylaxis.

Evaluation of Mycophenolic Acid Exposure Using a Limited Sampling Strategy in Renal Transplant Recipients

Background/Aims: While there are drug exposure equation models based on limited sampling times for mycophenolate mofetil (MMF), there are few for enteric-coated mycophenolate sodium (EC-MPS), and none that studied Chinese individuals. Our objective is to generate the optimal model equations for estimation of the mycophenolic acid (MPA) area under the plasma concentration-time curve from 0 to 12 h (MPA-AUC_0-12h) with a limited sampling strategy (LSS) for renal transplant recipients receiving EC-MPS. Methods: The pharmacokinetics in 31 Chinese renal allograft recipients treated with EC-MPS in combination with tacrolimus and steroids were determined. The model equations were generated by multiple stepwise regression analysis for estimation of the MPA-AUC. Results: A total of 31 patients with an average age and weight of 37.58 ± 10.9 years and 60.9 ± 10.7 kg, respectively, were included. Mean serum creatinine and glomerular filtration rate were 112.2 ± 17.7 μmol/l and 65.6 ± 14.6 ml/min, respectively. The mean values of AUC_0-12h, pre-dose MPA trough concentration (C₀), maximum concentrations (C_max), and time to reach C_max (T_max) were 61.17 ± 26.39 mg·h/l (range 22.9-123.0 mg·h/l), 4.98 ± 4.65 mg/l (range 0.13-20.04 mg/l), 17.54 ± 10.67 mg/l (range 4.08-42.36 mg/l), and 5.0 ± 2.6 h (range 1.0-10.5 h), respectively. The best predictive equation for estimation of MPA-AUC_0-12h was -3.63 + 8.35 × C₄ + 17.04 × C₇ + 13.74 × C₁₂ (r² = 0.7491), prediction bias (PE%) was 20.9 ± 20.37, and prediction precision (APE%) was 3.66 ± 29.20. Conclusions: This model provides an effective approach for estimation of full MPA-AUC_0-12h in Chinese adult renal allograft recipients treated with EC-MPS and tacrolimus.

Sequential maintenance therapy with cyclosporin A and mycophenolate mofetil for sustained remission of childhood steroid-resistant nephrotic syndrome

There is currently no established standard for maintenance therapy of steroid-resistant nephrotic syndrome (SRNS). We report the long-term clinical course, medication, pharmacokinetic data, and renal function of 23 children with primary, non-familial SRNS with focal segmental glomerulosclerosis (FSGS). To achieve initial remission, patients were treated with high-dose intravenous (i. v.) methylprednisolone and oral cyclosporin A (CsA). Maintenance therapy included transient alternate day oral prednisolone, CsA and angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers. In 18 patients, mycophenolate mofetil (MMF) (adjusted to achieve blood mycophenolic acid trough concentrations > 2 μg/mL) was sequentially added, and 16 patients were converted to MMF monotherapy. During a mean follow-up time of 7.0 years (1.7-16.5 years; cumulative observation time 161 patient-years), sustained remission could be achieved in all patients. Five of 23 patients (21%) experienced 10 relapses; all responded to relapse therapy. Maintenance therapy could be permanently discontinued in seven patients (30%). After conversion from CsA to MMF, renal function improved significantly; the eGFR at last follow-up was 137 (range 106-198) mL/min × 1.73 m(2). The mean number of anti-hypertensive drugs decreased from 1.86 per patient after initial remission to 0.57 on MMF monotherapy (P < 0.002). The data of this uncontrolled retrospective study indicate that in children with SRNS/FSGS achieving initial remission, a sequential steroid-free therapy consisting of a combination of CsA and MMF followed by MMF alone (with the addition of ACE inhibitors and angiotensin receptor blockers), can provide sustained long-term remission, preservation of renal function and better control of blood pressure.

Pharmacokinetic Drug Interaction of Mycophenolate With Co-Amoxiclav in Renal Transplant Patients

Pharmacokinetic Drug Interaction of Mycophenolate With Co-Amoxiclav in Renal Transplant Patients

Effects of uridine diphosphate glucuronosyltransferase 2B7 and 1A7 pharmacogenomics and patient clinical parameters on steady-state mycophenolic acid pharmacokinetics in glomerulonephritis

The role of pharmacogenomics, clinical and demographic parameters in pharmacokinetic predictions was evaluated in patients receiving mycophenolic acid (MPA). A cohort study design of patients with glomerulonephritis secondary to lupus nephritis and anti-neutrophil cytoplasmic antibody (ANCA) vasculitis was employed. Forty-six patients with lupus nephritis and ANCA vasculitis who were receiving MPA were recruited from the nephrology clinic. The study assessed the relative single and combined roles of genomic, clinical, and demographic characteristics on pharmacokinetic parameters using general linear models. The study focused on polymorphisms in UGT1A7, UGT2B7, and ABCB1/MDR1; all of which have limited data available concerning MPA pharmacokinetics. All patients had pharmacokinetic assessments for MPA and glucuronide metabolites (MPAG, AcMPAG). Genotyping was performed for known variants of UGTs (UGT1A9, UGT1A7, UGT2B7), and multidrug resistance protein (ABCB1/MDR1), involved in MPA disposition. Analyses included univariate and multivariate linear modeling. In univariate analyses, UGT2B7 heterozygosity (coefficient 0.3508; R (2)=0.0873) and UGT1A7 heterozygosity (coefficient 0.3778; R (2)=0.0966) predicted increased apparent oral clearance of MPA. UGT1A7 heterozygosity (coefficient -0.4647; R (2) 0.0897) predicted lower MPA trough concentrations. In multivariate assessments, higher urinary protein excretion, lower serum creatinine, and increased weight predicted greater apparent oral clearance of MPA (p < 0.0001). White race and higher serum creatinine predicted higher MPA trough concentrations (p < 0.0001). Higher exposure to MPA was predicted by decreased urinary protein excretion and increased serum creatinine. Clinical and demographic parameters were 2-4 times more important in MPA disposition than genotypes and explained 30-40% of the pharmacokinetic parameters.

Higher Mycophenolate Dose Requirements in Children Undergoing Hematopoietic Cell Transplant (HCT)

Little is known about dosing of mycophenolate mofetil in pediatric hematopoietic cell transplant recipients; therefore, dosing strategies using other settings have been extended to this population. The authors studied pharmacokinetics in 19 children (median 17 months) undergoing myeloablative hematopoietic cell transplant and receiving prophylactic mycophenolate and cyclosporine. All subjects except 2 received mycophenolate 15 mg/kg intravenously every 8 hours. The median (range) total mycophenolic acid area under the concentration-time curve (AUC)(0-8) was 12.6 mcg.h/mL (4.9-49.2), and unbound mycophenolic acid AUC(0-8) was 0.274 mcg.h/mL (0.037-1.4). Total and unbound mycophenolic acid trough concentrations were 0.27 (0.03-2.9) and 0.005 (0-0.034) mcg/mL, respectively. Mycophenolic acid trough concentrations were not good surrogates for overall exposure (AUC(0-8)), r(2) < or = 0.55. Mycophenolate dose requirements are higher in pediatric hematopoietic cell transplant recipients relative to pediatric organ transplant recipients. Children undergoing hematopoietic cell transplant should receive a mycophenolate mofetil dose of at least 15 mg/kg intravenously every 8 hours when used in combination with cyclosporine to achieve systemic concentrations near those proposed to be therapeutic in the adult hematopoietic cell transplant population.