Mycophenolic Acid Plasma Concentrations Research Articles

Evaluation of mycophenolic acid exposure in a patient with immune-related hepatotoxicity caused by nivolumab and ipilimumab therapy for malignant melanoma: a case report.

Guidelines such as the National Comprehensive Cancer Network recommend mycophenolate mofetil (MMF) for the treatment of severe steroid-refractory immune-related hepatotoxicity. Mycophenolic acid (MPA) is an active form of MMF that suppresses T- and B-lymphocyte proliferation and immune-related adverse events caused by immune checkpoint inhibitors. MPA has a narrow therapeutic range (37-70µg·h/mL) and overexposure increases the risk of leukopenia in transplantation. However, the optimal use of MMF in oncology has not yet been established; thus, monitoring plasma MPA concentrations is necessary to avoid excessive immunosuppression in oncology practice. We evaluated plasma MPA concentration in a 75-year-old man with immune-related hepatotoxicity following nivolumab and ipilimumab combination therapy for malignant melanoma. The patient developed severe hepatotoxicity after immunotherapy, and immunosuppressant therapy with corticosteroids was initiated. The patient then developed steroid-refractory immune-related hepatotoxicity; therefore, MMF (1,000mg twice daily) was co-administered. Seven days after the administration of MMF, the plasma MPA concentration was measured using an enzyme multiplied immunoassay technique. The area under the plasma concentration-time curve for MPA from 0 to 12h was 41.0µg·h/mL, and the same dose of MMF was continued. Grade 2 lymphocytopenia, which could be attributed to MMF, was observed during the administration period. Unfortunately, the patient was infected with SARS-CoV-2 and died from respiratory failure. Our patient did not exceed the upper limit of MPA levels as an index of the onset of side effects of kidney transplantation and achieved rapid improvement in liver function. Prompt initiation of MMF after assessment of the steroid effect leads to adequate MPA exposure. Therapeutic drug monitoring should be considered when MMF is administered, to avoid overexposure.

The Effects of Mycophenolate Mofetil and Cyclosporine with Concomitant Posaconazole Tablets in the Early Stage of Allogeneic Hematopoietic Stem Cell Transplantation

Background： Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) mainly applied the “Beijing regimen”(cyclosporine + methotrexate + mycophenolate mofetil（MMF）). This approach significantly reduces the risk of graft-versus-host disease (GVHD), increases the risk of infection. Posaconazole can significantly reduce the incidence of invasive fungal disease (IFD) during the immunosuppressive phase. Cyclosporine and posaconazole have significant drug interactions, with MMF also have drug interactions. However, there is limited research about drug interactions of simultaneous three-drug combination. Objective： Explore the effects of MMF and cyclosporine with concomitant posaconazole in allo-HSCT patients within 30 days and the breakthrough incidence of IFD within 100 days post-transplantation. Method: A single-arm, open-label, prospective trial was conducted to evaluate posaconazole tablet (300 mg q12h oral d1,300 mg/d) as secondary antifungal prophylaxis in allo-HSCT patients (18-65 years old) with previous proven or probable IFD (ChiCTR2200059472). Posaconazole and cyclosporine were started when conditioning began, while MMF was used one day before infusion of stem cell for one month with fixed dose of 2 g/d. The plasma concentration of posaconazole and mycophenolic acid (MPA) which is the active ingredient of MMF, were monitored weekly, cyclosporine was monitored twice one week until 30 days post-transplantation. Results: Thirty patients from July 2022 to March 2023 were enrolled in the trial, included 16 males and 14 females, acute myelogenous leukemia 22, acute lymphoblastic leukemia 2, myelodysplastic syndrome 2, aplastic anemia 4. All patients underwent haploidentical HSCT. All patients had history of IFD(5 proven IFD, 13 probable IFD and 12 possible IFD). At week1, 2, 3 and 4 after conditioning, The mean plasma concentrations of posaconazole were 0.47±0.29ug/ml, 0.66±0.32ug/ml,0.72±0.40ug/ml and 0.91±0.32ug/ml（Figure 1）. The mean plasma concentrations of cyclosporine were 138.20±35.33ng/ml, 190.61±48.07ng/ml,245.46±37.31ng/ml and 253.56±45.19ng/ml（Figure 2）.The mean plasma concentrations of MPA at week 2, 3 and 4 were 0.35±0.15mg/L, 0.89±0.36mg/L and 1.18±0.58mg/L (Figure 3). After week 1, concentration of cyclosporine of 13 cases was below 150ng/ml and the dosage was increased by 25% of the original dose, at week 4, concentration of cyclosporine of 9 cases was above 250ng/ml and the dosage was decreased by 25%. After posaconazole reached steady state concentrations at week 2, while cyclosporine reached target concentrations after the dose increase, MPA did not reach target concentrations at week 2. The concentrations of MPA significant increase without changing the MMF dose and reached target concentrations at week 3 simultaneous three-drug combination. Cyclosporine concentrations increased significantly at week 4 with stable concentrations of MPA and posaconazole, and 30% of patients required dose reduction of cyclosporine. Only one patient was diagnosed as aspergillus fumigatus pneumonia through NGS of pulmonary alveolar lavage fluid. The breakthrough incidence of IFD was 3.33%. Conclusion: Different times of administration lead to different times of interaction among the three drugs. The combination of cyclosporine and MMF leads to decrease in MPA concentrations, but the concentration of MPA can rapidly increase when combined with posaconazole. When target concentration of MPA is not reached in the first week, it is recommended to suspend dose modification and TDM in the second week. However, the accumulation of cyclosporine was significant in the fourth week, and it was recommended that cyclosporine should be monitored and adjusted within three weeks after the three drugs were combined. The cumulative breakthrough incidence of 3.33% is lower than reported in literaturesuggesting that posaconazole appears to be effective for secondary prophylaxis of IFD after allo-HSCT.

Evaluation of Plasma Concentrations of Mycophenolic Acid in Renal Transplant Patients Using LM1010 High-performance Liquid Chromatography

Plasma concentrations of mycophenolic acid (MPA), an immunosuppressive agent, have been measured in clinical settings using immunoassay methods or HPLC. However, immunoassay methods show cross-reactivity with metabolites of MPA glucuronide. Recently, the LM1010 high-performance liquid chromatography instrument was approved as a new general medical device. In this study, we compared the results of MPA plasma concentrations analyzed using the LM1010 method and the previously described HPLC method. Plasma samples obtained from 100 renal transplant patients (32 women and 68 men) were evaluated using both HPLC instruments. Deming regression analyses showed a very high correlation between the two instruments, with a slope of 0.9892 and an intercept of 0.0235 µg/mL (r2=0.982). Bland-Altman analysis showed an average of -0.0012 µg/mL between the LM1010 method and the previously described HPLC method. For the LM1010 method, the total run time for MPA analysis was 7 min, and the analytical time was short; however, the extraction recovery when using a spin column was extremely low for frozen plasma samples stored at -20°C for 1 month, and the volume required for the assay (150 µL) could not be collected. Thus, for the LM1010 method, analysis using fresh plasma samples was optimal. Overall, our findings showed that the LM1010 method was a rapid, accurate HPLC assay for MPA analysis and could be used in clinical practice for routine monitoring of MPA in fresh plasma samples.

Impact of carbapenem antibiotics on mycophenolate mofetil in hematopoietic stem cell transplant patients with interruption of the enterohepatic recycling: a retrospective study.

Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is widely used in the prophylaxis for graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation (HSCT). MPA undergoes enterohepatic recycling (EHR). Oral antibiotics can affect MPA concentration by reducing intestinal flora-mediated EHR. However, the effect of intravenous antibiotics on MPA concentration is not clear, especially in patients whose EHR is already interrupted. This study was conducted to determine whether intravenous carbapenem antibiotics (CBP) influence the pre-dose plasma concentration (C0) of MPA in HSCT patients when the EHR of MPA is interrupted by cyclosporine and gut decontamination. The HSCT patients who received immunosuppressive therapy with MMF and cyclosporine, as well as treatment with CBP were screened as potential candidates. Patients who lacked MPA C0 measurements before or during CBP use, had combination therapy of rifampin with MMF, or switched from IV to oral MMF were excluded. The liver/renal function, demographic information, albumin/cyclosporine concentration, MPA C0 and medication information were collected. The changes in the MPA C0 before and during CBP use were evaluated, and the influence of related clinical factors was also estimated. CBP resulted in a significant reduction in the MPA C0 from 0.65±0.33 to 0.43±0.30 µg/mL. Linear regression analysis indicated a weak correlation between the dose-normalized C0 of MPA and the dosage of CBP during CBP use (r2=0.129, P=0.009). Univariate and multivariate analysis confirmed that the MPA C0 had no relevance to rifaximin administration (P=0.249-0.700), demographics (P=0.118-0.599), fluctuation of plasma albumin (ALB, P=0.943 and 0.609) and cyclosporine concentrations (P=0.647 and 0.112), or liver and renal functions (P=0.078-0.887) no matter whether the CBP were used. However, compared with the non-gut decontamination group, larger interindividual variabilities and smaller decreases in MPA C0 (6.60% vs. 41.73%) during CBP therapy were seen in the gut decontamination group, although it was a nonsignificant trend. CBP decreased the MPA C0 in Chinese HSCT patients even when MMF is used in combination with cyclosporine and rifaximin. If antibiotics must be used, and CBP in particular, therapeutic drug monitoring should be performed to ensure adequate exposure.

1694. Coadministration of Rezafungin Does Not Impact the Pharmacokinetics of Cyclosporine, Ibrutinib, Mycophenolate Mofetil, or Venetoclax

Abstract Background Rezafungin (RZF) is a novel echinocandin antifungal (Figure 1) in development for treatment of candidemia and invasive candidiasis, and for prevention of invasive fungal diseases caused by Candida, Aspergilllus, and Pneumocystis (Figure 2). Vulnerable patient populations may receive antifungal prophylaxis with risks of drug-drug interactions (DDIs) that can alter the pharmacokinetics (PK) of immunosuppressive or anticancer agents. This study was conducted to evaluate the effect of RZF on cyclosporine (CY), mycophenolate mofetil (MM), venetoclax (VX), and ibrutinib (IB). Figure 1.Structure of RezafunginFigure 2.Rezafungin Phase 3 Program Methods A Phase 1, open-label study of 32 healthy inpatients (16 males [Group 1], 16 females [Group 2]) was conducted to assess DDIs between RZF (as perpetrator) and CY 200 mg, MM 500 mg (males only), IB 280 mg, or VX 50 mg (females only). Each was given alone and w/ IV RZF (1 h infusion; 400 mg followed by once-weekly 200 mg) with a suitable washout period between dosing (Figure 3). Validated LC-MS/MS methodology was used to determine plasma concentrations of mycophenolic acid, IB, VX and CY. Figure 3.Open-Label, Phase 1, DDI Study Design Results The PK of all 4 drugs were similar w/ and w/o RZF. Comparison of the exposure (AUC and Cmax) of the drugs given alone or w/ RZF is presented in Table 1. There were no clinically meaningful changes in exposure. Overall, all study drugs were well tolerated. Ten subjects (29.4%) experienced adverse events (AEs) following the administration of the substrate drugs alone and 15 subjects (46.9%) experienced AEs for the substrate drugs w/RZF. There were no deaths or serious adverse events. The most commonly reported AEs were headache and nausea. The majority of AEs were of mild intensity. Two subjects had one severe AE each (abdominal pain related to both RZF and VX and esophagitis related to CY). No trends in safety laboratory results were identified. Table 1.Summary of Statistical Comparisons of Cyclosporine, Mycophenolic Acid, Ibrutinib and Venetoclax Pharmacokinetic Parameters Following Administration of Cylosporine (200 mg), Mycophenolate Mofetil (500 mg), Ibrutinib (280 mg), and Venetoclax (50 mg) alone and in Combination with Rezafungin Conclusion Once weekly IV administration of RZF w/ single doses of CY, IB, MM and VX did not result in any clinically meaningful change in the exposure of the concomitant medications. No dose adjustments of CY, MM, IB, or VX are expected to be necessary when given in combination w/ RZF. The administration of RZF 400 mg followed by 2 once weekly doses of 200 mg, coadministered w/ CY, IB, and MM or VX, in healthy subjects was considered generally well-tolerated with an acceptable safety profile. Disclosures Shawn Flanagan, PhD, Cidara Therapeutics: Employee|Cidara Therapeutics: Stocks/Bonds Taylor Sandison, MD, MPH, Cidara Therapeutics: Employee|Cidara Therapeutics: Stocks/Bonds.

Estimation of Mycophenolic Acid Exposure in Chinese Renal Transplant Patients by a Joint Deep Learning Model.

To predict mycophenolic acid (MPA) exposure in renal transplant recipients using a deep learning model based on a convolutional neural network with bilateral long short-term memory and attention methods. A total of 172 Chinese renal transplant patients were enrolled in this study. The patients were divided into a training group (n = 138, Ruijin Hospital) and a validation group (n = 34, Zhongshan Hospital). Fourteen days after renal transplantation, rich blood samples were collected 0-12 hours after MPA administration. The plasma concentration of total MPA was measured using an enzyme-multiplied immunoassay technique. A limited sampling strategy based on a convolutional neural network-long short-term memory with attention (CALS) model for the prediction of the area under the concentration curve (AUC) of MPA was established. The established model was verified using the data from the validation group. The model performance was compared with that obtained from multiple linear regression (MLR) and maximum a posteriori (MAP) methods. The MPA AUC 0-12 of the training and validation groups was 54.28 ± 18.42 and 41.25 ± 14.53 µg·ml -1 ·h, respectively. MPA plasma concentration after 2 (C 2 ), 6 (C 6 ), and 8 (C 8 ) hours of administration was the most significant factor for MPA AUC 0-12 . The predictive performance of AUC 0-12 estimated using the CALS model of the validation group was better than the MLR and MAP methods in previous studies (r 2 = 0.71, mean prediction error = 4.79, and mean absolute prediction error = 14.60). The CALS model established in this study was reliable for predicting MPA AUC 0-12 in Chinese renal transplant patients administered mycophenolate mofetil and enteric-coated mycophenolic acid sodium and may have good generalization ability for application in other data sets.

Population Pharmacokinetics of Enteric-Coated Mycophenolate Sodium in Children after Renal Transplantation and Initial Dosage Recommendation Based on Body Surface Area.

Objective Enteric-coated mycophenolate sodium (EC-MPS) is widely used in renal transplant recipients. There is a lack of study on the pharmacokinetics of this drug in children. This study is aimed at developing a population pharmacokinetic model of mycophenolic acid in children who were treated with EC-MPS after renal transplantation and to recommend initial dosage. Methods Pediatric patients who had undergone renal transplantation and received EC-MPS were included. Data on demographic characteristics, biochemical tests, blood routine examinations, mycophenolic acid plasma concentrations, dosing amount and frequency of EC-MPS, and coadministered medications were retrospective collected from June 2018 to August 2019. Nonlinear mixed effect modeling methods were adopted to develop a population pharmacokinetic model with the data above. Additional data from September 2019 to July 2020 were used to validate the model. Simulations under different dosage regimen were conducted to evaluate the percentage of target attainment (PTA, AUC0-12h 30–60 mg·h/L). Results A total of 96 pediatric patients aged at 13.3 (range 4.3–18.0) years were included in the modeling group. Data from 32 patients aged at 13.0 (range 3.6–18.3) years were used to validate the model. A one-compartment model with a double extravascular absorption was developed. Body surface area (BSA) was added as a covariate. Simulations showed that for different dosing regimens, the highest percentage of target attainment is around 50%. The best dosing regimen is 180 mg every 48 hours for patients with BSA of 0.22–0.46 m2, 180 mg every 24 hours with BSA of 0.47–0.67 m2, 180 mg every 24 hours with BSA of 0.68–0.96 m2, 360 mg every 24 hours with BSA of 0.97–1.18 m2, 540 mg every 24 hours with BSA of 1.19–1.58 m2, and 360 mg every 12 hours with BSA of 1.59–2.03 m2. Conclusion BSA could affect the area under curve of mycophenolic acid with the administration of EC-MPS. Considering the inflexibility of the dosage form, future development of smaller amount per tablet suitable for younger children with BSA < 1.19 m2 is warranted.

Noncompartmental pharmacokinetics of three intravenous mycophenolate mofetil concentrations in healthy Standardbred mares.

Mycophenolate mofetil (MMF) is the prodrug of mycophenolic acid (MPA) which acts as an immunosuppressive agent. During the biotransformation of MMF to MPA, additional metabolites including MPA phenol glucuronide (MPAG), MPA acyl glucuronide (AcMPAG) and MPA phenol glucoside (MPG) are formed. To define the noncompartmental pharmacokinetic (PK) parameters of three single doses of intravenous (i.v.) MMF and its downstream metabolites in healthy horses. Six healthy Standardbred mares. Generic MMF (Par Pharmaceuticals; Chestnut Ridge, NY, USA) was reconstituted and administered as a single i.v. bolus at 1.0 mg/kg, 5.0 mg/kg and 10.0 mg/kg with an eight day washout between treatments. Blood samples were collected immediately before MMF administration and over 24 h. A liquid chromatography-tandem mass spectrometry assay was developed following FDA guidance to determine plasma MMF, MPA, MPAG, AcMPAG and MPG concentrations. Plasma concentrations were analysed independently, followed by calculation of geometric mean and coefficient of variation. Noncompartmental PK parameters were determined for MMF and all metabolites at all doses. MMF was rapidly converted to MPA in all horses. Each incremental dose of MMF resulted in increases in Cmax and AUCinf _obs for MPA and the three additional metabolites. Within the 10-fold dose range, the increase in Cmax and AUCinf _obs for MMF and its metabolites was nonlinear. Horses biotransform MMF into MPA, MPAG, AcMPAG and MPG via the glucuronidation and glucosidation clearance pathways. Equine reference PK profiles for MPA and the metabolites, MPAG, AcMPAG and MPG were established.

Influence of mycophenolate mofetil dosage and plasma levels on the occurrence of chronic lung allograft dysfunction in lung transplants: a retrospective cohort analysis.

Development of chronic lung allograft dysfunction is a limiting factor for post-lung transplant survival. We evaluated whether the dose of the immunosuppressant mycophenolate mofetil or plasma concentrations of the active metabolite mycophenolic acid affect the development of chronic lung allograft dysfunction. In this retrospective cohort study we recruited 71 patients with a lung transplant between 2010 and 2014 which survived the first year after transplantation up to 1 July 2021. An event-time-analytical Cox proportional-hazards regression model with time-varying-covariates (18,431 measurements for MPA, mycophenolate mofetil dosage, lymphocytes) was used to predict chronic lung allograft dysfunction, with adjustment for sociodemographic factors and lung function at baseline. 37 patients did not develop chronic lung allograft dysfunction (age 41.3 ± 15.6 years, baseline FEV1 95.5 ± 19.1% predicted) and 34 patients developed chronic lung allograft dysfunction (age 50.9 ± 13.3 years, baseline FEV1 102.2 ± 25.4% predicted). Mean mycophenolic acid did not differ significantly between the groups (2.8 ± 1.7 and 3.0 ± 2.3 mg/l; p = 0.724). In the first 4 post-transplant years the death rate was 25%. A total of 50% of the patients died by the ninth post-transplant year. There was a dose-effect relationship between mycophenolate mofetil dosage, mycophenolic acid (r2 = 0.02, p <0.001), as well as lymphocyte levels (r2 = -0.007, p <0.001), but only the traditional risk factor age predicted chronic lung allograft dysfunction. Continuously measured mycophenolic acid did not predict chronic lung allograft dysfunction (hazard ratio 0.98, 95% confidence interval 0.90-1.06, p = 0.64 over a period of 382.97 patient-years). Mycophenolate mofetil dosage and mycophenolic acid were not associated with chronic lung allograft dysfunction development. Thus, the mycophenolate mofetil dose or mycophenolic acid plasma concentration are not a primary factor related to organ rejection, but chronic lung allograft dysfunction may be influenced by other components of immunosuppression or other factors.

In Vitro Predictive Dissolution Test Should Be Developed and Recommended as a Bioequivalence Standard for the Immediate-Release Solid Oral Dosage Forms of the Highly Variable Mycophenolate Mofetil.

The prodrug mycophenolate mofetil (MMF), which is presystemically hydrolyzed into the pharmacologically active compound mycophenolic acid (MPA), has been widely used for the prophylaxis of acute allograft rejection in solid organ transplantation. However, the huge variability in the plasma concentration level makes the development of MMF drug products difficult due to the great challenge of meeting the traditional bioequivalence (BE) limits. Numerous models have been developed in the past decade to explain the variability, with the emphasis on characterizing the enterohepatic circulation. While the variability arising from systemic appearance can also contribute to the remarkable MPA variability to a great extent, it has been ignored for long for this Biopharmaceutics Classification System class 2 drug. To improve the design of the BE study for this highly variable (HV) drug, the variability of MMF pharmacokinetic (PK) profiles focusing on the absorption process was explored in a population approach. A total of 81 Chinese adult liver transplant recipients were enrolled and had their plasma concentrations of MPA and its metabolites measured by HPLC during one visit or multiple visits in a long-term MMF regimen. The population models were developed using NONMEM, and the data and the results of the model were analyzed by R. Two population PK models of MMF focusing on the absorption process were developed based on the plasma concentrations of MPA and its major metabolite 7-O-MPA-β-glucuronide (MPAG). The MPA PK profiles were best characterized by a two-compartment disposition model with zero inter-individual variability (IIV) of elimination coefficient (K20), lag time, but considerable intra-individual variability (IAV) in the form of inter-occasion variability regarding systemic appearance coefficient, K20, and central volume of distribution, when just using MPA plasma concentrations as observations. The second model took into consideration the EHC by including MPAG profiles as well. The results from both models showcased that the IAV played a far more significant role than the IIV in accounting for the variability of the MMF systemic appearance. This is in line with what was found in the BE study: the within-subject variability (WSV) of BE measures largely exceeded the corresponding between-subject variability. The great WSV of MMF can be mechanistically explained by the interplay of dissolution and solubility with the gastrointestinal (GI) physiological dynamics, especially the gastric emptying (GE) in the fasting state regulated by migrating motor complex, and GE and pH variations in the fed state by the caloric content with irregular patterns of GI motility and secretion. The results implied that for the immediate-release solid oral dosage forms of MMF, running a regular in vitro dissolution test for the fasting state and developing a predictive in vitro dissolution test with sufficient simulation of the GE dynamics and proximal small intestinal pH fluctuations for the fed state would be excellent surrogates for the in vivo BE test. Furthermore, a physiologically based predictive in vitro dissolution test under both fasting and fed conditions would be a new trend for the BE studies of all other HV drug products.

Pharmacokinetics and pharmacodynamics profiles of enteric-coated mycophenolate sodium in female patients with difficult-to-treat lupus nephritis.

Relapsed or resistant lupus nephritis (LN) is considered a difficult‐to‐treat type of LN, and enteric‐coated mycophenolate sodium (EC‐MPS) has been used in this condition. Therapeutic drug monitoring using the area under the plasma mycophenolic acid concentration from 0 to 12 h postdose (MPA‐AUC0–12h) ≥45 μg.h/ml is a useful approach to achieve the highest efficiency. This study assessed EC‐MPS’s pharmacokinetic (PK) and pharmacodynamic (PD) profiles and investigated an optimal level of the single time point of plasma MPA concentration. Nineteen biopsy‐proven patients with class III/IV LN received 1440 mg/day of EC‐MPS for 24 weeks. PK (maximum plasma MPA concentration [C max], time to C max, and MPA‐AUC0–12h) and PD (activity of inosine‐5′‐monophosphate dehydrogenase [IMPDH]) parameters were measured at weeks 2, 8, 16, and 24. We found that IMPDH activity decreased from baseline by 31–42% within 2–4 h after dosing, coinciding with the increased plasma MPA concentration. MPA‐AUC0–12h ≥45 μg.h/ml was best predicted by a single time point MPA concentration at C0.5, C2, C3, C4, and C8 (r 2 = 0.516, 0.514, 0.540, 0.611, and 0.719, respectively), independent of dose, albumin, urine protein/creatinine ratio, and urinalysis. The MPA‐C0.5 cutoff of 2.03 g/ml yielded the highest overall sensitivity of 85% and specificity of 88.2% in predicting MPA‐AUC0–12h ≥45 μg.h/ml. A single timepoint of plasma MPA‐C0.5 ≥2.03 μg/ml may help guide EC‐MPS adjustment to achieve adequate drug exposure. Further study of EC‐MPS used to validate this cutoff is warranted.

Pharmacokinetics of mycophenolic acid and external evaluation of two limited sampling strategies of drug exposure in patients with juvenile systematic lupus erythematosus

Mycophenolate mofetil (MMF), a pro-drug of mycophenolic acid (MPA), has become a major therapeutic option in juvenile systemic lupus erythematosus (jSLE). Monitoring MPA exposure using area under curve (AUC) has proved its value to increase efficacy and safety in solid organ transplantation both in children and adults, but additional data are required in patients with autoimmune diseases. In order to facilitate MMF therapeutic drug monitoring (TDM) in children, Bayesian estimators (BE) of MPA AUC0-12h using limited sampling strategies (LSS) have been developed. Our aim was to conduct an external validation of these LSS using rich pharmacokinetics and compare their predictive performance. Pharmacokinetic blood samples were collected from jSLE treated by MMF and MPA plasma concentrations were determined using high-performance liquid chromatography system with ultraviolet detection (HPLC-UV). Individual AUC0-12h at steady state was calculated using the trapezoid rule and compared with two LSS: (1) ISBA, a two-stage Bayesian approach developed for jSLE and (2) ADAPT, a non-linear mixed effects model with a parametric maximum likelihood approach developed with data from renal transplanted adults. We received 41 rich pediatric PK at steady state from jSLE and calculated individual AUC0-12h. The external validation MPA AUC0-12h was conducted by selecting the concentration-time points adapted to ISBA and ADAPT: (1) ISBA showed good accuracy (bias: - 0.8mgh/L), (2) ADAPT resulted in a bias of 6.7mg L/h. The corresponding relative root mean square prediction error (RSME) was 23% and 43% respectively. According to our external validation of two LSS of drug exposure, the ISBA model is recommended for Bayesian estimation of MPA AUC0-12h in jSLE. In the literature focusing on MMF TDM, an efficacy cut-off for MPA AUC0-12h between 30 and 45mgh/L is proposed in jSLE but this requires additional validation.

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.

Comparison of free plasma versus saliva mycophenolic acid exposure following mycophenolate mofetil administration in adult kidney transplant recipients

Therapeutic monitoring (TDM) of mycophenolic acid (MPA) has the potential to improve drug inefficacy and toxicities in kidney transplantation. However, measurement of plasma MPA concentrations is laborious and invasive. This study examined the utility of saliva compared with plasma based TDM of MPA. Paired blood and saliva samples were collected from 47 adult kidney transplant recipients pre- and at 1-, 2-, and 4-hours post mycophenolate mofetil administration. No relationship was observed between saliva MPA concentrations and either total or free plasma MPA concentrations (p > 0.05). This suggests that saliva is a poor direct marker of plasma MPA concentrations and therefore should not be used for MPA TDM.

Pharmacokinetics of mycophenolate mofetil following single-dose intravenous and single- and multiple-dose oral administration and clinicopathologic effects of mycophenolate mofetil following long-term oral administration in healthy horses.

To characterize the pharmacokinetics of mycophenolate mofetil (MMF) following single-dose IV or PO administration, characterize the pharmacokinetics of MMF following long-term PO administration, and describe the clinicopathologic effects of long-term MMF administration in horses. 12 healthy adult horses. In phase 1, 6 horses received a single IV (2.5 mg/kg) or PO (5 mg/kg) dose of MMF in a randomized balanced crossover assessment (≥ 2-week interval between administrations). In phase 2, 6 other horses received MMF for 60 days (5 mg/kg, PO, q 24 h for 30 days and then 5 mg/kg, PO, q 48 h for an additional 30 days). Following IV (single-dose) or PO (single- or multiple-dose) administration, MMF was rapidly converted to mycophenolic acid. For single-dose PO administration, mean ± SD maximum plasma mycophenolic acid concentration was 1,778.3 ± 441.5 ng/mL at 0.71 ± 0.29 hours. For single-dose IV administration, mean systemic clearance and volume of distribution at steady state were 0.689 ± 0.194 L/h/kg and 1.57 ± 0.626 L/kg, respectively. Following single doses, mean terminal half-life was 3.99 ± 0.865 hours for IV administration and 4.02 ± 1.01 hours for PO administration. The accumulation index following long-term PO administration was 1.0 ± 0.002, and the terminal half-life was 4.59 ± 1.25 hours following the final dose on day 60. None of the horses developed abnormal clinical signs or had any consistently abnormal clinicopathologic findings. Further investigation of the clinical efficacy of long-term MMF treatment of horses with autoimmune diseases is warranted.

Pharmacokinetic Model Analysis of Supralingual, Oral and Intravenous Deliveries of Mycophenolic Acid.

Mycophenolic acid (MPA) is commonly used for organ rejection prophylaxis via oral administration in the clinic. Recent studies have shown that MPA also has anticancer activities. To explore new therapeutic options for oral precancerous/cancerous lesions, MPA was designed to release topically on the dorsal tongue surface via a mucoadhesive patch. The objective of this study was to establish the pharmacokinetic (PK) and tongue tissue distribution of mucoadhesive MPA patch formulation after supralingual administration in rats and also compare the PK differences between oral, intravenous, and supralingual administration of MPA. Blood samples were collected from Sprague Dawley rats before and after a single intravenous bolus injection, a single oral dose, or a mucoadhesive patch administration on the dorsal tongue surface for 4 h, all with a dose of 0.5 mg/kg of MPA. Plots of MPA plasma concentration versus time were obtained. As multiple peaks were found in all three curves, the enterohepatic recycling (EHR) model in the Phoenix software was adapted to describe their PK parameters with an individual PK analysis method. The mean half-lives of intravenous and oral administrations were 10.5 h and 7.4 h, respectively. The estimated bioavailability after oral and supralingual administration was 72.4% and 7.6%, respectively. There was a 0.5 h lag-time presented after supralingual administration. The results suggest that the systemic plasma MPA concentrations were much lower in rats receiving supralingual administration compared to those receiving doses from the other two routes, and the amount of MPA accumulated in the tongue after patch application showed a sustained drug release pattern. Studies on the dynamic of drug retention in the tongue after supralingual administration showed that ~3.8% of the dose was accumulated inside of tongue right after the patch removal, ~0.11% of the dose remained after 20 h, and ~20.6% of MPA was not released from the patches 4 h after application. The data demonstrate that supralingual application of an MPA patch can deliver a high amount of drug at the site of administration with little systemic circulation exposure, hence lowering the potential gastrointestinal side effects associated with oral administration. Thus, supralingual administration is a potential alternative route for treating oral lesions.

Pharmacokinetics and Pharmacodynamics of Immediate- and Modified-Release Mycophenolic Acid Preparations in Healthy Beagle Dogs

Background: Mycophenolic acid (MPA) is a broad-acting immunomodulating agent that may be therapeutically beneficial for the treatment of immune-mediated diseases in canine patients.Objectives: To determine the suppressive effects of MPA on T-cell proliferation, and to assess the feasibility of a canine-specific q24 h modified-release MPA formulation (OKV-1001b).Animals: Fifteen healthy purpose-bred male beagle dogs.Methods: Two nearly identical open-label fifteen-day studies were conducted in which dogs were randomized to receive mycophenolate mofetil (MMF; 10 mg/kg q12h), or two doses of OKV-1001b (270 mg and 180 mg; q24h). Serial pharmacokinetic (PK) and pharmacodynamic (PD) samples were collected on Days 1, 8, and 15. MPA plasma concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), while an ex vivo T-cell proliferation assay assessed PD effects. Dogs were continuously monitored for evidence of side effects and gastrointestinal tolerability.Results: MPA induced inhibition of T-cell proliferation was observed following administration of all MPA preparations in a clear concentration-dependent manner. The PK/PD relationship was maintained across all days and time-points. Data generated herein suggest that MPA plasma concentrations above 600 ng/mL achieve at least 50% inhibition of T-cell proliferation.Conclusions and Clinical Importance: MPA holds therapeutic potential for treating dogs with immune-mediated disease, but clinical trials will be necessary to determine its safety and efficacy in naturally occurring disease. Likewise, q24h oral modified release MPA preparations that maintain MPA plasma concentrations between 600 and 1,000 ng/mL are warranted for further studies in client-owned dogs.

Pharmacokinetics of mycophenolic acid after haplo-hematopoietic stem cell transplantation in Japanese recipients.

Mycophenolate mofetil (MMF), a mycophenolic acid (MPA) prodrug, is used to prevent graft-versus-host disease (GVHD) in hematopoietic stem cell transplantation (HSCT). Although previous studies have reported that enterohepatic circulation (EHC) of MPA, which is usually observed in MMF-treated patients, does not occur in HSCT patients, it is unclear what happens in haploidentical-HSCT (haplo-HSCT) patients, who are using post-transplant cyclophosphamide. This study was conducted to investigate MPA pharmacokinetics in haplo-HSCT patients. Seventeen haplo-HSCT patients, who received MMF for GVHD prophylaxis, were enrolled in this study. We collected blood samples on days 14 and 28, and plasma MPA concentrations were measured by high-performance liquid chromatography; pharmacokinetic parameters such as area under the curve (AUC), mean residence time (MRT), and apparent oral clearance (CL/F) were measured with moment analysis. We also evaluated EHC as AUC6-12h/AUC0-12h. There was no significant difference in MPA pharmacokinetic parameters between days 14 and 28. There was also no difference between the pharmacokinetic parameter changes and diarrhea. Additionally, varying plasma MPA concentrations suggested that MPA EHC did not occur. In this study, we revealed the pharmacokinetics of MMF in Japanese haplo-HSCT recipients. Additionally, our study demonstrated that MPA EHC might not occur in Japanese haplo-HSCT recipients.

Plasma mycophenolic acid concentration and the clinical outcome after lung transplantation.

The therapeutic drug monitoring of mycophenolic acid (MPA) has been investigated for renal and heart transplantations; however, its usefulness in lung transplantation is unclear. The MPA area under the plasma concentration-time curve (AUC) was calculated in 59 adult lung transplant recipients. The MPA AUC0-12 s were compared among the three groups determined by the presence of adverse events (no events, infection, and chronic lung allograft dysfunction [CLAD]). Next, MPA AUC0-12 thresholds for the adverse events were identified by receiver operating characteristic analysis. Cumulative occurrence rate of the adverse events was compared between two groups (adequate and inadequate groups) according to the thresholds. The MPA AUC0-12 s in the no event, infection, and CLAD groups were 30.3±6.5, 36.8±10.7, and 20.6±9.6µg·h/mL, respectively (P=.0027), while the tacrolimus trough levels were similarly controlled in the groups. The thresholds of MPA AUC0-12 for the occurrence of infection and CLAD were 40.5 and 22.8µg·h/mL, respectively. The cumulative occurrence rate of adverse events of adequate group (15.3%) was significantly lower than that of inadequate group (56.0%) (P=.0050). The MPA AUC0-12 may affect the occurrence of adverse events in lung transplant recipients.

A Single Time Point Plasma Concentration of Mycophenolic Acid Predicts Enteric-Coated Mycophenolate Sodium Exposure in Thai Renal Transplant Recipients

A Single Time Point Plasma Concentration of Mycophenolic Acid Predicts Enteric-Coated Mycophenolate Sodium Exposure in Thai Renal Transplant Recipients