Mycophenolic Acid AUC Research Articles

Optimization of the dosing regimen of mycophenolate mofetil in pediatric liver transplant recipients

Mycophenolate mofetil (MMF) is now commonly used in pediatric liver transplant recipients, but no clear recommendations about the dosing regimen have been made for this population. The aim of this study was to determine the MMF dosage required for pediatric liver transplant recipients to achieve an area under the plasma concentration-time curve from 0 to 12 hours (AUC(0-12) ) for mycophenolic acid (MPA) greater than 30 mg hour/L. A pharmacokinetic study of 15 children (median age = 8.3 years, range = 1.1-15.2 years) was performed at a median of 11.0 months (range = 0.5-88.0 months) after liver transplantation. MMF was initially introduced at a median starting dose of 300 mg/m(2) twice a day (range = 186-554 mg/m(2) twice a day). Thirteen of the 15 patients had an MPA AUC(0-12) value less than 30 mg hour/L. The MMF dosage had to be increased in all patients except 1. The MMF dosage required to reach an MPA AUC(0-12) value greater than the defined target of 30 mg hour/L ranged from 371 to 1014 mg/m(2) /day. For 2 patients who received rifampin in addition to MMF, the MPA AUC(0-12) value remained low despite a 2-fold increase in the MMF dosage. In conclusion, an initial MMF dose of 600 mg/m(2) twice a day led to MPA AUC(0-12) values greater than the 30 mg hour/L threshold except when rifampin was coadministered. Because of the important interindividual variability of MPA pharmacokinetics, therapeutic drug monitoring is recommended for optimizing the daily MMF dosage. Furthermore, these results suggest that the coadministration of MPA with rifampin should be avoided.

Renal Graft Function and Low-Dose Cyclosporine Affect Mycophenolic Acid Pharmacokinetics in Kidney Transplantation

In kidney transplantation, the pharmacokinetics of mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is influenced by concomitant immunosuppressive therapy, including cyclosporine (CsA). However, whether in the setting of immunosuppressive therapy minimization CsA still affects MPA pharmacokinetics, particularly in relation to varying degree of renal graft function deterioration, remains ill defined. One hundred thirty-five complete MPA profiles were sequentially collected from 56 kidney transplant recipients given MMF and low-dose CsA as part of their immunosuppressive therapy. MPA pharmacokinetic parameters were correlated with blood CsA area under the curve (AUC0-12) and graft function as measured glomerular filtration rate (GFR). The relative contribution of CsA exposure and GFR to MPA kinetics in relation to other clinical parameters was determined by multivariate analysis. Dose-adjusted MPA AUC0-12 negatively correlated with CsA AUC0-12. MPA exposure significantly increased when CsA AUC0-12 was below 2000 ng hr/mL. Stratification of MPA profiles according to stages of renal dysfunction showed that dose-adjusted MPA AUC0-12 was higher (P<0.001) in patients with severe (stage 4: 70.37±27.93 μg hr/mL/g MMF) than in those with mild (stage 2: 47.46±11.66 μg hr/mL/g MMF) or moderate (stage 3; 47.48±15.22 μg hr/mL/g MMF) renal insufficiency. At multivariate analysis GFR, serum albumin and hemoglobin levels, use of gastroprotective medications, and time posttransplant were identified as independent determinants of MPA AUC0-12. In stable renal transplant recipients given MMF, tapering CsA dose and deterioration of renal graft function contribute to increased MPA exposure. Thus, monitoring plasma MPA pharmacokinetics should be advised, especially in patients on minimized CsA therapy with severe renal insufficiency.

Monitoring of Mycophenolic Acid Predose Concentrations in the Maintenance Phase More Than One Year After Renal Transplantation

Routine therapeutic drug monitoring of mycophenolic acid (MPA) is generally performed using the area under the concentration-time curve from 0 to 12 hours (AUC0-12) with recommended values between 30 and 60 μg·h/mL. The aim of this study was to examine whether the monitoring of the MPA predose concentration (C0) in patients who are stable for >1 year after renal transplantation was practical and to determine factors that cause MPA C0 variability among patients. Eighty-six Japanese patients who had undergone renal transplantation and were taking tacrolimus and who had their MPA C0 analyzed >6 times by high-performance liquid chromatography for >1 year posttransplantation were enrolled. Recipients with MPA AUC0-12 levels<30 μg·h/mL on day 28 and 1 year after transplantation had an MPA C0 of <2.0 μg/mL, with a sensitivity of 90.9% and a specificity of 70.7%. There was no significant difference in the mean dose-adjusted MPA C0>1 year after transplantation between subjects with either the UGT (1A1, 1A9, and 2B7) or drug transporter (SLCO1B3, ABCC2, and ABCG2) genotypes. However, in a multiple regression analysis, the dose-adjusted mean MPA C0>1 year after transplantation was significantly associated with age (P=0.0035), creatinine clearance (P=0.0001), and the dose-adjusted MPA AUC0-12 at 1 year (P=0.0147). To keep the MPA AUC0-12>30 μg·h/mL, the plasma threshold for maintaining the MPA C0 with tacrolimus should be set >2.0 μg/mL as determined by high-performance liquid chromatography. For patients who are stable for >1 year after transplantation, continued monitoring of the MPA C0 using the same samples used to monitor the tacrolimus C0 and the additional assessment of the MPA AUC0-12 at the 1-year time point seem to be a viable option. If a change of the mycophenolate mofetil dose seems necessary based on the routine MPA C0 information, the determination of MPA AUC0-12 using a limited sampling strategy is recommended.

The Pharmacokinetics of Enteric-Coated Mycophenolate Sodium and Its Gastrointestinal Side Effects in De Novo Renal Transplant Recipients of Hispanic Ethnicity

The aim of the study is to characterize the pharmacokinetics and the gastrointestinal side effect profiles of enteric-coated mycophenolate sodium (EC-MPS) in de novo kidney transplant patients of Hispanic ethnicity. The pharmacokinetic study of EC-MPS was conducted in 11 de novo kidney transplant patients of Hispanic ethnicity. Eight blood samples were obtained after EC-MPS was given at the steady state. Blood concentrations of mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) were measured. The mean age (± standard deviation) was 39.4 (± 12.3) years. The mean daily dose of EC-MPS at the time of the pharmacokinetic study was 1408 ± 108 mg. For MPA and MPAG, the time to peak concentration was 2.5 ± 1.3 hours and 4.6 ± 3.1 hours, respectively; the peak concentration (Cmax) was 19.3 ± 17.2 mg/L and 109.4 ± 49.2 mg/L; and the area under the curve from 6 to 12 hours (AUC6-12) was 32.2 ± 19.3 mg·hr/L and 373.7 ± 235.8 mg·hr/L, respectively, which represents 41.3% and 43.0% of AUC0-12. The AUC0-12 for MPA measured 77.8 ± 53.1 mg·hr/L and for MPAG 869.2 ± 388.8 mg·hr/L. Seven patients (64%) exhibited a second peak at approximately 8.3 hours after the dose at a mean concentration (± standard deviation) of 10.3 ± 7.6 mg/L. The Cmax or AUC of MPA does not correlate with overall Gastrointestinal Symptom Rating Scale scores or subscale scores, but the Cmax of MPAG correlates with indigestion subscale (P = 0.022), diarrhea (P = 0.032), and overall scores (P = 0.028). The AUC of MPAG also correlates with acid reflux (P = 0.024) and indigestion (P = 0.032). The pharmacokinetics of EC-MPS has a high variability in de novo kidney transplant patients of the Hispanic ethnicity, which was similar to other ethnic groups. The MPA exposure expressed by the AUC appears to be higher in Hispanic patients than those reported in other ethnic groups, which may be the result of various factors such as difference of the uridine diphosphate glucuronosyltransferase enzyme genotypes, but gastrointestinal side effects were acceptable and the Cmax or AUC of MPAG showed correlations with gastrointestinal symptoms.

The proton pump inhibitor pantoprazole and its interaction with enteric-coated mycophenolate sodium in transplant recipients

In this prospective study we investigated the impact of the proton pump inhibitor (PPI) pantoprazole on the bioavailability of mycophenolic acid (MPA) after oral administration of enteric-coated mycophenolate sodium (EC-MPS; Myfortic) in heart or lung transplant recipients. Previously we demonstrated that pantoprazole reduces the MPA exposure of mycophenolate mofetil (MMF; CellCept) by 34% in area under the concentration-time curve (AUC). Because gastrointestinal side-effects are common after organ transplantation, we investigated the effect of PPI on MPA levels in patients receiving EC-MPS. MPA plasma concentrations and inosine monophosphate dehydrogenase (IMPDH) activity at baseline, 30 minutes and 1, 2, 3 and 4 hours were obtained from 21 patients. These patients were treated with pantoprazole 40 mg once daily and EC-MPS twice daily at a mean dose of 960 mg. Measurements were repeated after pantoprazole withdrawal. MPA concentrations and IMPDH activities did not reveal any significant difference during PPI treatment and after withdrawal. MPA AUC, MPA C(max) (maximal MPA concentration), the time until C(max) was reached (T(max)) and IMPDH activity AUC all showed no significant difference. We did not find an influence of pantoprazole on EC-MPS pharmacokinetics such as we did for MMF in our previous investigation. A further prospective, large, cross-over study is planned to support these preliminary results. Given that MPA exposure by AUC correlates with the incidence of acute rejection episodes and transplant vasculopathy, the present findings may have clinical implications.

Evaluation of Limited Sampling Strategies for Mycophenolic Acid After Mycophenolate Mofetil Intake in Adult Kidney Transplant Recipients

Multiple limited sampling strategies (LSSs) have been proposed for estimation of mycophenolic acid (MPA) area under the concentration-time curve from 0 to 12 hours postdose (AUC 0-12) after mycophenolate mofetil intake. The aim of this study was to provide summary information on all published LSSs for MPA and to evaluate their predictive performance in an independent population of kidney transplant recipients. Seventy-eight LSSs for MPA were identified. Sixty-nine full AUC profiles were collected from 45 subjects (25 cotreated with cyclosporine and 20 with tacrolimus). Predicted MPA AUC 0-12, calculated by applying the relevant concentration measurements within the LSS equations, was compared with full AUC calculated by using all concentration measurements in the linear trapezoidal rule. Four error indices (median prediction error, median percentage prediction error [MPPE], root median squared prediction error, and median absolute percentage prediction error [MAPE]) were used to evaluate bias and imprecision. Twelve of the 25 LSSs for cyclosporine-cotreated recipients and one of the 53 LSSs for tacrolimus-cotreated recipients displayed acceptable (less than 15%) bias and imprecision. In the cyclosporine group, two equations demonstrated the highest predictive power, one that used four time points in the first 6 hours postdose (r2 = 0.84, MPPE 1.6%, MAPE 7.8%) and one that used four time points in the first 4 hours postdose (r2 = 0.76, MPPE -0.8%, MAPE 10.2%). In the tacrolimus group, an equation that used two time points in the first 4 hours postdose was superior (r2 = 0.80, MPPE -3.0%, MAPE 13.6%). Application of the LSSs most appropriate for cyclosporine-cotreated patients to the tacrolimus-cotreated group resulted in clinically unacceptable bias and imprecision and vice versa. High variability in performance of LSSs highlights the importance of validating any LSS before applying it to an alternative population. Attention to comedication use is of particular relevance when choosing a LSS.

A limited sampling strategy for estimation of the area under the curve (0 to 8 hours) of mycophenolic acid administered three times daily to liver transplant recipients

Objectives. Gastrointestinal side-effects caused by mycophenolic acid (MPA) are frequent in liver transplant recipients, and in these cases a switch from two to three daily doses is usually recommended. However, a limited sampling strategy for the estimation of MPA area under the curve from 0 to 8 hours (AUC(0–8h)) has not been made.Design and methods. In 22 liver transplant patients who were administered MPA three times daily, the trapezoidal extrapolated MPA AUC(0–8h) values using a sampling time from 0 to 2 hours were calculated.Results. A tentative therapeutic range for MPA AUC(0–8h) of about 20–40 μg.h/mL is proposed, and in the 13 patients with supratherapeutic values the total leukocyte blood count was significantly lower than in the 9 patients with AUC(0–8h) ≤ 40 μg.h/mL (P < 0.001). Significant negative correlations were found between the total leukocyte blood count and the MPA trough levels (r = −0.458; P < 0.05), AUC(0–8h) (r = −0.479; P < 0.05), and AUC(0–2h) (r = −0.437; P < 0.05). A significant correlation was found between the trapezoidal extrapolated AUC(0–8h) and trapezoidal AUC(0–2h) results (r = 0.850; P < 0.001).Conclusions. The trapezoidal extrapolated AUC(0–8h), and possibly trapezoidal AUC(0–2h), may be useful for routine therapeutic MPA monitoring in liver transplant recipients in which the dosing frequency is increased from twice to three times a day.

554 Histone deacetylase inhibitors mediate pharmacological rescue and increase membrane expression of ABCG2 harboring the Q141K single nucleotide polymorphism

This study aimed to evaluate the effect of UGT1A8*2, SLCO1B3 T334G, ABCC2 C-24T and ABCG2 C421A polymorphisms on the pharmacokinetics (PKs) of mycophenolic acid (MPA) and its phenolic glucuronide (MPAG) in healthy Chinese volunteers and in stable renal transplant patients.The data were extracted from comparative bioavailability studies conducted in 42 healthy individuals and 37 renal transplant patients. A complete PK profile was obtained over 48 h for healthy volunteers and over 12 h for the transplant patients. The MPA/MPAG plasma concentrations were measured by HPLC. The genotypes were determined using either the Taqman probe technique or direct sequencing. A multivariate analysis was used to assess the effect of the genotypes (UGT1A8*2, SLCO1B3 T334G, ABCC2 C-24T and ABCG2 C421A) and other covariates (age, weight, height, calculated creatinine clearance, serum albumin, haemoglobin and drug comedication) on the AUC4–12 and AUC0–12 for MPA and MPAG in the healthy volunteers and patients.In the healthy volunteers, the dose-adjusted geometric means (GM) of the MPA AUC4–12 in individuals with the SLCO1B3 334T allele were 30.4% lower than those values in the 334G homozygote carriers (P < 0.05); in the transplant patients, the steroid dose was associated with a negative effect on the AUC of MPAG (P < 0.03) and weight was associated with a negative effect on the AUC for MPA in the healthy volunteers and patients (P < 0.03). No other significant effect of genotype or of the other studied variables on AUC4–12 or AUC0–12 of MPA/MPAG was found in the healthy volunteers or patients.The PKs of MPA is affected by the SLCO1B3 polymorphism in healthy Chinese individuals. The absence of an effect of SLCO1B3 polymorphisms in transplant patients may be due to the co-administration of cyclosporine (CsA). Concomitant steroid dose and weight are two important covariates of the AUC of MPA and MPAG, which should be taken into account in clinical use. Further confirmatory in vivo studies are needed.

Variability in Free Mycophenolic Acid Exposure in Adult Liver Transplant Recipients During the Early Posttransplantation Period

Mycophenolate mofetil (MMF) pharmacokinetics variability in liver transplant recipients during the early posttransplantation period may be related to changes in mycophenolic acid (MPA) protein binding. This study aimed at characterizing the variation of free MPA exposure with respect to time since transplantation. Three groups (A, B, C) were compared. The median posttransplantation time was 12 days (A, n = 26 pharmacokinetic sessions), 36 days (B, n = 25), and 867 days (C, n = 21). The median MPA AUC(0-12) in group A (26.8 mg x h/L) was significantly lower than in groups B (45.2 mg x h/L, P = .031) and C (43.5 mg x h/L, P = .004). Free MPA AUC(0-12) was comparable whatever the time (0.41, 0.34, and 0.33 mg x h/L, respectively). MPA apparent clearance (CL/F) was significantly correlated with MPA free fraction (r = 0.60, P < .0001) and approximately 1.7-fold higher in group A compared to groups B and C (P < .05). Enhanced CL/F in relation with an increase in MPA free fraction results in a low AUC of total MPA during the first postoperative month, but on average, at the population level, the exposure to free MPA is not altered, suggesting that total MPA AUC should not be used to adapt MMF dosing during this period.

Population pharmacokinetics of mycophenolic acid in children and young people undergoing blood or marrow and solid organ transplantation

To characterize the population pharmacokinetics of mycophenolic acid (MPA) and evaluate dose regimens using a simulation approach and accepted therapeutic drug monitoring targets in children and young people undergoing blood or marrow, kidney and liver transplantation. MPA concentration-time data were collected using an age specific sampling protocol over 12h. Some patients provided randomly timed but accurately recorded blood samples. Total and unbound MPA were measured by HPLC. NONMEM was employed to analyze MPA pharmacokinetic data. Simulations (n= 1000) were conducted to assess the suitability of the MPA dose regimens to maintain total MPA AUC(0,12h) within the range 30 and 60mg l(-1) h associated with optimal outcome. A two-compartment pharmacokinetic model with first-order elimination best described MPA concentration-time data. Population mean estimates of MPA clearance, inter-compartmental clearance, volumes of distribution in the central and peripheral compartments, absorption rate constant and bioavailability were 6.42 l h(-1) , 3.74 l h(-1) , 7.24 l, 16.8l, 0.39h(-1) and 0.48, respectively. Inclusion of bodyweight and concomitant ciclosporin reduced the inter-individual variability in CL from 54.3% to 31.6%. Children with a bodyweight of 10kg receiving standard MPA dose regimens achieve an MPA AUC below the target range suggesting they may be at a greater risk of acute rejection. The population pharmacokinetic model for MPA can be used to explore dosing guidelines for safe and effective immunotherapy in children and young people undergoing transplantation.

Pharmacokinetics of mycophenolic acid in severe lupus nephritis

Mycophenolic acid (MPA) is an effective treatment for active lupus nephritis despite its variable efficacy in different ethnic groups. Here we tested whether pharmacokinetic monitoring may help to optimize dosing of MPA in an Asian population. Patients with biopsy-proven class III or IV lupus nephritis (ISN/RPS category) were treated with mycophenolate mofetil or enteric-coated mycophenolate sodium. One month after initiating treatment we measured plasma MPA levels in eight samples taken over a 12-h period after drug administration. The mean area under the time-dependent curve for MPA of responding patients was significantly higher than those not responding. Successful treatment was seen in patients with areas >45 mg h/l. The dosage of the drug was not related to MPA pharmacokinetics. In the mycophenolate mofetil group, however, MPA-area under the curve was positively, and significantly, correlated with trough or 1 h after dose concentrations and associated with a therapeutic response. Thus, our study shows that MPA pharmacokinetics were positively correlated with therapeutic responses of mycophenolate, suggesting that controlling the concentrations may improve its therapeutic efficacy in lupus nephritis. As the absorption and pharmacokinetic peak of enteric-coated tablets is slower, it is important to take different formulations into account when determining optimal MPA concentrations.

Pharmacokinetics and Pharmacodynamics of Mycophenolic Acid and Their Relation to Response to Therapy of Childhood-Onset Systemic Lupus Erythematosus

Mycophenolic acid (MPA) is the active form of mycophenolate mofetil (MMF), which is currently used off-label as immunosuppressive therapy in childhood-onset SLE (cSLE). The objectives of this study were to (1) characterize the pharmacokinetics (MPA-PK) and pharmacodynamics (MPA-PD) of MPA and (2) explore the relationship between MPA-PK and cSLE disease activity. MPA-PK [area under the curve from 0-12 hours (AUC(0-12))] and MPA-PD [inosine-monophosphate dehydrogenase (IMPDH) activity] were evaluated in cSLE patients on stable MMF dosing. Change in SLE disease activity while on MMF therapy was measured using the British Isles Lupus Assessment Group (BILAG) index. A total of 19 AUC(0-12) and 10 IMPDH activity profiles were included in the analysis. Large interpatient variability in MPA exposure (AUC(0-12)) was observed (mean ± SE: 32 ± 4.2 mg h/L; coefficient of variation: 57%). Maximum MPA serum concentrations coincided with maximum IMPDH inhibition. AUC(0-12) and weight-adjusted MMF dosing were only moderately correlated (r = 0.56, P = 0.01). An AUC(0-12) of ≥30 mg h/L was associated with decreased BILAG scores while on MMF therapy (P = 0.002). Weight-adjusted MMF dosing alone does not reliably allow for the prediction of exposure to biologically active MPA in cSLE. Individualized dosing considering MPA-PK appears warranted as this allows for better estimation of immunologic suppression (IMPDH activity). Additional controlled studies are necessary to confirm that an MPA AUC(0-12) of at least 30 mg h/L is required for cSLE improvement.

Mycophenolic acid area under the curve correlates with disease activity in lupus patients treated with mycophenolate mofetil

Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil (MMF), which is widely used to treat systemic lupus erythematosus (SLE). In transplantation, MPA area under the plasma concentration-time curve from 0 to 12 hours (MPA AUC(0-12)) is correlated with clinical outcome. We undertook the present study to assess possible relationships between SLE activity and MPA AUC(0-12). Using a Bayesian estimator, MPA AUC(0-12) was determined in 71 consecutive SLE patients (61 women and 10 men; mean +/- SD age 34 +/- 10 years) receiving a stable MMF dose. On the same day, SLE activity was assessed using the SLE Disease Activity Index (SLEDAI; active disease defined as a SLEDAI score > or = 6) and the British Isles Lupus Assessment Group (BILAG) index (active disease defined as BILAG A or B). Two groups were studied: patients with active SLE (mean +/- SD SLEDAI score 11.6 +/- 4.4; n = 26) and patients with inactive SLE (mean +/- SD SLEDAI score 1.9 +/- 1.6; n = 45). MPA AUC(0-12) correlated weakly with the dose of MMF (r = 0.33, P = 0.005). Mean +/- SD MPA AUC(0-12) in the group with active SLE was significantly lower than that in the group with inactive SLE (26.8 +/- 13.6 microg.hour/ml versus 46.5 +/- 16.3 microg.hour/ml; P < 0.0001). MPA AUC(0-12) was negatively correlated with the SLEDAI (r = -0.64, P < 0.0001). In multivariate analysis, MPA AUC(0-12) was the sole parameter associated with SLE activity (odds ratio 0.89 [95% confidence interval 0.83-0.96], P = 0.002). The MPA AUC(0-12) threshold value of 35 microg.hour/ml was associated with the lowest risk of active SLE. Our data show that SLE activity is strongly correlated with MPA AUC(0-12). An individualized dosing regimen of MMF, with a target AUC(0-12) of 35 microg.hour/ml, should be considered for SLE patients.

The occurrence of diarrhea not related to the pharmacokinetics of MPA and its metabolites in liver transplant patients

Mycophenolate mofetil (MMF) is a pro-drug that is hydrolyzed to release mycophenolic acid (MPA). Subsequently MPA is extensively metabolized to phenyl mycophenolic acid glucuronide (MPAG) and MPA acyl glucuronide (AcMPAG). It was presumed that the closest association is between plasma AcMPAG concentrations and the incidence of diarrhea. This study aimed to investigate the correlation between pharmacokinetics of MPA, MPAG, and AcMPAG and diarrhea in liver transplant recipients on MMF with tacrolimus. Sixty-seven patients receiving liver transplantation were included. The pharmacokinetics of MPA and its metabolites were monitored repeatedly in the early stage (within 2 weeks) and in the late stage after transplant. The plasma concentrations of MPA, MPAG, and AcMPAG were determined by the HPLC method. Twenty-two patients (32.8%) suffered from episodes of diarrhea. Compared with the data from the early stage, AUC(0-12h) of MPA, MPAG, and AcMPAG increased significantly in both groups in the later stage. AUC(0-12h) of MPA, MPAG, and AcMPAG were not different significantly between the group with diarrhea and the group without diarrhea, either in the early stage or in the late stage (P > 0.05). These results suggest that systemic exposures to MPA and its metabolites are not associated with the incidence of diarrhea in liver transplant recipients.

Pharmacokinetic and pharmacodynamic analysis of enteric‐coated mycophenolate sodium: limited sampling strategies and clinical outcome in renal transplant patients

Pharmacokinetic (PK) and pharmacodynamic (PD) monitoring strategies and clinical outcome were evaluated in enteric-coated mycophenolate sodium (EC-MPS)-treated renal allograft recipients. PK [mycophenolic acid (MPA)] and PD [inosine monophosphate dehydrogenase (IMPDH) activity] data were analysed in 66 EC-MPS and ciclosporin A (CsA)-treated renal allograft recipients. Adverse events were considered in a follow-up period of 12 weeks. Analyses confirmed a limited sampling strategy (LSS) consisting of PK and PD data at predose, 1, 2, 3 and 4 h after oral intake as an appropriate sampling method (MPA r(2)= 0.812; IMPDH r(2)= 0.833). MPA AUC(0-12) of patients with early biopsy-proven acute rejection was significantly lower compared with patients without a rejection (median MPA AUC(0-12) 28 microg*h ml(-1) (7-45) vs. 40 microg*h ml(-1) (16-130), P < 0.01), MPA AUC(0-12) of patients with recurrent infections was significantly higher compared with patients without infections (median MPA AUC(0-12) 65 microg*h ml(-1) (range 37-130) vs. 37 microg*h ml(-1) (range 7-120), P < 0.005). Low 12-h IMPDH enzyme activity curve (AEC(0-12)) was associated with an increased frequency of gastrointestinal side-effects (median IMPDH AEC(0-12) 43 nmol*h mg(-1) protein h(-1)[range 12-67) vs. 75 nmol*h mg(-1) protein h(-1) (range 15-371), P < 0.01]. Despite highly variable absorption data, an appropriate LSS might be estimated by MPA AUC(0-4) and IMPDH AEC(0-4) in renal transplant patients treated with EC-MPS and CsA. Regarding adverse events, the suggested MPA-target AUC(0-12) from 30 to 60 microg*h ml(-1) seems to be appropriate in renal allograft recipients.

Therapeutic drug monitoring of mycophenolate mofetil and enteric-coated mycophenolate sodium in patients with systemic lupus erythematosus

Objective: Mycophenolic acid (MPA), the active form of mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), is used to treat systemic lupus erythematosus (SLE). MMF and EC-MPS pharmacokinetics were examined to devise guidance for therapeutic drug monitoring (TDM) for SLE patients with normal renal function.Research design and methods: This observational study included 21 patients receiving MMF (1000 mg twice daily) and 14 taking EC-MPS (720 mg twice daily). MPA AUC between 0 and 12 h (AUC0–12h), Cmax, Tmax, and 12-h trough concentrations (C12h) were determined.Results: Means of dose-normalized MMF– or EC-MPS–MPA Cmax were 64.6 ± 25 and 61.4 ± 27.1 h mg/l, respectively. MPA Tmax for EC-MPS was longer and more variable than for MMF. MMF-MPA AUC0–12h and C12h were correlated (r = 0.78, p = 0.0001), but EC-MPS–MPA Cmax and single concentrations were weakly correlated. A limited-sampling strategy (LSS) combining Cmax and C12h gave satisfactory predictive performance to estimate MPA AUC0–12h after EC-MPS administration.Conclusions: For TDM in SLE patients with GFR > 60 ml/min/1.73 m2, C12h after MMF ingestion could predict MPA AUC0–12h, while an LSS around Tmax should be used for patients on EC-MPS.

Limited Sampling Strategies for Predicting Area Under the Concentration-Time Curve of Mycophenolic Acid in Islet Transplant Recipients

Mycophenolate mofetil is widely used in islet transplant recipients and its active metabolite, mycophenolic acid (MPA), exhibits wide pharmacokinetic variability. However, to our knowledge, no limited sampling strategy (LSS) exists for monitoring MPA in this subpopulation. To define optimal LSSs for MPA monitoring and to test their predictive performance in islet transplant recipients. After written informed consent was obtained and upon administration of a steady-state morning mycophenolate mofetil dose, blood samples were collected at 0, 0.3, 0.6, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours from 16 stable islet transplant recipients. MPA concentrations were measured by a validated high-performance liquid chromatography method with ultraviolet detection and pharmacokinetic parameters analyzed by noncompartmental modeling. All 16 patients' profiles were used to develop the LSSs via multiple regression analysis. Potential LSSs were restricted to ones having R(2) 0.90 or greater and 3 or fewer time points within the first 4 hours postdose. Resulting equations were validated for their predictive performance using the jackknife method, with acceptable criteria for bias and precision preset to within +/-15%. In addition, 14 published LSSs (in the renal transplant population) were tested in our islet transplant patients. Five LSSs met preset criteria and had conventional sampling times: AUC = 1.783 + 1.248C1 + 0.888C2 + 8.027C4 (R2 = 0.98, bias = -3.09%, precision = 9.53%) AUC = 2.778 + 1.413C1 + 0.963C3 + 7.511C4 (R2 = 0.97, bias = -3.22%, precision = 11.02%) AUC = 1.448 + 1.239C1 + 0.271C1.5 + 9.108 C4 (R2 = 0.96, bias = -1.90%, precision = 11.46) AUC = 1.410 - 0.259C0 + 1.443C1 + 9.622C4 (R2 = 0.96, bias = -2.68%, precision = 11.53%) AUC = 1.547 + 1.417C1 + 9.448C4 (R2 = 0.96, bias = -2.46%, precision = 11.14%) where AUC = area under the concentration-time curve. None of the other published LSSs in the renal transplant population met the preset criteria for bias and precision. To our knowledge, these are the first precise and accurate LSSs for predicting MPA AUC developed specifically for islet transplant recipients. The LSS that we recommend is the one utilizing 2 concentrations: AUC = 1.547 + 1.417C1 + 9.448C4. This equation is convenient and clinically feasible. Other islet transplant centers may wish to validate our equation in their population or use our template as a guide to develop accurate and precise LSSs specific to their patient population.

Limited Sampling Models and Bayesian Estimation for Mycophenolic Acid Area under the Curve Prediction in Stable Renal Transplant Patients Co-Medicated with Ciclosporin or Sirolimus

Mycophenolate mofetil is a prodrug of mycophenolic acid (MPA), an immunosuppressive agent used in combination with corticosteroids and calcineurin inhibitors or sirolimus for the prevention of acute rejection after solid organ transplantation. Although MPA has a rather narrow therapeutic window and its pharmacokinetics show considerable intra- and interindividual variability, dosing guidelines recommend a standard dosage regimen of 0.5-1.0 g twice daily in adult renal, liver and cardiac transplant recipients. The main objective of the present study was to develop a method to predict the MPA area under the plasma concentration-time curve during one 12-hour dosing interval (AUC(12)) by using multiple linear regression models and maximum a posteriori (MAP) Bayesian estimation methods in patients co-medicated with ciclosporin or sirolimus, aiming to individualize the dosage regimen of mycophenolate mofetil. Pharmacokinetic profiles of MPA and mycophenolic acid glucuronide (MPAG), the main metabolite of MPA, were obtained from 40 stable adult renal allograft recipients on three different occasions: the day before switching from ciclosporin to sirolimus co-medication (+/-7.4 months post-transplantation; period I) and at 60 days and 270 days after the switch (periods II and III). Blood samples for determination of MPA and MPAG concentrations in plasma were taken at 0 hours (pre-dose) and at 0.33, 0.66, 1.25, 2, 4, 6, 8 and 12 hours after oral intake of mycophenolate mofetil. The MPA AUC(12) was calculated by the trapezoidal method (the observed AUC(12)). Patients were randomly divided into (i) a model-building test group (n = 27); and (ii) a model-validation group (n = 13). Multiple linear regression models were developed, based on three sampling times after drug administration. Subsequently, a population pharmacokinetic model describing MPA and MPAG plasma concentrations was developed using nonlinear mixed-effects modelling and a Bayesian estimator based on the population pharmacokinetic model was used to predict the MPA AUC(12) based on three sampling times taken within 2 hours following dosing. Fifty-two percent of the observed AUC(12) values (three periods) in the 40 patients receiving a fixed dose of mycophenolate mofetil 750 mg twice daily were outside the recommended therapeutic range (30-60 microg x h/mL). The failure of the standard dose to yield an AUC(12) value within the therapeutic range was especially pronounced during the first study period. Of the multiple linear regression models that were tested, the equation based on the 0-hour (pre-dose), 0.66- and 2-hour sampling times showed the best predictive performance in the validation group: r2 = 0.79, relative root mean square error (rRMSE) = 14% and mean relative prediction error (MRPE) = 0.9%. The pharmacokinetics of MPA and MPAG were best described by a two-compartment model with first-order absorption and elimination for MPA, plus a compartment for MPAG, also including a gastrointestinal compartment and enterohepatic cycling in the case of sirolimus co-medication. The ratio of aminotransferase liver enzymes (AST and ALT) and the glomerular filtration rate significantly influenced MPA glucuronidation and MPAG renal excretion, respectively. Bayesian estimation of the MPA AUC(12) based on 0-, 1.25- and 2-hour sampling times predicted the observed AUC(12) values of the patients in the validation group, with the following predictive performance characteristics: r2 = 0.93, rRMSE = 12.4% and MRPE = -0.4%. Use of the developed multiple linear regression equation and Bayesian estimator, both based on only three blood sampling times within 2 hours following a dose of mycophenolate mofetil, allowed an accurate prediction of a patient's MPA AUC(12) for therapeutic drug monitoring and dose individualization. These findings should be validated in a randomized prospective trial.

Comparison of pharmacokinetics of mycophenolic acid and its metabolites between living donor liver transplant recipients and deceased donor liver transplant recipients

Living-donor liver transplantation (LDLT) has been considered an alternative method for treatment of patients with end-stage liver disease. However, the characteristics of pharmacokinetics of mycophenolic acid (MPA) in patients who underwent LDLT were not clear. This study was designed to compare the pharmacokinetics of MPA and its metabolites between LDLT patients and deceased donor liver transplant (DDLT) patients after oral administration of mycophenolate mofetil (MMF). Thirteen patients who underwent LDLT and 14 patients who underwent DDLT were enrolled prospectively. All patients received oral MMF administration (1.0 g, twice daily) in combination with tacrolimus (TAC). The plasma concentrations of MPA, free MPA, glucuronide (MPAG), and acyl glucuronide (AcMPAG) was determined by high-performance liquid chromatography method. There was a wide variation in various pharmacokinetic parameters of MPA and its metabolites in patients who underwent LDLT and DDLT after oral MMF administration. Although mean MPA area under the plasma concentration time curve for 0-12 hours (AUC(0-12h)) of MPA and MPAG in DDLT patients were higher than those in LDLT patients, there was no significant difference between the two groups. MPA concentration at 6 hours (C(6h)), C(10h), C(12h), and MPA AUC(6-12h) were significantly higher in DDLT group than those in LDLT group (P < 0.05). Inversely, higher free MPA AUC(0-12h) and significant free MPA fraction (P < 0.05) in LDLT patients were observed in DDLT patients when compared with DDLT group. AcMPAG concentrations at 4, 8, and 10 hours and AcMPAG AUC(0-12h) were significantly higher in the DDLT group (P < 0.05). In conclusion, after a fixed oral dose of MMF, DDLT patients had higher enterohepatic recycling contributing to total MPA exposure compared with LDLT patients. The function of glucuronide conjugation in LDLT patients was decreased compared with that in DDLT patients. Higher free MPA AUC(0-12h) and a significantly higher fraction of free MPA in LDLT patients suggested that a lower oral dose of MMF may be administered for patients who underwent LDLT.

Two sampling time profiles for the abbreviated estimation of mycophenolic acid area under the curve in adult renal transplant recipients treated with mycophenolate mofetil and concomitant tacrolimus

Various studies have revealed that mycophenolic acid (MPA) area under the time concentration curve (AUC) may have clinical value in mycophenolate mofetil dose adjustment. As the full AUC measurement is impractical in clinical practice, several abbreviated AUC profiles using pre-dose, and two or three post-dose samples have been proposed; however, the possible use of lower sampling time profiles has an unquestionable practical interest, and the aim of our study was the evaluation of several two-points algorithms using only one post-dose sample. In 60 MPA concentration-time profiles from 37 adult renal transplant patients treated with mycophenolate mofetil and concomitant tacrolimus, the MPA AUC values were estimated using the three sampling time algorithm (pre-dose, one-half and 2 h post-dose)of Pawinski et al. (Clinical Chemistry 48, 2002, 1497), trapezoidal extrapolated procedure according to Hale et al. (Clinical Pharmacology Therapeutics 64, 1998, 672), and two-points algorithm (pre-dose and 2 h post-dose) proposed by David-Neto et al. (Clinical Transplantation 19, 2005, 19). The AUC values estimated using the algorithm of Pawinski et al. had a very high correlation(r = 0.997, P < 0.001) with the trapezoidal extrapolated AUC results. The estimated AUC values obtained using the two-points algorithm of David-Neto et al. present a high correlation (r = 0.930, P < 0.001), acceptable mean prediction error (+3.3 +/- 1.8%), and a diagnostic efficiency of 94% in the classification of subtherapeutic, therapeutic, and supratherapeutic values, with respect to the three-points algorithm of Pawinskiet al. The two sampling time algorithm of David-Neto gave similar results to those of the three-sampling time algorithm of Pawinski, and both, with sampling over 2 h, may be useful for routine MPA AUC estimation in renal transplant recipients with concomitant tacrolimus. Both are unsuitable when unusually unpredictable pharmacokinetics are expected such as with entericcoated formulations.