Mycophenolic Acid AUC Research Articles

Safety of the reduced fixed dose of mycophenolate mofetil confirmed via therapeutic drug monitoring in de novo kidney transplant recipients.

Mycophenolate mofetil (MMF) is usually prescribed with a reduced fixed dose in Asian kidney transplant recipients (KTRs). However, the clinical efficacy and safety of the fixed dose have not yet been investigated via therapeutic drug monitoring. We evaluated whether reduced fixed-dose MMF is an optimal dosing strategy to achieve the therapeutic target of mycophenolic acid (MPA) exposure in Korean KTRs. This open-label, prospective study enrolled 50 de novo KTRs prescribed with tacrolimus, corticosteroid, and fixed-dose MMF (1.0-1.5 g/day). The trough level (C0) and area under the curve (AUC0-12 hr) of MPA were measured at 1 and 24 weeks after kidney transplantation (KT). The relationship of body weight (BW)-adjusted MMF dose with MPA C0 and MPA AUC0-12 hr was assessed using linear regression analysis. The initial fixed dose of MMF of 1.44 ± 0.16 g/day was adjusted in 24 patients (48.0%) and then reduced to a mean dose of 1.19 ± 0.31 g/day at 24 weeks after KT. Most patients (≥84.0%) attained the minimum required MPA C0 of 1.0 μg/mL and MPA AUC0-12 hr of 30 μg × hr/mL at 1 and 24 weeks. The BW-adjusted MMF dose demonstrated significant positive correlations with MPA C0 and MPA AUC0-12 hr at 1 and 24 weeks after KT. Moreover, 14 patients (28.0%) reported MPA-related adverse events that were predictable based on MPA AUC0-12 hr (cutoff level, 46.4 μg × hr/mL). The current reduced fixed-dose MMF strategy can help achieve the therapeutic target of MPA exposure in tacrolimus-treated Korean KTRs during the early posttransplant period.

External Validation of a Limited Sampling Strategy for the Estimation of Mycophenolic Acid Exposure Between Different Assay Methods: PETINIA and HPLC Methods.

A limited sampling strategy (LSS) for estimating the area under the plasma concentration-time curve (AUC0-12) of the immunosuppressant mycophenolic acid (MPA) is used for therapeutic drug monitoring (TDM) in clinical practice. Our study delves into the applicability of the MPA AUC0-12 LSS, originally developed using particle-enhanced turbidimetric inhibition immunoassay (PETINIA) measurements, to those obtained via high-performance liquid chromatography with ultraviolet detection (HPLC-UV). We developed an LSS for estimating MPA AUC0-12 based on PETINIA measurements in 32 adult kidney transplant patients who were receiving mycophenolate mofetil. Validation of this strategy was conducted in an additional 14 adult kidney transplant patients (validation sets) through measurements obtained by both PETINIA and HPLC-UV. Predictive performance was assessed using mean absolute error (MAE), root mean squared error (RMSE), and "good guess" defined as predicted AUC within observed AUC±15%. The three time point equation (0, 2, and 6h) emerged as optimal for estimating MPA AUC0-12, balancing predictive performance and usefulness in clinical settings. In validation sets, the coefficient of determination for observed versus predicted AUC0-12 was consistent between PETINIA (0.978) and HPLC-UV (0.958) measurements. Comparable MAE, RMSE, and "good guess" outcomes were observed for PETINIA (6.4%, 8.1%, and 85.7%, respectively) and HPLC-UV (7.6%, 9.4%, and 85.7%, respectively) measurements. Our findings support the application of the MPA AUC0-12 LSS, originally developed using PETINIA measurements, to those obtained via HPLC-UV.

A limited sampling model to estimate the area under the curve of mycophenolic acid in hematopoietic stem cell transplantation recipients.

Relationship between the areas under the curve (AUC) of mycophenolic acid (MPA) and the likelihood of rejection is well-established in solid organ transplantation recipients. In hematopoietic stem cell transplantation (HSCT), MPA AUC is also linked to graft versus host disease. This study aimed to develop a simplified method to estimate MPA AUC0-12 in Chinese patients undergoing allogeneic HSCT (allo-HSCT). Intensive sampling was conducted in 22 patients who were orally administered mycophenolate mofetil. Plasma concentrations of total MPA were measured, and a model predicting AUC0-12 using data from these 22 patients was constructed through regression analysis. The accuracy of the most suitable model was assessed in an additional 20 patients. None of the individual MPA concentrations showed a strong correlation with AUC0-12 (r2<0.7). Models utilizing 4 or more concentrations were found to effectively estimate MPA AUC0-12 (r2>0.87). The most operationally feasible model demonstrated good predictive performance with a mean absolute percentage error (APE%)<20%. Single MPA concentrations showed poor correlation with MPA AUC0-12. A model utilizing 4 oral concentrations (0, 0.5, 1, and 4h postdose) over a 12-h period could effectively estimate MPA AUC0-12 with precise results and minimal bias.

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

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

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

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

Transplant Prognosis in Kidney Transplant Recipients with Diabetes under Mycophenolic Acid-Focused Therapeutic Drug Monitoring.

Mycophenolate mofetil is a key immunosuppressant that is metabolized into mycophenolic acid (MPA). The prognostic impact of MPA-focused therapeutic drug monitoring on allograft prognosis has not been determined in kidney transplant recipients with diabetes. In this study, we assessed the pharmacokinetics of MPA and allograft prognosis in recipients with diabetes. This study retrospectively analyzed 64 adult kidney transplant recipients. MPA blood concentration data (e.g., the time to the maximum concentration (Tmax), and the area under the concentration–time curve from 0 to 12 h (AUC0–12)) were collected at 3 weeks and 3 months after kidney transplantation. Of the 64 recipients, 15 had pre-existing diabetes. At 3 months after kidney transplantation, the Tmax of MPA was significantly longer in recipients with diabetes (mean (standard deviation): 2.8 (2.1) h) than in recipients without diabetes (1.9 (1.1) h, p = 0.02). However, the allograft estimated glomerular filtration rate and acute rejection rate, including borderline change, did not differ according to the diabetes status in patients with adjusted AUC0–12 of MPA within the target range. In conclusion, a longer Tmax of MPA was observed in recipients with diabetes; however, acceptable allograft prognosis was observed in kidney transplant recipients with diabetes and a sufficient AUC0–12 of MPA.

Serum albumin level is associated with mycophenolic acid concentration in children with idiopathic nephrotic syndrome.

Mycophenolate mofetil is effective for the treatment of pediatric idiopathic nephrotic syndrome (INS). The dosage of mycophenolate mofetil is adjusted according to the serum concentration of mycophenolic acid (MPA). Kidney function or cyclosporine (CsA) concentrations affect serum MPA levels. However, few studies have focused on the association between serum concentrations of MPA and albumin. This retrospective observational study aimed to evaluate the relationship between the serum concentrations of MPA and albumin in INS children. Subjects were children with INS who underwent the therapeutic drug monitoring of CsA and MPA. We obtained the serum albumin (sAlb) concentration, estimated glomerular filtration rate (eGFR), age, and MPA and CsA areas under concentration-time curves from 0 to 12h (AUC0-12). Multiple linear regression analysis and generalized estimating equations were performed to predict values for MPA AUC0-12. We obtained information for 51 INS children with 261 MPA AUC0-12 measurements. The standardized regression coefficients of sAlb, eGFR, CsA AUC0-12, and age were 0.54, - 0.21, - 0.07, and 0.04, respectively. Furthermore, MPA AUC0-12 levels positively correlated with sAlb concentrations (p < 0.001) and were inversely correlated with eGFR values (p = 0.005) but not with CsA AUC0-12 (p = 0.24) and age (p = 0.65).Conclusion: Serum albumin concentration was strongly associated with total MPA concentration compared with kidney function or CsA values. Although patients with INS may have a low serum concentration of total MPA in the presence of low sAlb concentration, close attention should be paid to the interpretation of the low MPA values. What is Known: • The dosage of mycophenolate mofetil is adjusted according to the serum concentration of total mycophenolic acid. • Kidney function, cyclosporin concentrations, or serum albumin concentrations influence serum mycophenolic acid levels. What is New: • Serum albumin concentration is more strongly associated with total mycophenolic acid concentration than kidney function or cyclosporin values. • In children with nephrotic syndrome, the total mycophenolic acid concentration may not increase in the presence of severe hypoalbuminemia.

Pharmacokinetics of Mycophenolate Mofetil Metabolites in Older Patients on the Seventh Day After Renal Transplantation

Currently, immunosuppression schemes are age-independent; however, physiological changes may alter drugs' pharmacokinetics in the older population. We compared mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) pharmacokinetics among patients aged <60 and >60 years on the seventh day after renal transplantation. We included 7 and 10 renal transplant recipients, aged >60 and <60 years, respectively, treated with mycophenolate mofetil. MPA and MPAG concentrations were determined using the high-performance liquid chromatography method with ultraviolet detection (HPLC-UV). Noncompartmental pharmacokinetic analysis was performed. In patients aged >60 years, mean MPA and MPAG concentrations before the next dose and ratio of MPAG area under the concentration-time curve (AUC0-12) to MPA AUC0-12 were higher by 1.6-fold, 1.4-fold, and 1.9-fold, respectively. Other MPAG concentrations appeared to be slightly higher (1.2- to 1.5-fold) in older patients. MPA apparent clearance was similar in both groups, whereas volume of distribution at steady state was slightly higher (1.6-fold) in patients aged >60 years. The variability of most MPA and some MPAG pharmacokinetics was greater in patients aged >60 years. The MPA AUC0-12 target was achieved in 40% and 14% of patients aged <60 and >60 years, respectively. The highest MPAG concentrations and AUC0-12 were observed for patients with the lowest glomerular filtration rate. Higher variability of MPA and MPAG pharmacokinetic parameters, MPA AUC0-12 above the reference range, higher values of MPAG pharmacokinetics in patients with lower glomerular filtration rates, as well as lower proportion of patients achieving MPA targets all indicate the need for therapeutic drug monitoring in renal transplant recipients aged >60 years and to verify target MPA AUC0-12 for this population.

A Single Nucleotide Polymorphism in the SLCO1B3 Gene is Associated with Dose-Normalized Mycophenolic Acid AUC12

<h3>Purpose</h3> Lung transplant recipients are commonly maintained on mycophenolic acid (MPA). However, research has shown that transplant recipients experience a wide variability in MPA pharmacokinetics. We hypothesize that some of this variability is due to genetic factors. To this end we analyzed the relationship between MPA concentration and a hypofunctional polymorphism in the SLCO1B3 gene, rs7311358, which we have previously reported is associated with MPA-related clinical outcomes. <h3>Methods</h3> We performed full pharmacokinetic testing in 30 adult bilateral lung transplant recipients who were maintained on MPA and who had previously enrolled in our lung transplant genetic database. MPA levels were assessed using a high-performance liquid chromatography peak area quantitation. We calculated the 12-hour area under the curve (AUC₁₂) using the linear trapezoidal method. We used linear regression to evaluate the relationship between the SLCO1B3 polymorphism and the AUC₁₂. We also performed multivariate linear regression analysis to evaluate potential confounders. <h3>Results</h3> The SLCO1B3 rs7311358 polymorphism was present in 8 of 30 patients. These patients had a significantly lower dose normalized MPA AUC₁₂ than patients without the polymorphism (rs7311358 GG/GA 40.11 mg*h/L vs. rs7311358 AA 68.84 mg*h/L, p=0.041, Figure 1). Additionally, in multivariate testing the presence of the polymorphism remained significantly associated with MPA AUC₁₂. <h3>Conclusion</h3> We provide the first evidence that SLCO1B3 polymorphism rs7311358 is significantly associated with MPA dose normalized AUC₁₂ in lung recipients. Integration of this pharmacogenetic data with traditional pharmacokinetic testing could lead to more effective MPA management strategies.

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.

Pharmacokinetics of Enteric-Coated Mycophenolate Sodium Metabolites in Patients Over 60 Years Old Within the First Year After Renal Transplantation

ObjectiveIt is still unclear whether mycophenolic acid (MPA) doses should be adjusted for older patients. Therefore, we compared the pharmacokinetics of MPA, mycophenolic acid glucuronide (MPAG), and free MPA (fMPA) between older and younger renal transplant recipients. MethodsWe included 12 patients <60 years and 6 patients >60 years within the first year after renal transplantation, who were receiving enteric-coated mycophenolate sodium, tacrolimus, and steroids. Blood samples were collected up to 12 hours after drug administration. ResultsMPA and fMPA pharmacokinetics were similar for patients <60 and >60 years; however, the MPA area under the concentration-time curve from 0 to 12 hours (AUC0-12) was 1.2-fold lower in the older patients. MPAG pharmacokinetics were more than 1.5-fold higher in patients >60 years, which might be related to deteriorated renal function in older people. Moreover, the mean (MPAG AUC0-12)/(MPA AUC0-12) ratio was more than 2-fold higher in patients >60 years. The second maximal MPA concentration was more frequently observed in patients <60 years, although all patients received tacrolimus. The percentage of patients with MPA concentration before the next drug dose (Ctrough) and AUC0-12 within and below target was the same in both groups. All patients >60 years had MPA AUC0-12 >30 μg·h/mL within 22 to 114 days after transplantation. ConclusionsMPA therapeutic monitoring should be recommended in enteric-coated mycophenolate sodium--treated patients >60 years because MPA AUC0-12 exceeded the recommended value in half of the studied patients.

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.

Establishment of a Liquid Chromatography-Tandem Mass Spectrometry Method for the Determination of Immunosuppressant Levels in the Peripheral Blood Mononuclear Cells of Chinese Renal Transplant Recipients.

Monitoring immunosuppressant levels, such as mycophenolic acid (MPA), cyclosporin A (CsA), and tacrolimus (TAC), in peripheral blood mononuclear cells (PBMCs) could be useful in organ transplant patients administered individualized therapy. The authors developed a liquid chromatography-tandem mass spectrometry assay technique to simultaneously determine immunosuppressant levels in PBMCs and assess their pharmacokinetics in Chinese renal allograft recipients. PBMCs were isolated from the whole blood of 27 Chinese renal transplant patients using Ficoll-Paque Plus solution, and cell number was determined; acetonitrile treatment for protein precipitation, and gradient elution was performed on an Agilent Eclipse XDB-C18 column (3.5 μm, 2.1 × 100 mm) with mobile phase: water and methanol (containing 2 mM ammonium formate); flow rate: 0.3 mL·min. The calibration curves of MPA, CsA, and TAC had a linear range (ng·mL): 0.098-39.2 (r = 0.9987), 0.255-102 (r = 0.9969), and 0.028-11.2 (r = 0.9993), respectively. The extraction effects, matrix effects, and mean relative recovery of these immunosuppressants were 70.4%-93.2%, 72.7%-96.5%, and 90.1%-112.4%, respectively. The within-day and between-day coefficients of variation were <15%. The AUC0-12 of MPA in PBMCs correlated well with those in plasma. The level of MPA, CsA, and TAC in PBMCs might be more stable during dosing interval. The derived liquid chromatography-tandem mass spectrometry assay is suitable for simultaneously monitoring different immunosuppressants in PBMCs. Pharmacokinetic of MPA, CsA, and TAC displayed considerable interindividual variability. Intracellular monitoring of immunosuppressants may facilitate individualized therapy for renal allograft recipients.

A Limited Sampling Strategy for Therapeutic Drug Monitoring of Mycophenolate Mofetil for Prophylaxis of Acute Graft-Versus-Host Disease in Allogeneic Stem Cell Transplantation

A universally accepted strategy for therapeutic drug monitoring (TDM) of mycophenolate mofetil (MMF) in the prevention of acute graft-versus-host disease (aGVHD) in allogenic hematopoietic stem cell transplantation (alloHSCT) does not exist. We explored the feasibility of developing a limited sampling strategy (LSS) for TDM of MMF in this setting. Patients undergoing alloHSCT received standard MMF-cyclosporine prophylaxis, with MMF administered twice daily (BD) for matched transplant recipients or thrice daily (TID) in haploidentical transplantation. Intensive blood sampling was carried out on day 7 and area under the concentration–time curve (AUC) of mycophenolic acid (MPA), the active metabolite, was estimated using noncompartmental analysis. The ability of MPA exposure defined by AUC0-12 to discriminate between responders (patients who did not develop GVHD) and nonresponders (patients who developed GVHD) was determined by receiver operating characteristic curve analysis. Patients were divided into training and validation sets within BD and TID groups. Mathematical equations were developed from the training set to predict AUC0-12 from an abbreviated AUC involving a limited number of sampling points. The equations were validated in the validation set by comparing the MPA AUC0-12 predicted from LSS with the observed AUC0-12. It was observed that patients with AUC0-12 ≤18.99 mg*h/L had a higher risk of developing aGVHD [odds ratio (OR) = 2.63 (1.17 to 5.87), P = 0.06]. The benefit was more in matched transplant recipients [OR = 3.5 (1.30 to 9.49), P = 0.05] as compared to haploindentical transplant [OR = 2.8 (0.49 to 15.91), P = NS]. Using the mathematical equations, the observed AUC0-12 was predicted with 92.31% accuracy in the BD subset and 100% accuracy in the TID subset for a combined accuracy of 94.76%. A set of just three samples that constituted the abbreviated AUC1-4 was used to develop the predictive models. The LSS could be employed for the therapeutic monitoring of MMF particularly in patients undergoing matched hematopoietic stem cell transplantation.

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

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

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.

Pharmacokinetics of Enteric-Coated Mycophenolate Sodium in Lupus Nephritis (POEMSLUN).

Background:Mycophenolate mofetil or enteric-coated mycophenolate sodium (EC-MPS) and steroids are used for induction and maintenance therapy in severe lupus nephritis. Blood concentrations of mycophenolic acid (MPA), the active metabolite of these drugs, vary among patients with lupus nephritis. The objective of this study was to examine whether concentration-controlled (CC) dosing (through therapeutic drug monitoring) of EC-MPS results in a higher proportion of participants achieving target exposure of MPA compared with fixed-dosing (FD). An additional aim of the study was to evaluate the influence of CC dosing on clinical outcomes.Methods:Nineteen participants were randomly assigned either to the FD or CC group. All the participants were eligible to have free and total measurements of MPA over a period of 8–12 hours on 3 different occasions. Area under the concentration–time curve between 0 and 12 hours (AUC0-12) was calculated using noncompartmental methods. Dose of EC-MPS was titrated according to AUC0-12 in the CC group.Results:Thirty-two AUC0-12 measurements were obtained from 9 FD and 9 CC participants. Large inter-patient variability was observed in both groups but was more pronounced in the FD group. There were no significant differences between FD and CC participants in any pharmacokinetic parameters across the study visits, except for total C0 (FD 2.0 ± 0.3 mg/L versus CC 1.1 ± 0.3; P = 0.01) and dose-normalized C0 (FD 2.9 ± 0.2 mg/L/g versus CC 2.1 ± 0.7 mg/L/g; P = 0.04) at the second visit and total AUC0-12 (FD 66.6 ± 6.0 mg·h/L versus CC 35.2 ± 11.4 mg·h/L; P = 0.03) at the third visit. At the first study visit, 33.3% of the FD and 11.1% of the CC participants achieved the target area under the concentration–time curve (P = 0.58). From the second visit, none of the FD participants, compared with all the CC participants, achieved target AUC0-12 (P = 0.01). More CC participants achieved remission compared with FD participants (absolute difference of −22.2, 95% confidence interval 0.19 to 0.55; P = 0.62). The mean free MPA AUC0-12 was significantly lower in those who had complete remission.Conclusions:CC participants reached target AUC0-12 quicker. Larger studies are required to test clinical efficacy.

Evaluation of Multiple Linear Regression–Based Limited Sampling Strategies for Enteric-Coated Mycophenolate Sodium in Adult Kidney Transplant Recipients

Although multiple linear regression-based limited sampling strategies (LSSs) have been published for enteric-coated mycophenolate sodium, none have been evaluated for the prediction of subsequent mycophenolic acid (MPA) exposure. This study aimed to examine the predictive performance of the published LSS for the estimation of future MPA area under the concentration-time curve from 0 to 12 hours (AUC0-12) in renal transplant recipients. Total MPA plasma concentrations were measured in 20 adult renal transplant patients on 2 occasions a week apart. All subjects received concomitant tacrolimus and were approximately 1 month after transplant. Samples were taken at 0, 0.33, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours and 0, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 9, and 12 hours after dose on the first and second sampling occasion, respectively. Predicted MPA AUC0-12 was calculated using 19 published LSSs and data from the first or second sampling occasion for each patient and compared with the second occasion full MPA AUC0-12 calculated using the linear trapezoidal rule. Bias (median percentage prediction error) and imprecision (median absolute prediction error) were determined. Median percentage prediction error and median absolute prediction error for the prediction of full MPA AUC0-12 were <15% for 4 LSSs, using the data from the same (second) occasion. One equation (1.583C1 + 0.765C2 + 0.369C2.5 + 0.748C3 + 1.518C4 + 2.158C6 + 3.292C8 + 3.6690) showed bias and imprecision <15% for the prediction of future MPA AUC0-12, where the predicted AUC0-12 from the first occasion was compared with the full AUC0-12 from the second. All LSSs with an acceptable predictive performance included concentrations taken at least 6 hours after the dose. Only one LSS had an acceptable bias and precision for future estimation. Accurate dosage prediction using a multiple linear regression-based LSS was not possible without concentrations up to at least 8 hours after the dose.

Usefulness of limited sampling strategy for mycophenolic acid area under the curve considering postoperative days in living-donor renal transplant recipients with concomitant prolonged-release tacrolimus

BackgroundThe optimal dose of mycophenolate mofetil (MMF) in renal transplant patients has been recommended to be decided on the basis of area under the concentration-time curve (AUC0-12) of mycophenolic acid (MPA). Although meta-analysis has revealed that postoperative day (POD) is an influencing factor in MPA pharmacokinetics, there are no reports regarding a limited sampling strategy (LSS) for MPA AUC in consideration of POD. The aim of this study was to construct of an LSS considering POD that appropriately expresses the MPA AUC following renal transplantation and evaluation of the usefulness.MethodsSerum concentration–time profiles (measured AUC0-12) comprising nine sampling points over 12 h were analyzed in 36 living-donor renal transplant recipients after MMF administration with concomitant once-daily prolonged-release tacrolimus. Two LSSs were developed by stepwise multiple regression analysis (Method A: not classified by PODs; Method B: classified by PODs into POD < 31 and POD ≥ 31). Each LSS comprised four blood-sampling points within 6 h after MMF administration. Precision and reliability were verified by using root-mean-square error (RMSE), correlation coefficient (R2), and coefficient of determination (q2) by using leave-one-out cross-validation. The absolute values of the difference between measured and estimated AUCs (delta AUC) were compared for both estimating equations.ResultsOne-hundred samples obtained from 36 recipients for AUC0-12 comprised POD < 31 (n = 39) and POD ≥ 31 (n = 61). Estimation of AUC0-12 by Method B resulted in better accuracy and reliability (Method A: RMSE = 5.5, R2 = 0.85, q2 = 0.83; Method B: POD < 31: RMSE = 5.5, R2 = 0.86, q2 = 0.83; POD ≥ 31: RMSE = 3.9, R2 = 0.92, q2 = 0.89) and significantly lower median delta AUC compared with that by Method A (delta AUC: 2.6 (0.0–11.6) v.s. 3.9 (0.1–18.1), p = 0.032).ConclusionThese results suggest that LSS, classified as POD < 31 or POD > 31, would provide more accurate and reliable estimation of MPA AUC0-12 in Japanese living-donor renal transplant patients.

Influence of cyclosporine and everolimus on the main mycophenolate mofetil pharmacokinetic parameters: Cross-sectional study.

The objective of the present study was to assess the effect of cyclosporine (CsA) on the pharmacokinetic parameters of mycophenolic acid (MPA), an active mycophenolate mofetil (MMF) metabolite, and to compare with the effect of everolimus (EVR).Anonymized medical records of 404 kidney recipients were reviewed. The main MPA pharmacokinetic parameters (AUC(0–12) and Cmax) were evaluated.The patients treated with a higher mean dose of CsA displayed higher MPA AUC(0–12) exposure in the low-dose MMF group (1000 mg/day) (40.50 ± 10.97 vs 28.08 ± 11.03 h mg/L; rs = 0.497, P < 0.05), medium-dose MMF group (2000 mg/day) (43.00 ± 6.27 vs 28.85 ± 11.08 h mg/L; rs = 0.437, P < 0.01), and high-dose MMF group (3000 mg/day) (56.75 ± 16.78 vs 36.20 ± 3.70 h mg/L; rs = 0.608, P < 0.05).A positive correlation was also observed between the mean CsA dose and the MPA Cmax in the low-dose MMF group (Cmax 22.83 ± 10.82 vs 12.08 ± 5.59 mg/L; rs = 0.507, P < 0.05) and in the medium-dose MMF group (22.77 ± 8.86 vs 13.00 ± 6.82 mg/L; rs = 0.414, P < 0.01).The comparative analysis between 2 treatment arms (MMF + CsA and MMF + EVR) showed that MPA AUC(0–12) exposure was by 43% higher in the patients treated with a medium dose of MMF and EVR than in the patients treated with a medium dose of MMF and CsA.The data of the present study suggest a possible CsA versus EVR influence on MMF pharmacokinetics. Study results show that CsA has an impact on the main MPA pharmacokinetic parameters (AUC(0–12) and Cmax) in a CsA dose-related manner, while EVR mildly influence or does not affect MPA pharmacokinetic parameters. Low-dose CsA (lower than 180 mg/day) reduces MPA AUC(0–12) exposure under the therapeutic window and may lead to ineffective therapy, while a high-dose CsA (>240 mg/day) is related to greater than 10 mg/L MPA Cmax and increases the likelihood of adverse events.