Mycophenolic Acid Area Under The Curve Research Articles

#2047 Trough-level guided dosing is reliable for mycophenolate mofetil but not for enteric-coated mycophenolic sodium

Abstract Background and Aims While trough level (TL) guided dosing is usus for calcineurin inhibitors, mycophenolic acid (MPA) was marketed as a one-size-fits-all drug. TL has been reported to be a poor surrogate marker of MPA exposure by reason of complex pharmacokinetics. Measurement of area under the curve (AUC) remains the gold-standard for MPA dosing. Method We measured MPA TL and AUC in 299 KTRs at the University Hospital of Zurich. KTRs with agreement between TL and AUC target range of 40-60 mg/Lxh were compared to KTRs with missing agreement between TL and AUC for differences regarding baseline characteristics and co-medication. Results For mycophenolate mofetil (MMF, n = 218) a high correlation between TL and AUC was observed, p < 0.0001, r = 0.85, while correlation was only low for enteric-coated mycophenolate sodium (EC-MPS, n = 81), p = 0.002, r = 0.34, Fig. 1. However, a high correlation between MPA level 4 hours after EC-MPS intake (C4L) and AUC was found, p < 0.0001, r = 0.94. ROC analysis defined an MMF-TL range of >2.05 mg/l (sensitivity 68%, specificity 89%) and <3.05 mg/l (sensitivity 70%, specificity 81%) correlating with an AUC of 40-60 mg/Lxh. Lack of proton pump inhibitors (PPI) use was significantly associated with incorrect classification (n = 71/218). For EC-MPS C4L a range of >1.25 mg/l (sensitivity 98, specificity 100) and <4.4 mg/l (sensitivity 93, specificity 91) was defined for an AUC of 40-60 mg/Lxh. Here, non-tacrolimus-based immunosuppression was significantly associated with incorrect classification (n = 7/81). Conclusion MMF dosing according to TL highly correlates with AUC especially in KTRs treated with PPI. In contrast, EC-MPS dosing according to C4L is preferred especially in context of tacrolimus-based immunosuppression.

Limited sampling strategy and population pharmacokinetic model of mycophenolic acid in pediatric patients with systemic lupus erythematosus: application of a double gamma absorption model with SAEM algorithm.

Mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), is widely used in the treatment of systemic lupus erythematosus (SLE). It has been shown that its therapeutic drug monitoring based on the area under the curve (AUC) improves treatment efficacy. MPA exhibits a complex bimodal absorption, and a double gamma distribution model has been already proposed in the past to accurately describe this phenomenon. These previous population pharmacokinetics models (POPPK) have been developed using iterative two stage Bayesian (IT2B) or non-parametric adaptive grid (NPAG) methods. However, non-linear mixed effect (NLME) approaches based on stochastic approximation expectation-maximization (SAEM) algorithms have never been published so far for this particular model. The objectives of this study were (i) to implement the double absorption gamma model in Monolix, (ii) to compare different absorption models to describe the pharmacokinetics of MMF, and (iii) to develop a limited sampling strategy (LSS) to estimate AUC in pediatric SLE patients. A data splitting of full pharmacokinetic profiles sampled in 67 children extracted either from the expert system ISBA (n = 34) or the hospital Saint Louis (n = 33) was performed into train (75%) and test (25%) sets. A POPPK was developed for MPA in the train set using a NLME and the SAEM algorithm and different absorption models were implemented and compared (first order, transit, or simple and double gamma). The best limited sampling strategy was then determined in the test set using a maximum-a-posteriori Bayesian method to estimate individual PK parameters and AUC based on three blood samples compared to the reference AUC calculated using the trapezoidal rule applied on all samples and performances were assessed in the test set. Mean patient age and dose was 13years old (5-18) and 18.1mg/kg (7.9-47.6), respectively. MPA concentrations (764) from 107 occasions were included in the analysis. A double gamma absorption with a first-order elimination from the central compartment best fitted the data. The optimal LSS with samples at 30min, 2h, and 3h post-dose exhibited good performances in the test set (mean bias - 0.32% and RMSE 21.0%). The POPPK developed in this study adequately estimated the MPA AUC in pediatric patients with SLE based on three samples. The double absorption gamma model developed with the SAEM algorithm showed very accurate fit and reduced computation time.

Influence of SLCO1B1 Polymorphisms on the Pharmacokinetics of Mycophenolic Acid in Renal Transplant Recipients.

This study was designed to analyze the correlation between single nucleotide polymorphisms (SNP) related to drug metabolism and pharmacokinetics of mycophenolic acid (MPA) during long-term follow-up. A retrospective cohort study involving 71 renal transplant recipients was designed. Blood samples were collected to extract total DNAs, followed by target sequencing based on next-generation sequencing technology. The MPA area under the curve (AUC) was calculated according to the formula established in our center. The general linear model and linear regression model were used to analyze the association between SNPs and MPA AUC. A total of 689 SNPs were detected in our study, and 90 tagger SNPs were selected after quality control and linkage disequilibrium analysis. The general linear model analysis showed that 9 SNPs significantly influenced MPA AUC. A forward linear regression was conducted, and the model with the highest identical degree (r2=0.55) included 4 SNPs (SLCO1B1: rs4149036 [P < 0.0001], ABCC2: rs3824610 [P = 0.005], POR: rs4732514 [P = 0.006], ABCC2: rs4148395 [P = 0.007]) and 6 clinical factors (age [P < 0.0001], gender [P < 0.0001], the incident of acute rejection (AR) [P = 0.001], albumin [P < 0.0001], duration after renal transplantation [P = 0.01], lymphocyte numbers [P = 0.026]). The most relevant SNP to MPA AUC in this model was rs4149036. The subgroup analysis showed that rs4149036 had a significant influence on MPA AUC in the older group (P = 0.02), high-albumin group (P = 0.01), male group (P = 0.046), and both within-36-month group (P = 0.029) and after-36-month group (P = 0.041). The systematic review included 4 studies, and 2 of them showed that the mutation in SLCO1B1 resulted in lower MPA AUC, which was contrary to our study. A total of 4 SNPs (rs4149036, rs3824610, rs4148395, and rs4732514) were identified to be significantly correlated with MPA AUC. Rs4149036, located in SLCO1B1, was suggested to be the most relevant SNP to MPA AUC, which had a stronger influence on recipients who were elder, male, or with high serum albumin. Furthermore, 6 clinical factors, including age, gender, occurrence of acute rejection, serum albumin, time from kidney transplantation, and blood lymphocyte numbers, were found to affect the concentration of MPA.

Mycophenolic Acid Exposure Prediction Using Machine Learning

Therapeutic drug monitoring of mycophenolic acid (MPA) based on area under the curve (AUC) is well-established and machine learning (ML) approaches could help to estimate AUC. The aim of this work is to estimate the AUC of MPA in organ transplant patients using extreme gradient boosting (Xgboost R package) ML models. A total of 12,877 MPA AUC from 0 to 12 hours (AUC0-12h ) requests from 6,884 patients sent to our Immunosuppressant Bayesian Dose Adjustment expert system (https://abis.chu-limoges.fr) for AUC estimation and dose recommendation based on MPA concentrations measured at least at three sampling times (~20minutes, 1 and 3hours after dosing) were used to develop two ML models based on two or three concentrations. Data were split into a training set (75%) and a test set (25%) and the Xgboost models in the training set with the lowest root mean squared error (RMSE) in a 10-fold cross-validation experiment were evaluated in the test set and in 4 independent full-pharmacokinetic (PK) datasets from renal or heart transplant recipients. ML models based on two or three concentrations, differences between these concentrations, relative deviations from theoretical times of sampling, presence of a delayed absorption peak, and five covariates (dose, type of transplantation, associated immunosuppressant, age, and time between transplantation and sampling) yielded accurate AUC estimation performances in the test datasets (relative bias<5% and relative RMSE<20%) and better performance than MAP Bayesian estimation in the four independent full-PK datasets. The Xgboost ML models described allow accurate estimation of MPA AUC0-12h and can be used for routine exposure estimation and dose adjustment and will soon be implemented in a dedicated web interface.

The use of mycophenolate mofetil area under the curve.

Although mycophenolate mofetil (MMF) has been used successfully to treat a myriad of autoimmune diseases, its complex pharmacokinetics make it difficult to determine the true drug exposure for an individual patient. This review summarizes the body of literature focused on the gold standard measurement of the area under the curve (AUC) of mycophenolic acid (MPA), the active metabolite of MMF. Fixed dosing of MMF leads to highly variable drug exposure. Retrospective series have reported improved clinical outcomes when a minimum AUC value from 0 to 12 h (AUC0-12h) ≥30 mg h/l is achieved. MPA levels are affected by various drug interactions, hypoalbuminemia, and renal insufficiency and the measurement of free rather than total MPA levels is prudent in some situations. A limited number of studies employing prospective dose adjustment of MMF based on AUC0-12h measurements have yielded mixed results. Given the wide range of MPA AUC encountered in autoimmune diseases, dose adjustments of MMF based on AUC rather than fixed dosing of MMF should be considered in both clinical practice and clinical trials. Limited sampling strategies have been proposed to improve clinical feasibility of measurements, but a standard is yet to be defined.

The impact of omeprazole on mycophenolate pharmacokinetics in kidney transplant recipients.

BackgroundThe absorption rates of mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS) may be influenced by the concomitant use of omeprazole.MethodsOne hundred kidney transplant patients were recruited during their outpatient visits, including 50 on MMF and 50 on EC-MPS. At the clinic, a predose mycophenolic acid (MPA) sample (C0) was collected; subsequently, the participants received the proton-pump inhibitor omeprazole along with either MMF or EC-MPS. Two more blood samples were collected at 1.5 and 3.5 hours and used to estimate an area under the curve (AUC) from zero to 12 hours [AUC (0-12)].ResultsThe mean number of months after transplant was 92 months. The median AUC (0-12) and C0 results were 62.2 mg·h/L and 2.0 mg/L for the MMF group and 71.9 mg·h/L and 1.8 mg/L for the EC-MPS group (P = 0.160 and 0.225, respectively). Interestingly, 54% of the MMF group and 62% of the EC-MPS group showed AUCs above the target values. The correlation between MPA C0 and the predicted AUC was poor in both groups.ConclusionOmeprazole can be safely co-administered with either MMF or EC-MPS, as it did not compromise the MPA exposure. Unexpectedly, however, a high percentage of patients presented MPA AUCs exceeding the target value, highlighting the importance of periodically assessing MPA level.

Mycophenolic Acid Area under the Curve Monitoring via Limited Sampling Strategy in Pediatric Heart Transplant Recipients

Purpose The study aim was to investigate exposure to mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), after pediatric orthotopic heart transplantation (pOHT). Previous studies in pediatric kidney recipients demonstrated a relationship between MPA concentration and risk of rejection or hematologic side effects. The quantification of MPA in pOHT is not well established, and the relationship between a single-time-point-correlate and area under the curve (AUC) is lacking. We sought to assess the clinical individualization of MPA dosing after initiation of MPA AUC measurements in our patients. Methods Between April 2017 and September 2018, 81 pOHT were performed, from which 22 AUCs in 14 patients were collected via a 3 point limited sampling strategy. Indication for MPA measurement, MMF dose, frequency of dosage adjustment, and time from transplant were examined via retrospective chart review. The first year post pOHT biopsies are for concern of rejection based on frequent echocardiograms, or per DSAs, monitored at transplant and months 3, 6, and 12 thereafter. Results Median MPA AUC was 37.5 mg*h/L (range 14-216) at 61 days post-pOHT (range 11-4426). Median patient age was 10 years (range 46 days-16 years). Of 22 MPA AUCs collected, 12 warranted dosage adjustments for optimization. Within those, 9 patients' AUCs were re-measured post adjustment with 8 attaining goal range 30-60 mg*h/L. Median MMF dose was 500 mg/m^2, or 18.8 mg/kg, both twice daily. Fifty percent of all AUCs were for-cause indications: high-risk Epstein-Barr Virus donor positive, recipient negative (n=4); high-risk Cytomegalovirus donor positive, recipient negative (n=2); recent infections requiring systemic antimicrobials (n=4); and diagnosis of post transplant lymphoproliferative disorder (n=1). All but one (90.9%) of the for-cause AUC analyses merited dose adjustments. Three patients had baseline nausea; one displayed a supratherapeutic AUC. One reported nausea abatement following MMF decrease whereas two spontaneously resolved. Five reports of leukopenia were found, three with AUCs above 60 mg*h/L. All leukocyte levels normalized following MMF dosage reduction. Conclusion Patient specific tailoring of MMF via therapeutic drug monitoring of MPA AUC in pOHT may increase tolerability and diminish short and long term side effects of therapy.

Early Immunosuppressive Exposure of Enteric-Coated-Mycophenolate Sodium Plus Tacrolimus Associated with Acute Rejection in Expanded Criteria Donor Kidney Transplantation.

Background:Immunosuppressive agents are still inefficient in preventing biopsy-proven acute rejection (BPAR) after expanded criteria donor (ECD) kidney transplantation. The aim of this study was to investigate the relationships between early immunosuppressive exposure and the development of BPAR.Methods:We performed a retrospective study of 58 recipients of ECD kidney transplantation treated with enteric-coated-mycophenolate sodium, tacrolimus (Tac), and prednisone. The levels of mycophenolic acid-area under the curve (MPA-AUC)0-12h and Tac C0 were measured at the 1st week and the 1st month posttransplant, respectively. The correlation was assessed by multivariate logistic regression.Results:The occurrence rates of BPAR and antibody-mediated rejection were 24.1% and 10.3%, respectively. A low level of MPA-AUC0-12h at the 1st week posttransplant was found in BPAR recipients (38.42 ± 8.37 vs. 50.64 ± 13.22, P < 0.01). In addition, the incidence of BPAR was significantly high (P < 0.05) when the MPA-AUC0-12h level was <30 mg·h-1·L-1 at the 1st week (15.0% vs. 44.4%) or the Tac C0 was <4 ng/ml at the 1st month posttransplant (33.3% vs. 21.6%). Multivariable logistic regression analysis showed that the MPA-AUC0-12h at the 1st week (OR: 0.842, 95% CI: 0.784-0.903) and the Tac C0 at the 1st month (OR: 0.904, 95% CI: 0.822–0.986) had significant inverse correlation with BPAR (P < 0.05).Conclusions:Low-level exposure of MPA and Tac C0 in the early weeks posttransplant reflects an increased acute rejection risk, which suggested that MPA-AUC0-12h <30 mg·h-1·L-1 and Tac C0 <4 ng/ml should be avoided in the first few weeks after transplantation.

The utility of trough mycophenolic acid levels for the management of lupus nephritis.

Monitoring of mycophenolic acid (MPA) levels may be useful for effective mycophenolate mofetil (MMF) dosing. However, whether commonly obtained trough levels are an acceptable method of surveillance remains debatable. We hypothesized that trough levels of MPA would be a poor predictor of area under the curve (AUC) for MPA. A total of 51 patients with lupus nephritis who were on MMF 1500 mg twice a day and had a 4-h AUC done were included in this study. MPA levels were measured prior to (C0) and at 1 (C1), 2 (C2) and 4 (C4) h, followed by 1500 mg of MMF. The MPA AUC values were calculated using the linear trapezoidal rule. Regression analysis was used to examine the relationship between the MPA trough and AUC. Differences in the MPA trough and AUC between different clinical and demographic categories were compared using t-tests. When grouped by tertiles there was significant overlap in MPA, AUC 0-4 and MPA trough in all tertiles. Although there was a statistically significant correlation between MPA trough levels and AUC, this association was weak and accounted for only 30% of the variability in MPA trough levels. This relationship might be even more unreliable in men than women. The use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was associated with increased MPA trough levels and AUC at 0-4 h (AUC0-4). Trough levels of MPA do not show a strong correlation with AUC. In clinical situations where MPA levels are essential to guide therapy, an AUC0-4 would be a better indicator of the adequacy of treatment.

Mycophenolate Mofetil Therapy in Children With Idiopathic Nephrotic Syndrome: Does Therapeutic Drug Monitoring Make a Difference?

Idiopathic nephrotic syndrome (INS) necessitates administration of corticosteroids or corticoid-sparing agents in 60% of the cases for prolonged periods resulting in serious adverse effects. To avoid these complications, we investigated the efficacy and safety of mycophenolate mofetil (MMF) in our retrospective single-center study with 15 patients presenting with complicated courses of INS and aspired to estimate a cutoff level for mycophenolic acid-area under the curve (MPA-AUC) values, which can predict relapses with high sensitivity. Seven of 15 patients stayed in remission while receiving MMF. Average frequency of relapses was 1.39 (0.28-2.5) per year. In case of relapses, patients had lower predose and estimated AUC0-12 levels of MPA (P = 0.02 and 0.001, respectively). Based on the results of receiver operating characteristic analysis, we consider an estimated MPA-AUC0-12 lower than 44.6 mg·h·L(-1) as a risk factor for future relapses (91% sensitivity, 57% specificity, P = 0.06) because the prevalence of relapse is significantly lower (0.07 versus 0.5, P = 0.02), if the estimated MPA-AUC0-12 is >44.6 mg·h·L(-1). During MMF administration, we did not detect any adverse event requiring discontinuation of treatment. In conclusion, we demonstrate MMF as an alternative treatment for children with complicated INS to maintain remission without serious side effects. Furthermore, we propose a higher therapeutic target range of MPA-AUC0-12 (>45 mg·h·L(-1)) than used in transplanted children underlining the crucial role of therapeutic drug monitoring.

Development and validation of limited sampling strategy equation for mycophenolate mofetil in children with systemic lupus erythematosus.

The aim of this study was to establish a limited sample strategy (LSS) to predict the mycophenolic acid (MPA) area under the curve (AUC)(0-12) in children with systemic lupus erythematosus (SLE). Three months after initiation of mycophenolate mofetil (MMF) 26 children with SLE presented for therapeutic drug monitoring of MPA. On the day of the test, 10 specimens were collected, analyzed, and MPA AUC(0-12) was calculated. Using step-wise regression analysis, LSS equations were developed. Using bootstrap validation, the predictive performance was calculated. The measured mean (standard deviation) for the trough concentration and AUC(0-12) were 2.55 (1.57) μg/ml and 62.6 (21.67) mg.h/L, respectively. The range of trough concentrations and AUC(0-12) were 0.7–5.54 μg/ml and 22.1–104.8 mg.h/L, respectively. The interindividual variability (%CV) for dose normalized AUC(0-12) and dose normalized Ctrough was 46.5% and 61.1%, respectively. The correlation between the concentrations at the different time points and MPA AUC(0-12) ranged from 0.05 (1.5 h) to 0.56 (4 h). Two LSS equations that included 4 or 5 time points up to 3 h were developed and validated. The 4 point LSS had a correlation (R2) of 0.88 and the 5 point LSS an R2 of 0.87. With respect to the 4 point and 5 point MPA LSS AUC(0-12), the bias was 1.92% and 1.96%, respectively, and the imprecision was 11.24% and 11.28%, respectively. A 4 point LSS which concludes within 3 h after the administration of the MMF dose was developed and validated, to determine the MPA AUC(0-12) in children with SLE.

Mycophenolic mofetil optimized pharmacokinetic modelling, and exposure-effect associations in adult heart transplant recipients

Mycophenolic acid (MPA) area under the curve (AUC) has been associated with graft outcome. The aims of our study were: (1) to develop pharmacokinetic tools to optimize MPA inter-dose AUC estimation in heart transplant patients; and (2) to investigate the relationships between acute allograft rejection and MPA AUC, trough level (C0) or mycophenolate mofetil (MMF) dose.Two independent modeling approaches (parametric and non parametric) were used to fit 56 rich MPA pharmacokinetic (PK) profiles collected from 40 adult heart transplant recipients enrolled in the PIGREC study, receiving MMF and a calcineurin inhibitor (CNI), in the first year post-transplantation. In addition, associations between drug exposure (MPA C0, AUC and MMF dose) and acute rejection or MMF adverse events were investigated using time-dependent Cox models with stratification on the type of calcineurin inhibitor. Exposure threshold values were investigated using ROC curve analysis.The 2 models developed fit adequately the data and the use of their combination yielded 100% consistency with the measured AUC in terms of strategy of dose adjustment (maintain, increase or decrease). MPA measured AUC adjusted on CNI exposure was significantly associated with rejection (per unit increase: HR [95% CI]=0.97 [0.95–0.99], p=0.0122), while no effect was shown for adverse events attributable to MMF. An AUC threshold of 50mg×h/L was proposed (sensitivity=77%, specificity=25%) beyond which the risk of rejection was significantly increased (low vs. high: HR=3.48 [1.21–10.0], p=0.0204).The tools developed have already been made available to the heart transplant community on our ISBA website (https://pharmaco.chu-limoges.fr).

Mycophenolic acid AUC in Thai kidney transplant recipients receiving low dose mycophenolate and its association with UGT2B7 polymorphisms.

BackgroundDespite use of a lower mycophenolate dose in Thai kidney transplant patients, acceptable graft and patient outcomes can be achieved. We therefore examined the pharmacokinetics of mycophenolic acid (MPA) by area under the curve (AUC) and investigated genetic contribution in mycophenolate metabolism in this population.MethodsKidney transplant recipients with stable graft function who were receiving mycophenolate mofetil 1,000 mg/d in combination with either cyclosporine or tacrolimus, and prednisolone were studied. The MPA concentration was measured by fluorescence polarization immunoassay (FPIA), at predose and 1, 1.5, 2, 4, 6, 8, 10, and 12 hours after dosing. Genetic polymorphisms in UGT1A8, UGT1A9, and UGT2B7 were examined by denaturing high-performance liquid chromatography (DHPLC)-based single-base extension (SBE) analysis.ResultsA total 138 patients were included in study. The mean AUC was 39.49 mg-h/L (28.39–89.58 mg-h/L), which was in the therapeutic range. The correlation between the predose MPA concentration and AUC was poor. The mean AUC in the tacrolimus group was higher than that in the cyclosporine group. Polymorphisms in UGT2B7 showed significant association with AUC.ConclusionMost of our patients with reduced mycophenolate dose had the AUC within the therapeutic range. Genetic polymorphisms in UGT2B7 may play a role in MPA metabolism in Thai kidney transplant patients.

Mycophenolate mofetil in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis: a prospective pharmacokinetics and clinical study

Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) treatment strategy is based on immunosuppressive agents. Little information is available concerning mycophenolic acid (MPA) and the area under the curve (AUC) in patients treated for AAV. We evaluated the variations in pharmacokinetics for MPA in patients with AAV and the relationship between MPA-AUC and markers of the disease. MPA blood concentrations were measured through the enzyme-multiplied immunotechnique (C(0), C(30), C(1), C(2), C(3), C(4), C(6) and C(9)) to determine the AUC. Eighteen patients were included in the study. The median (range) MPA AUC(0-12) was 50·55 (30·9-105·4) mg/h/l. The highest coefficient of determination between MPA AUC and single concentrations was observed with C(3) (P < 0·0001) and C(2) (P < 0·0001) and with C(4) (P < 0·0005) or C(0) (P < 0·001). Using linear regression, the best estimation of MPA AUC was provided by a model including C(30), C(2) and C(4): AUC = 8·5 + 0·77 C(30) + 4·0 C(2) + 1·7 C(4) (P < 0·0001). Moreover, there was a significant relationship between MPA AUC(0-12) and lymphocyte count (P < 0·01), especially CD19 (P < 0·005), CD8 (P < 0·05) and CD56 (P < 0·05). Our results confirm the interindividual variability of MPA AUC in patients treated with MMF in AAV and support a personalized therapy according to blood levels of MPA.

Pilot Study on the Efficacy and Safety of Generic Mycophenolate Mofetil (Mycept) Compared With Cellcept Among Incident Low-Risk Primary Kidney Transplant Recipients

AimThe aim of this study was to establish the efficacy and safety of generic mycophenolate mofetil (Mycept) and determine the bioequivalence with Cellcept. This will provide patients an alternative cost-effective option that may improve compliance and long-term outcome. MethodsThis was a comparative study between 2 nonconcurrent matched groups on Mycept and Cellcept. A total of 56 patients were included based on criteria (20 incidental patients on Mycept, matched to 20 historical patients on Cellcept, and 16 additional incidental patients on Cellcept). Patient and graft survival and safety parameters were reviewed at 6 months. Bioequivalence of Mycept with Cellcept was done by measuring area under the curve (AUC) of mycophenolic acid (MPA), maximum concentration, and time to maximum concentration for 16 patients in each group. ResultsTwenty incidental Mycept patients completed 6 months of follow-up. No significant difference was observed in survival (P = 1.0), graft function (P = .2320), and rejection episodes (P = .6250) between groups. The most common side effect of Mycept was hematologic and infectious. The MPA AUC of Mycept (37.38 ng/mL) was within the recommended MPA of 30–60 ng/mL. The maximum concentration (6.06 ng/mL) and time to maximum concentration (1.19 hours) of the 10 Mycept patients were not significantly different from the 10 Cellcept patients. ConclusionThere was no proven statistically significant difference between Mycept and Cellcept in efficacy and graft survival at 6 months after kidney transplantation. Hematologic side effects were noted more frequently among patients on Mycept and monitoring regularly is recommended.

Population Pharmacokinetics and Bayesian Estimation of Mycophenolic Acid Exposure in Heart Transplant Recipients: Comparison of Two Approaches

Purpose Mycophenolic acid (MPA) area under the curve (AUC) has been reported as an important marker of graft outcome. The aim of our study was to develop: (i) population pharmacokinetic (POPPK) models in adult heart transplant patients using a parametric (P) and a nonparametric (NP) approach; and (ii) two independent Bayesian estimators (BE) enabling AUC determination using a limited sampling strategy. Methods and Materials Fifty-six MPA pharmacokinetic (PK) profiles were collected from 39 adult heart transplant patients given mycophenolate mofetil. POPPK analysis was performed using both the parametric iterative two-stage Bayesian method and the nonparametric adaptive grid approach (using Pmetrics R package). The PK profiles were fitted to a one-compartment model with first-order elimination combined to two gamma laws to describe the absorption phase. Results PK profiles were divided into a development dataset (n=37) and a validation dataset (n=19). For each approach, a POPPK model was developed that accurately fitted the observed data. In the validation group, the BE developed using each model yielded good AUC estimation performance (bias of -1.26±19.33% (P) and -1.12±19.34% (NP)) on the basis of a 20, 60, 180 and 360 minutes sampling schedule. Accordingly, dose adjustment (for a 45 mg.h/L target AUC) based on BE was similar to that proposed on the basis of the reference AUC (trapezoidal AUC using all the available concentrations) in 79% (P) and 84% (NP) of the patients. Conclusions The PK profiles of MPA in heart transplant patients are more complex than those observed in kidney graft recipients. Bayesian estimators allowing the determination of MPA AUC using a limited number of blood samples have been developed using 2 totally independent population modelling approaches, the combination of which now increase the accuracy of our results. They are now available on our ISBA website (https://pharmaco.chu-limoges.fr) for routine dose adjustment.

Limits to Intensified Mycophenolate Mofetil Dosing in Kidney Transplantation

Studies have shown that achieving adequate exposure of mycophenolic acid (MPA) early post transplant is associated with less acute rejection in kidney recipients. Intensified dosing with the equivalent of mycophenolate mofetil (MMF) 3 g daily in tacrolimus-treated patients has been shown to increase exposure however about 15% remain below the lower therapeutic threshold of MPA area under the curve (AUC) of 30 mg · hr⁻¹ · L⁻¹ early post transplant. A post hoc analysis of this study showed that a target MPA AUC >40 mg · hr⁻¹ · L⁻¹ was most effective. The primary objective of this study was to determine whether 4 g daily of MMF would result in a greater proportion achieving adequate MPA exposure. MMF 4 g daily was used in tacrolimus treated de novo kidney transplant recipients. A 3-point limited sample strategy was used to measure MPA AUC on days 5 and 14. Doses were adjusted at day 5 if exposure was high. In 30 patients, the mean AUC was 63 ± 28 mg · hr⁻¹ · L⁻¹ on day 5, with 13% (4/30) ≤ 30 mg · hr⁻¹ · L⁻¹ and 57% (17/30) >60 mg · hr⁻¹ · L⁻¹. The target MPA AUC was <40 mg · hr⁻¹ · L⁻¹ in 23% (7/30). Three patients developed gastrointestinal toxicity and required dose changes. Acute rejection occurred in only 2 patients (grade 1A and 2B) within 3 months (day 5 MPA AUCs were 29.9 and 33 mg · hr⁻¹ · L⁻¹. On day 14 the mean AUC was 46 ± 17 mg · hr⁻¹ · L⁻¹. Many were on MMF doses >2 g daily (8 on 3 g and 9 on 4 g daily). Compared to MMF 3 g daily, 4 g daily dose not result in a greater proportion adequately exposed. Rejections were few and occurred in the lower MPA exposed recipients. More than 50% of patients needed doses of MMF >2 g daily for 2 weeks to avoid underexposure. If intensified MPA dosing is considered, exceeding 3 g daily in tacrolimus-treated patients provides no added benefit.

A limited sampling schedule to estimate mycophenolic Acid area under the concentration-time curve in hematopoietic cell transplantation recipients.

Mycophenolate mofetil (MMF) is a key component of postgrafting immunosuppression in hematopoietic cell transplant (HCT) recipients. The plasma area under the curve (AUC) of its active metabolite, mycophenolic acid (MPA), is associated with MMF efficacy and toxicity. This study developed a population pharmacokinetic model of MPA in HCT recipients and created limited sampling schedules (LSSs) to enable individualized pharmacotherapy. A retrospective evaluation of MPA concentration-time data following a 2-hour MMF intravenous (IV) infusion was conducted in 77 HCT recipients. The final model consisted of 1 and 2 compartments for MMF and MPA pharmacokinetics, respectively. The mean estimated values (coefficient of variation, %) for total systemic clearance, distributional clearance, and central and peripheral compartment volumes of MPA were 36.9 L/h (34.5%), 15.3 L/h (80.4%), 11.9 L (71.7%), and 182 L (127%), respectively. No covariates significantly explained variability among individuals. Optimal LSSs were derived using a simulation approach based on the scaled mean squared error. A 5-sample schedule of 2, 2.5, 3, 5, and 6 hours from the start of the infusion precisely estimated MPA AUC(0-12 h) for Q12-hour IV MMF. A comparable schedule (2, 2.5, 3, 4, and 6 hours) similarly estimated MPA AUC(0-8) (h) for Q8-hour dosing.

Diminished Mycophenolic Acid Exposure Caused by Omeprazole May Be Clinically Relevant in the First Week Posttransplantation

Some studies have reported a decreased absorption of mycophenolic acid (MPA) from mycophenolate mofetil (MMF) in renal transplanted (RTx) patients under proton-pump inhibitors (PPIs). There is still a lack of information regarding (1) whether this effect occurs when MMF is administered with either tacrolimus or cyclosporine A [calcineurin inhibitors (CNIs)], (2) whether the effect has the same amplitude during the first year after RTx, and finally (3) whether this decrease in exposure is clinically relevant. We retrospectively analyzed the omeprazole effect in 348 12-hour pharmacokinetic samplings [area under the curve (AUC)(0-12h)] performed on days 7, 14, 30, 60, 180, and 360 after RTx in 77 patients who participated in previous trials. For all periods, the groups with and without PPI did not differ in all variables. By mixed-model analysis of variance, PPI reduced the MPA AUC(0-12h) (P < 0.0008) in the patients under both CNIs mainly due to decreased absorption (P = 0.049). In the tacrolimus group, a lower exposure seemed also due to a decreased MPA reabsorption at 10-12 hours. The PPI effect remains throughout the first year but was clinically more important on day 7. By Cox analysis, the use of PPI was associated with a 25% less chance of being adequately exposed to MPA (95% confidence interval 0.58-0.99, P = 0.04). Similarly, the number of patients underexposed to MPA (AUC < 30 ng·h/mL) was higher at most periods in the PPI group but again not statistically significant. These data indicate that PPI decreases the MPA exposure when associated with both CNIs but particularly in the first week after RTx. In this period, the MMF dose should be increased. This effect lasts throughout the first year but does not seem to be clinically relevant after the first week.

Pharmacokinetic monitoring of mycophenolic acid in heart transplant patients: Correlation the side-effects and rejections with pharmacokinetic parameters

Mycophenolate mofetil is a commonly used immunosuppressant in heart transplantation but pharmacokinetic monitoring is not routinely done. We performed a prospective pilot multi-center trial in de-novo heart transplant recipients to evaluate the pharmacokinetics (PK) of mycophenolic acid (MPA) at multiple time points in the first year following transplant.<br /> MPA trough and estimated area-under-the-curve (AUC) values were obtained at multiple visits from 21 enrolled patients. We attempted to correlate the side-effects and rejections with PK parameters.<br /> MPA AUC and trough levels increased modestly over 12 months with substantial inter and intra patient variability. Cardiac rejection was associated with low MPA AUC values with a threshold of <36.2 mg×h/L during the first two post-transplant weeks. A threshold of 2-weeks average MPA trough level of 1.43 mg/L provided a sensitivity 82% and a specificity of 60%.<br /> Adequate MPA levels are associated with decreased risk of allograft rejection. For patients with Cyclosporine co-immunosuppression, we propose an MPA trough of 1.4 mg/L and an MPA AUC of 36 mg × h/L as threshold values for dose adjustments. We recommend monitoring MPA levels at 1, 2 and 4 weeks, 6 months, 1 year and whenever an unexplained side-effect or allograft rejection occurs. Additional MPA AUC measurements are recommended when trough levels do not explain the clinical picture.<br />