Effects of calcineurin inhibitors on pharmacokinetics of mycophenolic acid and its glucuronide metabolite during the maintenance period following renal transplantation

Mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF) has been introduced into renal transplant immunosuppressant protocols in combination with calcineurin inhibitors (CNIs) and steroids. This study compared the pharmacokinetic profiles of MPA and its major metabolite MPA glucuronide (MPAG) in combination with tacrolimus (TAC) or cyclosporine (CyA) during the maintenance period (>6 months) following renal transplantation. There was no difference between TAC and CyA-treated groups in MPA plasma concentration before drug administration (C(0)). MPA C(0) in TAC and CyA-treated patients did not differ from that in patients who were not treated with a CNI. In patients treated with a CNI, MPAG C(0) was significantly greater in those treated with CyA compared with TAC. The MPAG/MPA ratio in CyA-treated patients was significantly greater than that in the TAC-treated group. We observed that C(0) of MPA was negatively correlated with that of TAC and CyA. Positive correlation between MPA C(0), MPAG C(0) and serum creatinine was stronger in patients treated with CyA compared with TAC. Our study suggests that CyA, but not TAC, inhibits enterohepatic circulation of MPAG as a secondary excretion pathway, and that renal function makes a major contribution to elimination of MPA and MPAG. We indicate that it may be necessary to estimate biliary excretion of MPAG to avoid the risk of intestinal injury in patients receiving combination therapy with TAC during the maintenance period.     

Pharmacokinetics and protein binding of mycophenolic acid in stable lung transplant recipients

Mycophenolate mofetil (MMF) use is increasing in solid organ transplantation. Mycophenolic acid (MPA), the active metabolite of MMF, is highly protein bound and only free MPA is pharmacologically active. The average MPA free fraction in healthy adult individuals, stable renal transplant recipients, and heart transplant recipients is approximately 2 to 3%. However, no data are currently available on MPA protein binding in stable lung transplant recipients and little is known regarding MPA's pharmacokinetic characteristics after lung transplantation. The purpose of this study was to characterize the pharmacokinetic profile and protein binding of MPA in this patient population. Seven patients were entered into the study. On administration of a steady-state morning MMF dose, blood samples were collected at 0, 1, 2, 3, 4, 5, 6, 8, 9, 10, and 12 hours post-dose. Total MPA concentrations were measured by a validated HPLC method with UV detection and followed by ultrafiltration of pooled samples for free MPA concentrations. Area under the curve (AUC), peak concentration (Cmax), time to peak concentration (Tmax), trough concentration (Cmin), free fraction (f), and free MPA AUC were calculated by traditional pharmacokinetic methods. Patient characteristics included; 3 males and 4 females, an average of 4.4 years post-lung transplant (range, 0.3-11.5 yr), mean (+/- SD) age of 50 +/- 10 years and weight 69 +/- 20 kg. Mean albumin concentration was 37 +/- 3 g/L and serum creatinine was 142 +/- 49 micromol/L. All patients were on cyclosporine and prednisone. MMF dosage ranged from 1 to 3 g daily (35.5 +/- 14.1 mg/kg/d; range, 15.2-60.0 mg/kg/d). Mean (+/- SD) AUC was 45.78 +/- 18.35 microg.h/mL (range, 16.56-74.22 microg.h/mL), Cmax was 17.37 +/- 7.69 microg/mL (range, 4.92-26.63 microg/mL), Tmax was 1.2 +/- 0.4 hours (range, 1.0-2.0 h), Cmin was 3.12 +/- 1.41 microg/mL (range, 1.47-4.82 microg/mL), f was 2.90 +/- 0.56% (range, 2.00-3.40%), and free MPA AUC was 1.29 +/- 0.50 microg.h/mL (range, 0.54-1.88 microg.h/mL). This is the first study to determine these pharmacokinetic characteristics of MPA in the lung transplant population. Further studies should focus on identification of MMF dosing strategies that optimize immunosuppressive efficacy and minimize toxicity in lung allograft recipients.     

In vivo higher glucuronidation of mycophenolic acid in male than in female recipients of a cadaveric kidney allograft and under immunosuppressive therapy with mycophenolate mofetil

Mycophenolate mofetil (MMF), an immunosuppressant drug used in organ transplantation to prevent rejection, is being used increasingly in association with cyclosporine and tacrolimus. Mycophenolic acid (MPA) is primarily metabolized in the liver to its 7-O-glucuronide (MPAG) derivative. The concentrations of MPAG in serum are many times the concentrations of MPA. Although MPAG has not shown immunosuppressant activity, it was postulated that it could displace MPA from its binding sites on albumin and hence increase the biologic effects of MPA. This effect could be important for patients with acute renal failure; under this condition, MPAG was shown to accumulate. The goal of this study was to document the MPAG/MPA concentration ratio in 100 renal transplant patients under a mixed immunosuppressive therapy. Further, the study addressed the question of whether MPAG can displace MPA in vivo from bound albumin in a representative renal transplant patient population under immunosuppressive therapy. Levels of MPAG and MPA were measured by high-performance liquid chromatography. The distribution of the ratios was not parametric as it tailed toward elevated values. After a square root transformation of the data, parametric analysis was possible. The average MPAG/MPA ratio was 15.0 +/- 2.2 for men versus 7.7 +/- 0.9 for women. Men treated with MMF and tacrolimus showed a lower ratio than patients treated with MMF and cyclosporine, confirming that tacrolimus inhibits glucuronidation of MPA. Further, it was determined that at physiologic concentrations, MPAG does not increase the amount of free MPA. Because MPAG can favor the elimination of MPA, it can be concluded that gender differences and cotreatment with tacrolimus must be taken into consideration when MMF is being administered.     

Clinical pharmacokinetics of mycophenolate mofetil in Japanese renal transplant recipients: A retrospective cohort study in a single center

Mycophenolate mofetil (MMF), a morpholinoethyl ester of mycophenolic acid (MPA), is currently widely used in organ transplantation as an immunosuppressant. The usefulness of therapeutic drug monitoring (TDM) of MPA after MMF dosing is not clear in Japanese renal transplant patients. In this study, to obtain more information for TDM of MPA, the association between MPA pharmacokinetic characteristics and the development of the side effects, and the effect of other concomitant immunosupressants such as cyclospoline A (CyA), tacrolimus (FK) and predonisolone (PSL) on MPA pharmacokinetics were investigated in detail. Moreover, the effects of enterohepatic recirculation (EHRA) on pharmacokinetic characteristics of MPA and the development of the side effects were also investigated. AUC(MPA)(0-9) with FK medication was 1.3-1.9 times higher than that with CyA medication, and the contribution to the plasma level of MPA of FK might be smaller than that of CyA, because EHRA inhibition by CyA was 2 times greater than that by FK. AUC(MPA)(0-9) was not influenced by PSL. The association between AUC(MPA)(0-9) and the development of the side effects was not observed; however, the development of side effects (leukopenia and diarrhea) in the EHRA group was 2 times higher than that in the non-EHRA group. These results suggested that TDM for MPA after MMF dosing was desirable in Japanease transplant patients. However, though not frequently, AUC obtained by multiple blood sampling after MMF dosing was needed. In addition, EHRA has led to increasing interest in MMF medication.     

Pharmacokinetic role of protein binding of mycophenolic acid and its glucuronide metabolite in renal transplant recipients

Mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is used to prevent graft rejection in renal transplant recipients. MPA is glucuronidated to the metabolite MPAG, which exhibits enterohepatic recirculation (EHC). MPA binds for 97% and MPAG binds for 82% to plasma proteins. Low plasma albumin concentrations, impaired renal function and coadministration of cyclosporine have been reported to be associated with increased clearance of MPA. The aim of the study was to develop a population pharmacokinetic model describing the relationship between MMF dose and total MPA (tMPA), unbound MPA (fMPA), total MPAG (tMPAG) and unbound MPAG (fMPAG). In this model the correlation between pharmacokinetic parameters and renal function, plasma albumin concentrations and cotreatment with cyclosporine was quantified. tMPA, fMPA, tMPAG and fMPAG concentration–time profiles of renal transplant recipients cotreated with cyclosporine (n = 48) and tacrolimus (n = 45) were analyzed using NONMEM. A 2- and 1-compartment model were used to describe the pharmacokinetics of fMPA and fMPAG. The central compartments of fMPA and fMPAG were connected with an albumin compartment allowing competitive binding (bMPA and bMPAG). tMPA and tMPAG were modeled as the sum of the bound and unbound concentrations. EHC was modeled by transport of fMPAG to a separate gallbladder compartment. This transport was decreased in case of cyclosporine cotreatment (P < 0.001). In the model, clearance of fMPAG decreased when creatinine clearance (CrCL) was reduced (P < 0.001), and albumin concentration was correlated with the maximum number of binding sites available for MPA and MPAG (P < 0.001). In patients with impaired renal function cotreated with cyclosporine the model adequately described that increasing fMPAG concentrations decreased tMPA AUC due to displacement of MPA from its binding sites. The accumulated MPAG could also be reconverted to MPA by the EHC, which caused increased tMPA AUC in patients cotreated with tacrolimus. Changes in CrCL had hardly any effect on fMPA exposure. A decrease in plasma albumin concentration from 0.6 to 0.4 mmol/l resulted in ca. 38% reduction of tMPA AUC, whereas no reduction in fMPA AUC was seen. In conclusion, a pharmacokinetic model has been developed which describes the relationship between dose and both total and free MPA exposure. The model adequately describes the influence of renal function, plasma albumin and cyclosporine co-medication on MPA exposure. Changes in protein binding due to altered renal function or plasma albumin concentrations influence tMPA exposure, whereas fMPA exposure is hardly affected.     

Pharmacokinetic study of mycophenolic acid in Korean kidney transplant patients

The purpose of this study was to characterize the pharmacokinetic parameters of mycophenolic acid (MPA) in Korean kidney transplant recipients. Plasma MPA concentrations of 10 Korean kidney transplant recipients administered a lower dose of mycophenolate mofetil (MMF; 750 mg twice a day) were measured at 2 weeks of MMF therapy by high-performance liquid chromatography (HPLC). The plasma MPA concentration-time curve pattern of patients taking lower doses of MPA was consistent with previously reported profiles of patients taking the fully recommended doses. The plasma MPA concentration-time curve was characterized by an early sharp peak within 1 hour and a small second peak in some patients at 4 to 12 hours postdose. The mean C(max) and AUC were 8.73 +/- 4.65 microg/mL and 18.45 +/- 4.25 microg*h/mL, respectively. The mean fraction of free MPA was 1.60% +/- 0.23%. Patients' age, weight, body surface area, and renal function did not influence the AUC. The free fraction of MPA appeared not to be affected by serum albumin and renal function when creatinine clearance was above 40 mL/min. Regression analysis between each plasma concentration and AUC for the limited sampling strategy of MMF therapeutic drug monitoring demonstrated that the concentrations of predose and 1- and 8-hour postdose were positively correlated with AUC (r = 0.74545, p = 0.0133; r = 0.68485, p = 0.0289; and r = 0.63636, p = 0.0479, respectively). The pattern of the concentration-time profile of MPA in Korean kidney recipients was similar to the results of other studies performed in Caucasians, although there was interindividual variability of AUC, C(max), and t(max). MPA concentrations of predose and 1- and 8-hour postdose were positively correlated with AUC.     

Population pharmacokinetics of mycophenolic acid in kidney transplant pediatric and adolescent patients

Current data on mycophenolate mofetil (MMF) suggest that there is a pharmacokinetic/pharmacodynamic relationship between the mycophenolic acid (MPA) area under the curve (AUC) during treatment and both the risk of acute rejection and the occurrence of side effects. The aim of this study was to characterize the population pharmacokinetics of MPA in kidney transplant patients between the ages of 2 and 21 years and to propose a limited sampling strategy to estimate individual MPA AUCs. Forty-one patients received long-term oral MMF continuous therapy as part of a triple immunosuppressive regimen, which also included cyclosporine or tacrolimus (n=3) and corticosteroids. Therapy was initiated at a dose of 600 mg/m twice daily. The population parameters were calculated from an initial group of 32 patients. The data were analyzed by nonlinear mixed-effect modeling using a 2-compartment structural model with first-order absorption and a lag time. The interindividual variability in the initial volume of distribution was partially explained by the fact that this parameter was weight-dependent. Fifteen concentration-time profiles from 13 patients were used to evaluate the predictive performance of the Bayesian approach and to devise a limited sampling strategy. The protocol, involving two sampling times, 1 and 4 hours after oral administration, allows the precise and accurate determination of MPA AUCs (bias -0.9 microg.h/mL; precision 6.02 microg.h/mL). The results of this study combine the relationships between the pharmacokinetic parameters of MPA and patient covariates, which may be useful for dose adjustment, with a convenient sampling procedure that may aid in optimizing pediatric patient care.     

Concentrations of mycophenolic acid and glucuronide metabolites under concomitant therapy with cyclosporine or tacrolimus

Mycophenolate mofetil [MMF, the prodrug of mycophenolic acid (MPA)] is usually administered at double doses with cyclosporine than with tacrolimus because it is believed that MPA exposure is lower during cyclosporine therapy. This study aimed to compare 12 hour, steady-state concentration-time profiles of MPA and its phenol- and acyl-glucuronide metabolites (MPAG and AcMPAG, respectively) in stable kidney transplant recipients maintained either on cyclosporine (n = 12) or tacrolimus (n = 12). During the absorption phase in the cyclosporine group, dose-normalized concentrations of total and free MPA were significantly higher but the overall area under the concentration-time curve (AUC0-12) was not significantly different. Additionally, exposure to AcMPAG was higher in the cyclosporine group (P < 0.05). Ten of 12 patients in the cyclosporine group were on ketoconazole therapy; however, the exposure to MPA or MPAG was not different when MMF was given orally to Sprague-Dawley rats with or without ketoconazole. In conclusion, cyclosporine modulates the disposition of MPA and metabolites differently from tacrolimus; however, patients on cyclosporine may not require double doses of MMF to achieve the same exposure.     

Effect of cyclosporine withdrawal on mycophenolic acid pharmacokinetics in kidney transplant recipients with deteriorating renal function: preliminary report.

Mycophenolic acid (MPA) concentrations are lower in transplant recipients receiving mycophenolate mofetil (MMF) and cyclosporine compared with MMF with tacrolimus. It is not clear whether this is due to an effect of cyclosporin or tacrolimus on MPA pharmacokinetics. To study this effect, kidney transplant recipients with deteriorating renal function (n = 5) receiving cyclosporin and steroids were given mycophenolate mofetil over 4 weeks during a run-in phase (1 g/d in week 1, 1.5 g/d in week 2, 2 g/d starting from week 3). From week 5 the cyclosporin dose was reduced, and it was completely withdrawn at week 10. Creatinine, MPA, and MPA glucuronide metabolites (MPAG, AcMPAG) were determined before (week 4) and after (week 11 and week 32) cyclosporin was withdrawn. Cyclosporin withdrawal was associated with increased MPA areas under the curve (AUCs) and predose concentrations in four of the five patients. In contrast, MPAG and AcMPAG AUCs as well as predose MPAG concentrations significantly decreased. Six months after cyclosporin withdrawal, MPA AUC and predose values tended to return to initial values, whereas metabolite concentrations remained low. Cyclosporin discontinuation caused an acute increase in MPA exposure and a concomitant reduction in metabolite concentrations. The results are consistent with the hypothesis that cyclosporin attenuates the enterohepatic recirculation of MPAG/MPA.     

Review of the immunosuppressant enteric-coated mycophenolate sodium

Enteric-coated mycophenolate sodium (EC-MPS; myfortic, Novartis Pharma AG) is an advanced formulation delivering mycophenolic acid (MPA). EC-MPS was designed to improve MPA-related upper gastrointestinal adverse events by delaying the release of MPA until reaching the small intestine. At a dose of 720 mg, EC-MPS exhibits equivalent MPA exposure (area under the concentration curve [AUC]) and maximal MPA concentration (C(max)) to mycophenolate mofetil (MMF; CellCept, Roche AG) 1000 mg. The time to maximal MPA concentration (T(max)) for EC-MPS is delayed relative to that for MMF, consistent with a functioning enteric coating. EC-MPS 720 mg b.i.d. has demonstrated therapeutic equivalence to MMF 1000 mg b.i.d. in renal transplant patients. Recent clinical trials have demonstrated that EC-MPS is as effective and safe as MMF in both de novo and maintenance renal transplant patients. Furthermore, studies have confirmed that maintenance patients can be safely converted from MMF to EC-MPS with no compromise of efficacy or safety. EC-MPS therefore presents physicians and patients with a valid alternative MPA therapy with a comparable efficacy and safety profile to MMF.     

Pharmacokinetic study of mycophenolate mofetil in patients with systemic lupus erythematosus and design of Bayesian estimator using limited sampling strategies

BACKGROUND: Monitoring of the area under the plasma concentration-time curve (AUC) of mycophenolic acid (MPA) has been developed for individual dose adjustment of mycophenolate mofetil (MMF) in renal allograft recipients. MMF is currently used as an off-label drug in the treatment of systemic lupus erythematosus (SLE), but factors of its exposition may be different in these patients and need to be determined for therapeutic drug monitoring (TDM) purposes. OBJECTIVE: The aim of the study was to develop a maximum a posteriori probability (MAP) Bayesian estimator of MPA exposition in patients with SLE, with the objective of TDM based on a limited sample strategy. METHODS: Twenty adult patients with SLE given a stable 1 g/day, 2 g/day or 3 g/day dose of MMF orally for at least 10 weeks were included in the study. MPA was measured by high-performance liquid chromatography (HPLC) coupled to a photodiode array detector (11 plasma measurements over 12 hours post-dose per patient). Free MPA concentrations were measured by HPLC with fluorescence detection. Two different one-compartment models with first-order elimination were tested to fit the data: one convoluted with a double gamma distribution to describe secondary concentrations peaks, and one convoluted with a triple gamma distribution to model a third, later peak. RESULTS: A large interindividual variability in MPA concentration-time profiles was observed. The mean maximum plasma concentration, trough plasma concentration, time to reach the maximum plasma concentration and AUC from 0 to 12 hours (AUC(12)) were 13.6 +/- 8.4 microg/mL, 1.4 +/- 1.2 microg/mL, 1.1 +/- 1.2 hours and 32.2 +/- 17.1microg . h/mL, respectively. The mean free fraction of MPA was 1.7%. The one-compartment model with first-order elimination convoluted with a triple gamma distribution best fitted the data. Accurate Bayesian estimates of the AUC(12) were obtained using three blood samples collected at 40 minutes, 2 hours and 3 hours, with a coefficient of correlation (R) = 0.95 between the observed and predicted AUC(12) and with a difference of <20% in 16 of the 20 patients. CONCLUSION: A specific pharmacokinetic model was built to accurately fit MPA blood concentration-time profiles after MMF oral dosing in SLE patients, which allowed development of an accurate Bayesian estimator of MPA exposure that should allow MMF monitoring based on the AUC(12) in these patients. The predictive value of targeting one specific or different AUC values on patients' outcome using this estimator in SLE will need to be evaluated.     

Mycophenolic acid and mycophenolic acid glucuronide pharmacokinetics in pediatric liver transplant recipients: effect of cyclosporine and tacrolimus comedication

Determinants of the wide interindividual variability of the pharmacokinetics of mycophenolic acid (MPA) in 21 stable pediatric liver transplant recipients were investigated in relation to the kinetics of the drug's major phenolic glucuronide metabolite (MPAG), cyclosporin (CsA), or tacrolimus (Tac) co-medication and liver and renal function. Trough concentrations (C(0) ) most reliably predicted the area under the curve (AUC) of 0-7 hours MPA plasma concentrations (r (2) = 0.650). Co-medication with CsA demanded higher MPA mofetil (MMF) doses to achieve equivalent trough levels than Tac (362 vs. 178 mg per mg/L, P= 0.004). Median MPA C(0) (range) was significantly lower during CsA co-therapy when corrected for MMF dose (2.8 vs. 5.6 mg MPA/L for Tac, P= 0.006). The AUC of MPAG was correspondingly higher during CsA co-medication (229 vs. 94 mg/L/h for Tac, P = 0.012) with the MPA-to-MPAG ratio at C(0) correspondingly lower (0.10 vs. 0.14, respectively, P = 0.04). This suggested contrasting effects of CsA and Tac on MPA glucuronidation or its excretion and enterohepatic recirculation. MPAG AUC was correlated to body weight and creatinine clearance. Children with elevated aspartate transaminase (AST; but with no evidence of rejection on liver biopsy, n = 7) had significantly lower MPA trough levels compared with those in whom AST was normal (0. 77 vs. 1.76 mg/L, P = 0.05), but there was no difference in the MMF dose per body weight. Examination of the MPA profiles in these subjects showed significantly lower MPA concentrations from 120 minutes after dose until the end of the 7-hour profile and suggest an accelerated clearance or decreased enterohepatic recirculation.)     

Gender-related differences in mycophenolate mofetil-induced gastrointestinal toxicity in rats.

Mycophenolate mofetil (MMF), the prodrug of mycophenolic acid (MPA), is included in current combination immunosuppressive regimens following organ transplant. Treatment with MMF often results in dose-limiting gastrointestinal (GI) side effects. The underlying mechanisms responsible for these side effects are not fully understood, but exposure of the intestinal epithelia to MPA during enterohepatic recycling may be involved. The present study demonstrated that female rats are more susceptible to MMF-induced GI toxicity than male rats. Female Sprague-Dawley rats treated chronically with an oral dose of 50 mg of MPA equivalents/kg/day experienced greater GI toxicity than male rats, as measured by diarrhea grade and weight loss. Intestinal microsomes harvested from the upper jejunum of female rats had approximately 3-fold lower MPA glucuronidation rates compared with male rats. In the remaining areas of the small and large intestine, there was also a trend toward decreased glucuronidation in the female rats. The area under the plasma concentration-time curve (AUC) for MPA following an oral dose of 50 mg of MPA equivalents/kg was roughly similar between genders, whereas the AUC for mycophenolic acid phenolic glucuronide (MPAG) was significantly lower in female rats. Female rats also excreted half of the biliary MPAG as male rats. The greater susceptibility of female rats to MMF-induced gastrointestinal toxicity, despite diminished intestinal MPA exposure via reduced biliary excretion of MPAG, may result from reduced protection of enterocytes by in situ glucuronidation. Likewise, susceptibility to MMF-induced GI toxicity in humans may also result from variable intestinal glucuronidation due to UDP glucuronosyltransferase polymorphisms or differential expression.     

Long-term pharmacokinetics of mycophenolic acid in pediatric renal transplant recipients over 3 years posttransplant

Data on exposure to mycophenolic acid (MPA), the active moiety of mycophenolate mofetil (MMF), in pediatric renal transplant recipients beyond the first year posttransplant are scarce. The authors therefore analyzed the long-term pharmacokinetics of MPA in 25 pediatric patients treated with 600 mg MMF/m body surface area twice a day in conjunction with cyclosporine A and prednisone. Plasma samples for 12-hour pharmacokinetic profiles were collected on day 7, and after 3, 9, 24, and 36 months posttransplant. Both the actual and the dose-normalized MPA-area under the concentration-time curve (AUC0-12) increased approximately 2-fold between day 7 and month 9 but stabilized thereafter. Both the actual and the dose-normalized MPA-AUC0-12 at months 24 and 36 were comparable to that at month 9. Presuming a therapeutic window of 30-60 mg h/L, 15 (60%) of 25 patients at day 7 had an MPA-AUC0-12 <30 mg h/L, indicating potential underexposure, whereas the proportion of patients with an MPA-AUC0-12 <30 mg h/L between months 3 and 36 was low (5%-17%). These data suggest that the recommended MMF dose of 600 mg/m body surface area twice a day in conjunction with cyclosporine A leads to MPA underexposure early posttransplant in a significant subset of patients, indicating a need for a higher initial MMF dose. Dose-normalized MPA exposure increases in the first 9 months posttransplant, consistent with a reduced MPA metabolism and increased enterohepatic recycling of MPA.     

Comparison of pharmacokinetics of mycophenolic acid and its glucuronide between patients with lupus nephritis and with kidney transplantation

The pharmacokinetics of mycophenolic acid (MPA) and its glucuronide (mycophenolic acid phenolic glucuronide, MPAG) in lupus nephritis (LN) have not been fully characterized. The aim of this study was to evaluate the pharmacokinetics of MPA and MPAG in LN patients by comparing the pharmacokinetics with those of kidney transplant (KT) recipients. Six LN patients (World Health Organization class IV and V) and 24 KT recipients [8 recipients treated with tacrolimus (Tac) and 16 with cyclosporine (CyA)] during the early posttransplantation period were enrolled. Pharmacokinetic parameters of MPA and MPAG were compared between LN patients and Tac-treated or CyA-treated KT recipients. The area under the concentration-time curve (AUC0-12) of MPA normalized to mycophenolate mofetil (MMF) dose (mg/kg) was significantly lower in LN patients and CyA-treated KT recipients than in Tac-treated KT recipients [median (range), 2.19 (0.87-4.23), 2.36 (1.13-5.74), and 4.86 (3.25-6.75) microg x h/mL per mg/kg, P < 0.05 and P < 0.01, respectively]. Dose-normalized MPAG AUC0-12 was significantly lower in LN patients and slightly lower in Tac-treated KT recipients than in CyA-treated KT recipients [median (range), 35.0 (8.34-69.8), 51.6 (34.4-94.8), and 84.1 (34.7-152) microg x h/mL per mg/kg, P < 0.05 and P = 0.13, respectively]. The ratio of MPA AUC5-12 to AUC0-12, an estimate of MPA enterohepatic recirculation, was slightly higher in LN patients and Tac-treated KT recipients than in CyA-treated KT recipients [median (range), 0.44 (0.35-0.56), 0.45 (0.42-0.61), and 0.34 (0.22-0.55), P = 0.29 and P = 0.10, respectively]. Serum creatinine was significantly lower in LN patients than in Tac-treated and CyA-treated KT recipients. In conclusion, the pharmacokinetics of MPA in LN patients is characterized by high MPA clearance and in CyA-treated KT recipients. Despite this higher clearance of MPA, MPAG AUC0-12 was lower in LN patients most likely due to better renal function in LN patients.     

Review of the immunosuppressant enteric-coated mycophenolate sodium

Enteric-coated mycophenolate sodium (EC-MPS; myfortic^®, Novartis Pharma AG) is an advanced formulation delivering mycophenolic acid (MPA). EC-MPS was designed to improve MPA-related upper gastrointestinal adverse events by delaying the release of MPA until reaching the small intestine. At a dose of 720 mg, EC-MPS exhibits equivalent MPA exposure (area under the concentration curve [AUC]) and maximal MPA concentration (C_max) to mycophenolate mofetil (MMF; CellCept^®, Roche AG) 1000 mg. The time to maximal MPA concentration (T_max) for EC-MPS is delayed relative to that for MMF, consistent with a functioning enteric coating. EC-MPS 720 mg b.i.d. has demonstrated therapeutic equivalence to MMF 1000 mg b.i.d. in renal transplant patients. Recent clinical trials have demonstrated that EC-MPS is as effective and safe as MMF in both de novo and maintenance renal transplant patients. Furthermore, studies have confirmed that maintenance patients can be safely converted from MMF to EC-MPS with no compromise of efficacy or safety. EC-MPS therefore presents physicians and patients with a valid alternative MPA therapy with a comparable efficacy and safety profile to MMF.     

Predicting the usefulness of therapeutic drug monitoring of mycophenolic acid: a computer simulation

The usefulness of therapeutic drug monitoring (TDM) of mycophenolate mofetil (MMF) was investigated with a computer simulation model. For a fixed-dose (FD) and a concentration-controlled (CC) MMF dosing regimen exposure to mycophenolic acid (MPA) was compared. A nonlinear mixed-effects model (NONMEM) for MPA based on extensive pharmacokinetic data from 140 renal transplant recipients who all used cyclosporine and corticosteroids as maintenance immunosuppressive therapy provided Bayesian estimates for MPA oral clearance on 9 occasions during the first 24 weeks after transplantation. In 45 of these patients, the estimates for MPA oral clearance were used to calculate values for the area under the curve (AUC) of MPA. In the CC group, MMF doses were adjusted based on the calculated AUC, targeting at an AUC level of 45 mg.h/L. In the FD group, MMF doses were fixed at 1000 mg. On day 7 after transplantation, significantly more AUC values were on target (AUC range 30-60 mg.h/L) in the CC group than in the FD group: 76% versus 13%, respectively, P < 0.001. To accomplish this, a doubling of MMF dose was necessary in more than half of the patients after the AUC assessment on day 3 after transplantation. Between-patient variability (BPV) in AUC (average CV% for all occasions) was reduced in the CC regimen: 23% versus 44% in the FD group. By using TDM, adequate MPA exposure appears to be obtained more rapidly, and BPV in exposure is reduced. To reach target AUC levels as soon as possible in this cyclosporine-treated population, it appears that larger MMF doses as currently recommended are necessary in the first month after transplantation.     

Influence of metal cations on plasma trough concentration of mycophenolic Acid and its glucuronide in tacrolimus-treated and cyclosporine-treated kidney transplant recipients

The aim of this study was to evaluate the plasma trough concentrations (C(0)) of mycophenolic acid (MPA) and its major metabolite MPA 7-O-glucuronide (MPAG) in metal cation (MC)(-) (non-treated) and MC(+) (co-treated) patients who received tacrolimus (Tac) or cyclosporine (CyA). Fifty-nine Japanese stable kidney transplant recipients receiving immunosuppressive regimens containing mycophenolate mofetil (MMF) and a calcineurin inhibitor (CNI) were included in this study. Seven in the 25 patients receiving Tac and 8 in the 34 patients receiving CyA were treated with concomitant MCs administration. Multiple regression analysis revealed that concomitant MCs and CyA administration influenced MPA C(0). Their standardized partial regression coefficients were -0.29 and -0.41, respectively. Stratified analysis based on CNI treatment revealed that MPA C(0) decreased significantly by 56% with concomitant MCs administration in Tac-treated patients. There was no significant difference in MPA C(0) between the MC(-) and MC(+) groups in CyA-treated patients. With respect to MPAG C(0), MC(+) group tended to be lower by 26% than MC(-) group in Tac-treated patients. There was no significant difference in MPAG C(0) between the MC(-) and MC(+) groups in CyA-treated patients. Concomitant MCs administration did not affect the C(0) ratio of MPAG to MPA in either Tac- or CyA-treated patients. In conclusion, MCs co-administration decrease MPA C(0) in patients receiving Tac and may cause lower MPA exposure. There are little pharmacokinetic interactions between MMF and concomitant MCs in CyA-treated patients.     

Long-term changes in mycophenolic acid exposure in combination with tacrolimus and corticosteroids are dose dependent and not reflected by trough plasma concentration: a prospective study in 100 de novo renal allograft recipients

Tacrolimus and cyclosporine A have different effects on exposure to concomitantly administered mycophenolate mofetil (MMF), measured as the mycophenolic acid (MPA) dose interval area under the plasma concentration versus time curve (AUC0-12 h) or the plasma MPA predose concentration (C0). This has led to recommendations in using a 50% lower dose of MMF in combination with tacrolimus compared to cyclosporin A. At present, no long-term data are available regarding the pharmacokinetics (PK) of different dosages of MMF in combination with tacrolimus and the clinical variables that influence the dose-exposure relationship of MPA. A prospective 12-month pharmacokinetic study was performed in 100 de novo renal transplant recipients treated with two different MMF dosages (1 g/day vs. 2 g/day) in combination with tacrolimus and corticosteroids. MPA AUC data were collected 7 days, 6 weeks, and 3 and 12 months posttransplantation, and model-independent PK parameters were calculated. Clinical variables that could possibly influence MPA PK were evaluated. The MPA AUC0-12 h significantly increased toward 6 weeks (p < 0.05) but only in the 2-g MMF dosing group. The MPA AUC0-12 h in the 1-g MMF group reached its nadir at 3 months, while in the 2-g MMF group, it remained elevated until 3 months, returning to baseline values by 12 months. This differential evolution in exposure was not only inadequately reflected by the corresponding MPA C0 concentrations, but the MPA C0 concentrations also were not significantly different between the two dosing groups at early postgrafting (day 7) and at 12 months. Using multiple stepwise regression analysis, C0 (r = 0.51, p < 0.0001) and end-of-dose interval MPA plasma concentration (C12: r2 = 0.61, p < 0.0001) were found to poorly predict MPA AUC0-12 h, while MPA plasma concentrations at 4 hours (C4: r2 = 0.85, p < 0.0001) and 6 hours postdosing (C6: r2 = 0.83, p < 0.0001) were superior but hampered by a large prediction bias and imprecision. An abbreviated 2-hour AUC measurement (r2 = 0.78), using three sampling points (C0, C40 [MPA plasma concentration 40 min postdosing], C2), provided the best compromise between a monitoring tool that is theoretically ideal and practically feasible. MPA pharmacokinetics were not influenced by recipient age, gender, and body weight or by serum albumin concentrations, allograft function, or corticosteroid or tacrolimus dose. Mild hepatic dysfunction early after grafting did result in significantly reduced MPA exposure (MPA AUC0-12 h, p = 0.01 and C0, p = 0.03). In this study, it was demonstrated for the first time that the dynamics of long-term MPA pharmacokinetics in combination with tacrolimus differ according to the daily MMF dose and that this effect is not adequately reflected by MPA trough concentrations. Using the latter as a routine measure for therapeutic drug monitoring might mislead clinicians into drawing wrong conclusions in terms of relating questions of efficacy or toxicity to MPA exposure.     

Enteric-coated mycophenolate sodium provides higher mycophenolic acid predose levels compared with mycophenolate mofetil: implications for therapeutic drug monitoring

The delayed release of mycophenolic acid (MPA) from enteric-coated mycophenolate sodium (EC-MPS) may lead to different MPA predose (C0) levels compared with mycophenolate mofetil (MMF). A post hoc analysis was performed on MPA morning predose values assessed in 88 maintenance renal transplant patients from three studies converted from MMF (1000 mg twice a day) to equimolar EC-MPS (720 mg twice a day) or vice versa, both in combination with cyclosporine. The median MPA predose level was approximately 30% higher when patients received EC-MPS (2.40 microg/mL; range, 0.49-39.30 microg/mL) compared with MMF (1.83 microg/mL; range, <0.1-12.80 microg/mL). Rare cases (3.0%) of high MPA C0 levels 15 microg/mL or greater were observed with EC-MPS consistent with a very prolonged release of MPA from this formulation. Both EC-MPS and MMF exhibited a poor correlation between MPA C0 levels and exposure as assessed by MPA area under the curve. Physicians targeting a certain MPA predose level have to be aware of the higher morning C0 levels with EC-MPS, whereas the overall MPA exposure is not different to MMF.