Plasma Mycophenolic Acid Research Articles

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.

Quantification of mycophenolic acid in human plasma by liquid chromatography with time-of-flight mass spectrometry for therapeutic drug monitoring.

This study presents, for the first time, the development and validation of a liquid chromatography and time-of-flight mass-spectrometry (LC-TOF-MS) based assay to quantify mycophenolic acid (MPA) in patient samples as part of a routine therapeutic drug monitoring service. MPA was extracted from 50 μl human plasma by protein precipitation, using sulindac as internal standard (IS). Separation was obtained on a Luna™ Omega polar C18 column kept at 40°C. The mobile phase consisted of a mixture of acetonitrile-deionized water (50:50, v/v) with 0.1% formic acid at a flow rate of 350 μl/min. Analyte and IS were monitored on a TOF-MS using a Jet-Stream™ (electrospray) interface running in positive mode. Assay performance was evaluated by analysing patient plasma (N = 69) and external quality assessment (N = 6) samples. The retention times were 2.66 and 2.18 min for MPA and IS, respectively. The lower limit of quantification of MPA was 0.1 μg/ml. The within- and between-assay reproducibility results ranged from 1.81 to 10.72%. Patient and external quality assessment sample results were comparable with those obtained previously by an in-house validated LC-MS/MS method. This method showed satisfactory analytical performance for the determination of MPA in plasma over the calibration range of 0.1-15.0 μg/ml.

Population Pharmacokinetic Model of Plasma and Cellular Mycophenolic Acid in Kidney Transplant Patients from the CIMTRE Study.

Background and ObjectiveMycophenolate mofetil is widely used in kidney transplant recipients. Mycophenolate mofetil is hydrolysed by blood esterases to mycophenolic acid (MPA), the active drug. Although MPA therapeutic drug monitoring has been recommended to optimise the treatment efficacy by the area under the plasma concentration vs time curve, little is known regarding MPA concentrations in peripheral blood mononuclear cells, where MPA inhibits inosine monophosphate dehydrogenase. This study aimed to build a pharmacokinetic model using a population approach to describe MPA total and unbound concentrations in plasma and into peripheral blood mononuclear cells in 78 adult kidney transplant recipients receiving mycophenolate mofetil therapy combined with tacrolimus and prednisone.MethodsTotal and unbound plasma concentrations and peripheral blood mononuclear cell concentrations were assayed. A three-compartment model, two for plasma MPA and one for peripheral blood mononuclear cell MPA, with a zero-order absorption and a first-order elimination was used to describe the data.ResultsMycophenolic acid average concentrations in peripheral blood mononuclear cells were well above half-maximal effective concentration for inosine monophosphate dehydrogenase and no relationship was found with the occurrence of graft rejection. Three covariates affected unbound and intracellular MPA pharmacokinetics: creatinine clearance, which has an effect on unbound MPA clearance, human serum albumin, which influences fraction unbound MPA and the ABCB1 3435 C>T (rs1045642) genetic polymorphism, which has an effect on MPA efflux transport from peripheral blood mononuclear cells.ConclusionThis population pharmacokinetic model demonstrated the intracellular accumulation of MPA, the efflux of MPA out of the cells being dependent on P-glycoprotein transporters. Nevertheless, further studies are warranted to investigate the relevance of MPA concentrations in peripheral blood mononuclear cells to dosing regimen optimisation.Electronic supplementary materialThe online version of this article (10.1007/s40268-020-00319-y) contains supplementary material, which is available to authorized users.

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.

Estimation of Abbreviated Mycophenolic Acid Area Under the Concentration- Time Curve during Stable Post-transplant Period by Limited Sampling Strategy.

The Area Under the Concentration-time curve (AUC) of Mycophenolic Acid (MPA), is a valid prognosticator of the risk of rejection and the gold standard in its Therapeutic Drug Monitoring (TDM), over time post-transplantation. This study aimed to investigate MPA pharmacokinetic parameters and develop a Limited Sampling Strategy (LSS) to estimate an abbreviated MPA AUC, in the stable phase post-renal transplantation. In this study, 19 patients with normal graft function (glomerular filtration rate >70 ml/min) who fulfilled the inclusion and exclusion criteria were involved. Blood samples at various times were taken in the stable phase after transplantation. MPA plasma concentration was measured by reverse-phase high-performance liquid chromatography. MPA AUC0-12h was calculated using the linear trapezoidal rule. Multiple stepwise regression analysis was used to determine the minimal time points of MPA levels that could be used to yield model equations best fitted to MPA AUC 0-12h. The findings of this study were compared with the results of our previous study, which was done similarly in the early phase post-renal transplantation. The results demonstrated that the MPA-AUC and clearance were not affected over time, but MPA-tmax was significantly lower in the stable phase in comparison with the early phase (P=0.001). The best regression equation for AUC estimation in the stable phase was AUC=9.57*C6+27.238 (r2=0.907). The validation of the method was performed using the jackknife method. The mean prediction error of these models was not different from zero (P > 0.05) and had a high root mean square prediction error (7.91). In conclusion, the pharmacokinetics of MPA could be affected by time after transplantation, making it essential to develop a limited sampling strategy as an efficacious approach for therapeutic drug monitoring during the stable post-transplant period.

A short overview on mycophenolic acid pharmacology and pharmacokinetics.

Immunosuppressive therapy is used in solid organ transplant treatment, and mycophenolic acid (MPA) is one of the immunosuppressive drugs most used worldwide. It is a potent, selective, non-competitive, and reversible inosine monophosphate dehydrogenase (IMPDH) inhibitor that acts to inhibit guanine synthesis. To improve solubility, MPA is used as the prodrug mycophenolate mofetil (MMF) or as an enteric-coated mycophenolate sodium salt (EC-MPS). It is metabolized into mycophenolic acid phenyl glucuronide (MPAG), the inactive and major metabolite, and into acyl glucuronide (AcMPAG), pharmacologically active. In kidney transplantation, combined immunosuppressive therapy with cyclosporine (CsA) and tacrolimus (Tac) is widely used, showing beneficial effects. This paper aimed to review papers published in the last two decades and discuss factors that can interfere with the pharmacokinetics of MPA. Data collected confirm that MPA plasma levels should be monitored to evaluate immunosuppressive therapy since pharmacokinetics can be influenced by factors such as interpatient variability, coadministration of other immunosuppressive agents, post-transplant period, renal function, and dose. However, to perform drug monitoring, costs and facility may be limitations. Monitoring MPAG together with MPA would be a great improvement in therapy as it represents a big part of MPA levels and can be related to the increase of adverse effects.

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.

Determination and validation of mycophenolic acid by a UPLC-MS/MS method: Applications to pharmacokinetics and tongue tissue distribution studies in rats

Mycophenolic acid (MPA) has being used clinically for organ rejection prophylaxis. Recent studies have revealed that MPA can also act as a chemo-sensitizing agent when used in combination with various chemotherapeutic agents in a cancer type-specific manner, including with oxaliplatin on oral squamous cell carcinoma (OSCC) cells. To prepare for the analysis of a novel drug delivery route for MPA absorption via oral mucosa as a potential therapeutic product, it is essential to develop and validate a highly sensitive analytical method for the quantification of MPA in biological samples for pharmacokinetic and tissue distribution studies. Herein, we report a sensitive, specific and reproducible UPLC-MS/MS method to do so. Blank rat plasma or tongue tissue homogenates coupled with griseofulvin, as internal standard, was used for generating standard curves ranging from 0.5 to 1000 ng/mL (r > 0.9990) for both plasma and tongue tissue homogenates. The chromatographic separation was achieved by a reverse phase ACE Excel 2 Super C18 column with a flow rate of 0.4 mL/min under gradient elution. Mass detection was performed under positive ionization electrospray. Inter- and intra-day accuracy and precision of the assay were ≤15% in both plasma and tongue tissue homogenates. The matrix effect was non-significant and extraction recovery rates were within 87.99% and 109.69% in plasma and tongue homogenates, respectively. The validity of this assay has been confirmed by measuring MPA in rat plasma for pharmacokinetics following intravenous administration of 0.5 mg/kg of mycophenolate sodium, as well as monitoring MPA in rat tongues for tissue distribution and detecting MPA that diffused into systemic circulation following a 4-h transmucosal delivery of 357 μg/cm2 of mycophenolate sodium.

Plasmapheresis Reduces Mycophenolic Acid Concentration: A Study of Full AUC0-12 in Kidney Transplant Recipients.

Background: Mycophenolic acid (MPA), a crucial immunosuppressive drug, and plasmapheresis, an effective immunoreduction method, are simultaneously used for the management of various immune-related diseases, including kidney transplantation. While plasmapheresis has been proven efficient in removing many substances from the blood, its effect on MPA plasma levels remains unestablished. Objectives: To evaluate the full pharmacokinetics of MPA by measuring the area under the time–concentration curve (AUC0–12), which is the best indicator for MPA treatment monitoring after each plasmapheresis session, and to compare the AUC0–12 measurements on the day with and on the day without plasmapheresis. Methods: A cross-sectional study was conducted in kidney transplantation recipients who were taking a twice-daily oral dose of mycophenolate mofetil (MMF, Cellcept®) and undergoing plasmapheresis at King Chulalongkorn Memorial Hospital, Bangkok, Thailand, during January 2018 and January 2019. The MPA levels were measured by an enzymatic method (Roche diagnostic®) 0, 1/2, 1, 2, 3, 4, 6, 8, and 12 h after MMF administration, for AUC0–12 calculation on the day with and on the day without plasmapheresis sessions. Plasmapheresis was started within 4 h after administering the oral morning dose of MMF. Our primary outcome was the difference of AUC0–12 between the day with and the day without plasmapheresis. Results: Forty complete AUC measurements included 20 measurements on the plasmapheresis day and other 20 measurements on the day without plasmapheresis in six kidney transplant patients. The mean age of the patients was 56.2 ± 20.7 years. All patients had received 1000 mg/day of MMF for at least 72 h before undergoing 3.5 ± 1.2 plasmapheresis sessions. The mean AUC on the day with plasmapheresis was lower than that on the day without plasmapheresis (28.22 ± 8.21 vs. 36.79 ± 10.29 mg × h/L, p = 0.001), and the percentage of AUC reduction was 19.49 ± 24.83%. This was mainly the result of a decrease in AUC0–4 of MPA (23.96 ± 28.12% reduction). Conclusions: Plasmapheresis significantly reduces the level of full AUC0–12 of MPA. The present study is the first to measure the full AUC0–12 in MPA-treated patients undergoing plasmapheresis. Our study suggests that a supplementary dose of MPA is necessary for patients undergoing plasmapheresis.

The development of a population physiologically based pharmacokinetic model for mycophenolic mofetil and mycophenolic acid in humans using data from plasma, saliva, and kidney tissue.

Mycophenolic acid (MPA) is used widely to prevent graft rejection in kidney-transplant patients. Therapeutic drug monitoring (TDM) in plasma requires an invasive procedure that is inconvenient, especially in pediatric patients. TDM in saliva is a more convenient non-invasive alternative compared with plasma. A population physiologically based pharmacokinetic (Pop-PBPK) model of mycophenolate mofetil (MMF) and MPA with enterohepatic recycling was built and verified using previously published plasma, saliva, and kidney biopsy data in healthy and kidney-transplant adult patients. The verified model was then used to predict experimentally observed plasma and saliva MMF and MPA TDM data in Jordanian pediatric kidney transplant patients measured using LC-MS/MS. A correlation was established between plasma and saliva exposures in pediatrics. The developed LCMS was sensitive to both MMF and MPA in plasma and saliva. The developed Pop-PBPK model predicted well the previously reported MMF and MPA levels in plasma, saliva, and kidney tissue and those observed in the current study (more than 75% of observed data points were within 90% predictive interval of population simulations). A statistically significant correlation was found between plasma and saliva exposures for both MMF (Pop-PBPK predicted and observed) and MPA (Pop-PBPK predicted). Both MPA and MMF can be classified as class III compounds in the Salivary Excretion Classification System. Saliva is an alternative body fluid to plasma that can be used for TDM of MPA and MMF in kidney-transplant patients in pediatrics. Exposure to MPA and MMF in plasma, saliva, and kidney tissue was reliably predicted using the developed Pop-PBPK model.

The pharmacokinetics of mycophenolic acid in rats with orotic acid induced nonalcoholic fatty liver disease.

Post-transplantation nonalcoholic fatty liver disease (NAFLD) is common in liver transplant recipients. Changes in the expression levels and activities of drug-metabolizing enzymes and drug transporters have been reported in patients with NAFLD and relevant rodent models. Here, we evaluated whether the pharmacokinetics of mycophenolic acid (MPA), an immunosuppressant, would be altered in rats with NAFLD. NAFLD was induced by feeding a diet containing 1% (w/w) orotic acid for 20 days. The extent of hepatic glucuronidation of MPA to a major metabolite, mycophenolic acid-7-O-glucuronide (MPAG), did not differ between rats with NAFLD and controls. The expression levels of hepatic multidrug resistance-associated protein 2, responsible for biliary excretion of MPAG, were comparable in rats with NAFLD and controls; the biliary excretion of MPAG was also similar in the two groups. Compared with control rats, rats with NAFLD did not exhibit significant changes in the areas under the plasma concentration - time curves of MPA or MPAG after intravenous (5 mg/kg) or oral (10 mg/kg) administration of MPA. However, delayed oral absorption of MPA was observed in rats with NAFLD compared with controls; the MPA and MPAG peak plasma concentrations fell significantly and the times to achieve them were prolonged following oral administration of MPA.

Determination of mycophenolic acid in human plasma by ultra-performance liquid chromatography-tandem mass spectrometry and its pharmacokinetic application in kidney transplant patients.

To implement and validate an analytical method by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC MS/MS) to quantify mycophenolic acid (MPA) in kidney transplant patients. Quantification of MPA was performed in an ACQUITY UPLC H Class system coupled to a Xevo TQD detector and it was extracted from plasma samples by protein precipitation. The chromatographic separation was achieved through an ACQUITY HSS C18 SB column with 0.1% formic acid and acetonitrile (60:40vol/vol) as mobile phase. The pharmacokinetic parameters were calculated by non-compartmental analysis of MPA plasma concentrations from 10 kidney transplant patients. The linear range for MPA quantification was 0.2-30 mg/L with a limit of detection of 0.07 mg/L; the mean extraction recovery was 99.99%. The mean intra- and inter-day variability were 2.98% and 3.4% with a percentage of deviation of 8.4% and 6.6%, respectively. Mean maximal concentration of 10 mg/L at 1.5 h, area under the concentration-time curve of 36.8 mg·h/L, elimination half-life of 3.9 h, clearance of 0.32 L/h/kg and volume of distribution of 1.65 L/kg were obtained from MPA pharmacokinetics profiles. A simple, fast and reliable UPLC-MS/MS method to quantify MPA in plasma was validated and has been applied for pharmacokinetic analysis in kidney transplant patients.

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.

Limited Sampling Strategy for the Estimation of Mycophenolic Acid and its Acyl Glucuronide Metabolite Area under the Concentration-Time Curve in Japanese Lung Transplant Recipients.

The dose of mycophenolate mofetil (MMF) used to prevent rejection after lung transplantation is often adjusted based on the 12-hour area under the concentration-time curve (AUC0-12) of mycophenolic acid (MPA). A limited sampling strategy (LSS) is useful to define the pharmacokinetic (PK) profiles of MPA and mycophenolic acid acyl glucuronide (AcMPAG). Therefore, this study aimed to design a LSS based on multiple linear regression for estimating the AUC0-12 of MPA and AcMPAG at the minimum blood sampling points in Japanese lung transplant patients with concomitant tacrolimus. Forty-five lung transplantation recipients were enrolled in a PK study of MPA, mycophenolic acid glucuronide (MPAG), and AcMPAG. The plasma MPA, MPAG, and AcMPAG concentrations were determined just before and at 0.5, 1, 2, 4, 8, and 12 hours after dosing. The AUC0-12 of MPA and AcMPAG was calculated using a linear trapezoidal rule from the plasma concentration of each blood sampling time. LSS was used to develop models for estimated AUC in the model group (n = 23) and was evaluated in the validation group (n = 22). The best three time-point equation was 4.04 + 1.64·C1 + 3.08·C4 + 5.17·C8 for MPA, and -0.13 + 3.01·C1 + 3.51·C4 + 5.74·C8 for AcMPAG. The prediction errors (PE) and the absolute prediction errors (APE) were within the clinically acceptable ± 5% and 15% range, respectively (MPA: PE = 2.00%, APE = 11.66%, AcMPAG: PE = 0.98%, APE = 14.69%). The percentage of estimated AUC0-12 within ± 15% of the observed AUC0-12 was 77.27% for MPA and 81.82% for AcMPAG. LSS using three time-point (C1, C4, and C8) provides the most reliable and accurate simultaneous estimation of the AUC0-12 of MPA and AcMPAG in Japanese lung transplant patients.

High plasma mycophenolate acid concentration in the early phase of induction therapy predicts good renal outcome in lupus nephritis

Objectives: To identify the prognostic predictive factor of complete renal response (CR) at week 12 by focusing on the plasma mycophenolic acid (MPA) concentration in induction therapy in lupus nephritis.Methods: We prospectively enrolled patients with biopsy-proven LN class III/IV who were hospitalized between 2016 and 2017. As an induction therapy, mycophenolate mofetil was continuously introduced at 2000 mg/day. We measured the MPA plasma concentration at two time points depending on the induction therapy phase, early (week 4) or middle (week 12). The association between these concentrations and CR rate at week 12 was evaluated.Results: Ten patients were enrolled. A significantly higher AUC0–12 between 0 and 12 h of MPA at the early phase was observed in the patients with CR at week 12 than in those without (p = .03). All the patients with high MPA-AUC0–12 (> 40 mg h/L) at the early phase achieved CR at week 12, but no such association was found at the middle phase. The multivariate analysis revealed that MPA-AUC0–12 was selected as an independent predictive factor of CR at week 12 (odds ratio: 1.12; 95% confidence interval: 1.01–1.45, p = .02).Conclusion: The high AUC0–12 of MPA at the early phase of induction therapy may predict good renal response.

Limited sampling strategy to predict mycophenolic acid area under the curve in pediatric patients with nephrotic syndrome: a retrospective cohort study

PurposeLimited sampling strategy (LSS) is a precise and relatively convenient therapeutic drug monitoring method. We evaluated LSSs for mycophenolic acid (MPA) in children with nephrotic syndrome treated with mycophenolic mofetil (MMF) and validated the LSSs using two different approaches.MethodsWe measured MPA plasma concentrations in 31 children using HPLC-UV method and received 37 MPA pharmacokinetic profiles (0–12 h). For six children, MPA profiles were estimated twice after two MMF doses. LSSs were developed using multilinear regression with STATISTICA and R software and validated using validation group and bootstrap method, respectively.ResultsThe best three time point equations included C1, C3, C6 (good guess 83%, bias − 2.78%; 95% confidence interval (CI) − 9.85–0.46); C1, C2, C6 (good guess 72%, bias 0.72%; 95% CI − 5.33–7.69); and C1, C2, C4 (good guess 72%, bias 2.05%; 95% CI − 4.92–13.01) for STATISTICA software. For R software, the best equations consisted of C1, C3, C6 (good guess 92%, bias − 2.69%; 95% CI − 27.18–33.75); C0, C1, C3 (good guess 84%, bias − 2.11%; 95% CI − 24.19–22.29); and C0, C1, C2 (good guess 84%, bias − 0.48%; 95% CI − 30.77–54.07). During validation, better results were obtained for R evaluations, i.e., bootstrap method.ConclusionsThe most useful equations included C0, C1, C3 and C0, C1, C2 time points; however, the most precise included C1, C3, C6 time points because of MPA enterohepatic recirculation. Better results were obtained for bootstrap validation due to greater number of patients. Validated LSS should be used only in the population for which it was developed. As there is growing evidence that underexposure of MPA is associated with insufficient treatment response, we recommend the introduction of therapeutic drug monitoring for MPA in children with nephrotic syndrome.

The Association between IMPDH II Gene 3757t > C and Ugt1a9 Gene T-275a Polymorphisms with Plasma Mycophenolic Acid among Renal Transplant Recipients

ESRD is a major health problem imposing great burden on the society. Dialysis either haemodialysis or peritoneal and transplantation are the two alternating treatment modalities. Transplantation became the preferred solution with lifetime monitoring immunosuppressive drugs. Urinary CXCL10 is used for early detection of renal rejection. Mycophenolate is one of the important immunosuppressive drugs used among renal transplant recipients.

Limited Sampling Strategy for Estimating Mycophenolic Acid Exposure on Day 7 Post-Transplant for Two Mycophenolate Mofetil Formulations Derived From 20 Chinese Renal Transplant Recipients

PurposeTo assess the pharmacokinetic properties of mycophenolate mofetil (MMF) dispersible tablets and capsules by the enzyme multiplied immunoassay technique (EMIT) in Chinese kidney transplant recipients in the early post-transplantation phase and to develop the equations to predict mycophenolic acid (MPA) area under the 12-hour concentration-time curve (AUC0-12h) using a limited sampling strategy (LSS). MethodsForty patients who underwent renal transplantation from brain-dead donors were randomly divided into dispersible tablets (Sai KE Ping; Hangzhou Zhongmei Huadong Pharma) and capsules (Cellcept; Roche Pharma, Why, NSW, Australia) groups, and treated with MMF combined with combination tacrolimus and prednisone as a basic immunosuppressive regimen. Blood samples were collected before treatment (0) and at 0.5,1, 1.5, 2, 4, 6, 8, 10, and 12 hours post-treatment and 7 days after renal transplantation. Plasma MPA concentrations were measured using EMIT. LSS equations were identified using multiple stepwise linear regression analysis. ResultsThe peak concentration (Cmax) in the MMF dispersible tablets (MMFdt) group (7.0 ± 2.8) mg/L was reduced compared with that in the MMF capsules (MMFc) group (10.8 ± 6.2 mg/L; P = .012); time to peak concentration in the MMFdt group was 3.2 ± 2.3 hours, which was nonsignificantly elevated compared with that of the MMFc group (2.2 ± 1.7 hours). Three-point estimation formulas were generated by multiple linear regression for both groups: MPA-AUCMMFdt = 3.542 + 3.332C0.5h + 1.117C1.5h + 3.946C4h (adjusted r2 = 0.90, P < .001); MPA-AUCMMFc = 8.149 + 1.442C2h + 1.056C4h + 7.133C6h (adjusted r2 = 0.88, P < .001). Both predicted and measured AUCs showed good consistency. ConclusionsAfter treatment with MMF dispersible tables or MMF capsules, the Cmax of MPA for the MMFdt group was significantly lower than that of the MMFc group; there was no significant difference in other pharmacokinetic parameters. Three-time point equations can be used as a predictable measure of the AUC0-12h of MPA.