Mycophenolic acid metabolite profile in renal transplant patients receiving enteric-coated mycophenolate sodium or mycophenolate mofetil

Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is an effective immunosuppressive treatment in renal transplant recipients but is known to have gastrointestinal side effects. Enteric-coated mycophenolate sodium (EC-MPS; myfortic) is a new formulation for delivering MPA. This open-label, two-period, cross-over study was carried out to characterize the time course of MPA and its metabolites, mycophenolic acid glucuronide (MPAG) and acyl mycophenolic acid glucuronide (AcMPAG) in stable renal transplant patients (n = 40) after 28-day chronic dosing with EC-MPS (720 mg bid) or MMF (1000 mg bid). The relative abundance and exposure of all three compounds was also assessed. EC-MPS demonstrated the typical pharmacokinetic profile of an enteric-coated formulation with a delayed release of MPA compared with MMF (Tmax 2.5 versus 1.0 hours, respectively). Consistent with a similar disposition of MPA, both EC-MPS and MMF treatments resulted in the same ratio of MPAG to MPA exposure, 23:1. Furthermore, comparison of the AUC of MPAG and AcMPAG for both treatments indicated that steady state MPAG exposure was 75 to 90 times that of AcMPAG, confirming MPAG as the predominant metabolite of MPA. AcMPAG has been identified as a possible active metabolite of MPA; the present study indicates that AcMPAG may contribute around 14% of the exposure to active drug after administration of MPA. Both EC-MPS and MMF treatments were well tolerated over the 1-month period of chronic treatment. In summary, consistent with its enteric-coated design, EC-MPS delays delivery of MPA, but results in similar exposure to that provided by MMF.     

Pharmacokinetics and pharmacodynamics of mycophenolate sodium (EC-MPS) co-administered with cyclosporine in the early-phase post-kidney transplantation

Mycophenolate drug levels are decreased by co-administration of cyclosporine. However, mycophenolate levels may be associated with insufficient immunosuppression. We investigated the pharmacokinetics of 720 mg mycophenolate sodium (EC-MPS) and inosine monophosphate dehydrogenase (IMPDH) activity under co-medication with cyclosporine and steroids within the first 30 d after kidney transplantation (n = 24). Blood samples were drawn at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 h after the morning dose. Plasma concentrations of mycophenolic acid, its glucuronide metabolites (MPAG; AcMPAG), and free MPA were determined using validated HPLC-DAD. IMPDH activity in leukocytes was analyzed chromatographically. Only six of 24 patients had an MPA-AUC(12h) within the putative therapeutic range of 40-60 mg/L·h. MPA clearance was high with 29 L/h. fMPA-AUC(12h) (r = -0.429, p = 0.04) and MPAG-AUC(12h) correlated significantly with the glomerular filtration rate, while total MPA did not. The MPAG-AUC(12h) was about 52-fold higher than the corresponding values for MPA, whereas the AcMPAG-AUC(12h) reached about 20.4% of the respective MPA-AUC(12h.) We found significant correlations between IMPDH inhibition and MPA concentration (r = -0.665; p < 0.0001), fMPA (r = -0.446; p = 0.003), and AcMPAG (r = -0.459; p = 0.002) but not with MPAG. Only 25% of the patients attained the therapeutic range for MPA-AUC under standard EC-MPS dose during the early-phase post-transplantation. We recommend that EC-MPS should be given in higher doses (3 × 720 mg) in the early post-transplant period when co-administered with cyclosporine.     

Influence of renal insufficiency on pharmacokinetics of ACYL-glucuronide metabolite of mycophenolic acid in renal transplant patients

The acyl glucuronide of mycophenolic acid (AcMPAG) is a metabolite with in vitro immunosuppressive activity. The chemical properties of acyl glucuronides have been associated with the toxicity of some drugs. The aim of our study was to analyze the influence of renal insufficiency on the pharmacokinetics of AcMPAG. Areas under the 12-hour curve (AUC(0-12h)) of MPA, glucuronide of MPA (MPAG), and AcMPAG were determined by high performance liquid chromatography performed in 20 renal transplantation patients under treatment with mycophenolate mofetil (MMF), cyclosporine, and steroids. They were divided between a group with preserved renal function (group I, mean creatinine clearance [Clcr] of 105 +/- 7 mL/min) and one with advanced renal insufficiency (group II, mean Clcr of 27 +/- 5 mL/min). There was no difference in MMF dose or MPA-AUC(0-12h) values between groups. Mean predose levels of AcMPAG-C0 and AcMPAG-AUC(0-12h) were much higher in group II than in group I (0.5 +/- 2 vs 1.6 +/- 1 microg/mL and 12 +/- 2 vs. 32 +/- 19 microg*h/mL respectively, P < .005). The present data suggested that AcMPAG, a metabolite with immunosuppressive activity that may be related to toxic effects of MPA, is renally eliminated. Its levels can significantly rise in patients with renal insufficiency. Although further studies with more patients are required to determine the role of AcMPAG in MPA toxicity, we believe that this accumulation may be of clinical relevance.     

Cyclosporine Interacts with Mycophenolic Acid by Inhibiting the Multidrug Resistance-Associated Protein 2

In mycophenolate mofetil (MMF)-treated organ transplant recipients, lower mycophenolic acid (MPA) plasma concentrations have been found in cyclosporine (CsA) compared with tacrolimus (Tac)-based immunosuppressive regimens. We previously demonstrated that CsA decreases exposure to MPA and increases exposure to its metabolite MPA-glucuronide (MPAG), possibly by interfering with the biliary excretion of MPAG. To elucidate the role of the multidrug resistance-associated protein (Mrp)-2 in the interaction between MMF and CsA, we treated three groups of 10 Mrp2-deficient rats (TR- rat) for 6 days with either vehicle, CsA (8 mg/kg) or Tac (4 mg/kg) by oral gavage. Hereafter, co-administration with MMF (20 mg/kg) was started in all groups and continued through day 14. The 24-h MPA/MPAG area under the concentration-time curve (AUC) was determined after single (day 7) and multiple MMF doses (day 14). On both study days, there were no significant differences in the mean MPA and MPAG AUC between CsA and Tac-treated animals. We conclude that the pharmacokinetics of MMF are comparable in Mrp2-deficient rats receiving either CsA or Tac as co-medication. This finding suggests that CsA-mediated inhibition of the biliary excretion of MPAG by the Mrp2 transporter is the mechanism responsible for the interaction between CsA and MMF.     

Lack of Correlation Between MMF Dose and MPA Level in Pediatric and Young Adult Cardiac Transplant Patients: Does the MPA Level Matter?1

To determine the correlation between mycophenolate mofetil (MMF) dose and mycophenolic acid (MPA) level as well as its impact on rejection among young cardiac transplant recipients (OHT), trough concentrations of MPA and its metabolite, mycophenolic acid glucuronide (MPAG), were measured following MMF doses of 1200 mg/m2/d (max 3000 mg/d). Corresponding endomyocardial biopsy (EMB) grades and calcineurin inhibitor levels were recorded with simultaneous MPA/MPAG levels. Correlation coefficients were derived between MMF dose and MPA/MPAG levels. Contingency analysis evaluated the relation between MPA level and EMB score. Twenty-six patients (median age 15.4 years) had 120 MPA/MPAG levels measured. Average MMF dose was 1208.8 mg/m2/d with median MPA and MPAG concentrations: 2.1 (therapeutic: 1.0-3.5 microg/mL) and 48 microg/mL (reference range: 35-100 microg/mL), respectively. Only 50% of patients consistently achieved therapeutic levels with standard dosing. No correlation was found between MMF dose and MPA/MPAG levels. In the presence of therapeutic calcineurin inhibition, EMB grade > or = 2 occurred more with MPA concentrations < 2.5 microg/mL (p = 0.01). In young OHT patients, MMF dose does not correlate with MPA/MPAG levels, and standard MMF dosing fails to consistently achieve 'therapeutic' MPA concentrations. An MPA trough level < 2.5 microg/mL was more frequently associated with EMB grade > or = 2. Concentration rather than dose-driven management is a more prudent strategy when using MMF.     

Pharmacokinetics of intravenous mycophenolate mofetil after allogeneic blood stem cell transplantation

BACKGROUND: Mycophenolate mofetil (MMF) has shown synergistic effects in combination with cyclosporin A (CsA) in prevention of acute graft versus host disease (GvHD) after allogeneic blood stem cell transplantation (BSCT) in preclinical animal models. After having measured low plasma levels of the active metabolite mycophenolic acid (MPA) in recipients of allogeneic blood stem cell transplants after oral administration of MMF, we initiated a phase I/II study evaluating different dose levels of the intravenous (i.v.) formulation together with standard dose CsA. METHODS: A total of 15 patients received i.v. MMF in two split doses for 21 d after allogeneic BSCT from related (n=9) and unrelated (n=6) donors. Total daily doses of 25, 28, 31 and 34 mg/kg were investigated in 3-5 patients at each dose level. Plasma concentrations of MPA and its metabolite mycophenolic acid glucuronide (MPAG) were measured by high-performance liquid chromatography (HPLC). RESULTS: Mean trough blood levels of MPA ranged between 68.8 and 340 ng/mL with a median of 146.7 ng/mL. The mean MPA AUC0-12 h after first dose ranged between 19349+/-5087 ng * h/mL and 25705+/-3042 ng * h/mL and correlated with the dose level of MMF. The incidence of acute GvHD>grade I was 40%. No dose limiting toxicities were observed. CONCLUSIONS: The application of i.v. MMF is safe at a weight-adjusted dose between 25 and 34 mg/kg after allogeneic BSCT. The measured trough blood levels of MPA in patients after BSCT were ten times lower than in healthy volunteers. The toxicity induced by the conditioning therapy seems to negatively influence the pharmacokinetic behavior of MMF, MPA and MPAG.     

Mycophenolic acid (MPA) and its glucuronide metabolites interact with transport systems responsible for excretion of organic anions in the basolateral membrane of the human kidney.

BACKGROUND: Mycophenolic acid (MPA), the active moiety of the prodrug mycophenolate mofetil, is widely used in immunosuppressive regimens after kidney, liver or heart transplantation. MPA is metabolized predominantly to the inactive 7-O-glucuronide (MPAG). A minor fraction is converted to the pharmacologically active acyl glucuronide (AcMPAG). All compounds ultimately are eliminated via the kidneys. Due to their structures, MPA and its metabolites are candidate substrates for the human organic anion transporters 1 (OAT1) and 3 (OAT3) as well as for the Na+-dicarboxylate cotransporter 3 (NaDC3). METHODS: Human (h)OAT1, hOAT3 and hNaDC3 were expressed from in vitro synthesized cRNA in collagenase-defolliculated Xenopus laevis oocytes. On day 3 post-injection, measurements were made of (i) substrate-associated currents using MPA and MPAG (only in hNaDC3-expressing oocytes) and (ii) uptake of [3H]p-aminohippurate (hOAT1) or [3H]estrone sulfate (hOAT3) in the absence or presence of either MPA, MPAG or AcMPAG. RESULTS: In hNaDC3-expressing oocytes at -60 mV, MPA (0.1 mM) as well as MPAG (0.1 mM) induced inward currents that were 17 and 25% of the currents evoked by succinate (1 mM). Vice versa, currents induced by succinate (1 mM) were partially inhibited by MPA and MPAG. hOAT1 and hOAT3 were potently inhibited by MPA (IC50 1.24 and 0.52 microM, respectively). Human OAT3, but not hOAT1, was additionally inhibited by both glucuronide metabolites of MPA in a concentration-dependent manner (IC50 15.2 microM for MPAG and 2.88 microM for AcMPAG), consistent with a preference of hOAT3 for more bulky substrates compared with hOAT1. CONCLUSIONS: MPA and its metabolites potently interact with renal organic anion transporters hOAT1 and hOAT3, and thereby may interfere with the renal secretion of antiviral drugs, cortisol and other organic anions.     

Pharmacokinetics and tolerance of mycophenolate mofetil in renal transplant children

Mycophenolate mofetil (MMF) is a prodrug that is hydrolyzed to the active immunosuppressant mycophenolic acid (MPA). The drug is now widely prescribed for adult renal transplant recipients and its use has been extended to pediatric patients, although pharmacological data in this age group are limited. Nine pediatric renal transplant recipients received MMF with corticosteroids and either cyclosporine or tacrolimus a median of 55 months (range 7.5–124 months) months after transplantation. The pharmacokinetic parameters of MPA and MPA glucuronide (MPAG) were determined at steady state by high-performance liquid chromatography after administration of MMF at the oral dose of 494±142 mg/m² twice daily. MPA was rapidly absorbed, with a peak concentration at 1.4 h. The mean plasma concentration of MPA at steady state was 4.7±1.3 μg/ml. The areas under the plasma concentration-time curves (AUCs) over 12 h (between two administrations) were 57.0±15.3 μg.h/ml for MPA and 1,515±722 μg.h/ml for MPAG, and the apparent oral clearance was 11.7±7.0 and 0.5±0.4 l/h for MPA and MPAG, respectively. Assuming that the pharmacokinetics of MPA was dose dependent, the mean concentration at steady state and the AUC for MPA were calculated for the recommended dosage schedule of 600 mg/m² every 12 h and were 6.3±2.7 μg/ml and 75.2±32.9 μg.h/ml, respectively. The tolerance of MMF was studied prospectively with a follow-up of 1.1±0.2 years. Gastrointestinal disorders requiring dosage reduction or discontinuation of therapy, observed in five of nine patients, occurred at an incidence higher than expected from adult data. Our results suggest that the dose of 600 mg/m² every 12 h extrapolated from adult data for use in pediatric patients would be associated with plasma levels and AUCs higher than expected and may be associated with a higher incidence of side-effects, primarily gastrointestinal. Received: 3 August 1998 / Revised: 19 January 1999 / Accepted: 19 January 1999     

Effect of mycophenolate mofetil on hematological side effects incidence in renal transplant recipients

Mycophenolate mofetil (MMF), an immunosuppressant administered after solid organ transplantation, is generally well tolerated; however, it frequently causes hematological toxicity. In this study, we aimed to assess the relation between the pharmacokinetic parameters of MMF metabolites (mycophenolic acid [MPA] and 7‐O‐MPA glucuronide [MPAG]) and the adverse effects on the hematopoietic system in renal transplant recipients. The four‐h pharmacokinetic profiles of MPA and MPAG were determined using the HPLC method for MMF‐treated patients (n = 61) among 106 renal transplant recipients (during the late post‐transplant period) participating in the study. Anemia was more frequently observed in the study group compared with the control group (30.7% vs. 20.0%) and although the difference was insignificant, plasma iron concentrations were significantly higher in patients treated with MMF (32.9 ± 9.4 μmol/L vs. 28.7 ± 9.4 μmol/L; p = 0.032). Iron supplementation was more frequently applied to patients with anemia (48.2%) compared with patients with hemoglobin within the norm (20.3%; p = 0.005). As all MPAG pharmacokinetic parameters correlated negatively with hemoglobin and hematocrit, and MPAG pharmacokinetic parameters were higher in patients with anemia, MPAG may be the predicting factor of MMF side effects. In renal transplant recipients, especially with deteriorated renal function, extensive iron supplementation may be ineffective as anemia was associated with declined renal function and was not caused by low iron concentration.     

Glucocorticoids interfere with mycophenolate mofetil bioavailability in kidney transplantation

BACKGROUND: Steroids have been shown to induce the hepatic glucuronyltransferase (GT) expression enhancing the activity of uridine diphosphate-GT, the enzyme responsible for mycophenolic acid (MPA) metabolism. The impact of steroids on MPA pharmacokinetics, however, has not been investigated to date. METHODS: As a part of a steroid-sparing clinical trial, we studied the effect of steroids on MPA bioavailability in 26 kidney transplant recipients. RESULTS: Despite that the MMF dose did not change significantly with time, dose-normalized MPA AUC0-12h was lower during the first month (triple therapy, high doses of steroids) than at month 6 post-surgery (triple therapy, low maintenance dose of steroids (32.94 +/- 10.98 vs. 50.87 +/- 22.37 microg/mL. h; P < 0.01). During the steroid tapering and withdrawal phase (from month 6 to 21 post-Tx), plasma MPA trough and peak concentration as well as AUC0-12h progressively increased, while plasma MPA clearance and MPAG (the major MPA metabolite) trough levels declined. Renal function was stable throughout. Since cyclosporine A (CsA) may interfere with MPA pharmacokinetics, MPA and CsA also were measured in an additional control group of 12 kidney transplant patients at month 21 post-Tx who were still on triple therapy (MMF, CsA and steroids). Despite a similar CsA exposure, the control group had a significantly lower MPA AUC0-12h and higher MPAG trough concentration than patients on dual therapy at month 21 post-Tx. CONCLUSION: These findings indicate that steroids interfere with MPA bioavailability, and that discontinuation of the drug results in higher MPA exposure, which may compensate at least in part for the lower immunosuppressive level achieved with the remaining dual therapy with CsA and MMF.     

Mycophenolic acid clinical pharmacokinetics influenced by a cyclosporine C2 based immunosuppressive regimen in renal allograft recipients

Therapeutic drug monitoring of mycophenolic acid (MPA) in combination with cyclosporine 2-h concentration (CsA C2, n = 68) or tacrolimus trough concentration (n = 10) was investigated by repeated measurements of MPA and MPA-glucuronide (MPAG) trough concentrations in renal allograft recipients during the first 3 months post-transplant. The acute rejection rate was lower (19% vs. 43%; P < 0.05) in patients achieving CsA C2 target range during the first week (1600-2000 microg/l), n = 26, compared with those who did not, n = 42. Median MPA concentration was 0.9 and 1.2 microg/ml in patients within or below C2 range, respectively (P = 0.19). CsA C2 correlated with MPAG-to-MPA ratio (P < 0.01, r = 0.91) and gamma-glutamyl-transpeptidase (GGT, P < 0.01, r = 0.86). Total MPA concentration increased during the 3 months, but not in patients on tacrolimus. High CsA C2 lowered the acute rejection rate and plasma MPA. High CsA C2 is associated with elevated GGT, probably because of cholestatic effects, which explain the increased MPAG-to-MPA ratio. Increasing MPA concentration is ascribed to per-protocol CsA C2 reductions. In conclusion, CsA may confound the relationship between MPA and the incidence of rejection, and contribute to the difficulty of obtaining a therapeutic range for MPA in clinical practice.     

The impact of P-glycoprotein and Mrp2 on mycophenolic acid levels in mice

Considerable variability has been observed in the exposure to mycophenolic acid (MPA) in transplant patients. The objective of this study was to clarify the roles of two important transporters, P-gp and Mrp2, in MPA absorption using an in vivo model. FVB strain wild-type, Mdr1a/1b(-/-) and Mrp2(-/-) mice were subjected to the administration of mycophenolate mofetil (MMF) alone or MMF in combination with cyclosporine (CsA), an immunosuppressive inhibitor of P-gp and Mrp2. At 30 min following treatment, the MPA levels in Mdr1a/1b(-/-) and Mrp2(-/-) mice were markedly increased as compared to wild-type mice. In contrast to the reduced MPA concentrations observed at 60 and 120 min in the CsA-treated groups, CsA produced increased mycophenolate glucuronide (MPAG) plasma levels in CsA-treated mice at each sampling time. Brain concentrations of MPA were elevated in the Mdr1a/1b(-/-) mice at 30 min after MMF in conjunction with increased plasma MPA concentrations, but not in the wild-type or the Mrp2(-/-) mice. This study demonstrated that: a) MPA appears to be a substrate for P-gp, and b) MPA plasma concentrations are influenced by multiple membrane transporters. Drug-transporter interactions must be considered in patients receiving mycophenolic acid products.     

Mycophenolate mofetil pharmacokinetics in renal transplant recipients on peritoneal dialysis

We prospectively studied the impact of peritoneal dialysis (PD) on the pharmacokinetics of mycophenolic acid (MPA) in five patients following renal transplantation. Three patients had a glomerular filtration rate (GFR) of less than 10 ml/min and two had a GFR of more than 40 ml/min. Pharmacokinetics of MPA and of its main metabolite, mycophenolic acid glucuronide (MPAG), were studied during two consecutive 12-h periods (with and without PD). After initiation of PD in patients with severe renal impairment (GFR < 10 ml/min), MPA-area-under-the-concentration-curve (AUC) decreased up to 59 % and MPAG-AUC decreased up to 26 %. We did not observe any substantial changes in the MPA-AUC or MPAG-AUC of either patient with a GFR above 40 ml/min. Patients with a reduced GFR had much higher MPAG values than patients with a GFR above 40 ml/l; yet, we did not observe any differences in the MPA values. We found a significant inverse correlation between GFR and MPA-AUC (r = 0.81, P < 0.05) and between GFR and MPAG-AUC (r = 0.94, P < 0.01). While MPA was found only in traces in the peritoneal ultrafiltrate, the cumulative amount of MPAG removed by PD reached up to 2 g/12 h, representing 1.2 g of MPA. This is the first report describing a reduction in MPA-AUC and MPAG-AUC during PD. Further studies are needed to completely understand the pharmacokinetics of mycophenolate mofetil during PD. Received: 20 June 1997 Accepted: 26 August 1997     

Pharmacokinetics of mycophenolate mofetil in patients with end-stage renal failure

BACKGROUND: Mycophenolate mofetil (MMF) acts as a prodrug for the immunosuppressive drug mycophenolic acid (MPA). It is rapidly converted to MPA following oral ingestion. MPA is metabolized to MPA glucuronide (MPAG), which is renally excreted. This study examines the pharmacokinetics of MPA and MPAG in patients with end-stage renal failure who were on hemodialysis (N = 10) or peritoneal dialysis (N = 10) treatment. METHODS: After an overnight fast, a single oral dose of 1 g MMF was given. Plasma concentrations of MPA and MPAG were measured from 0 (predose) to 36 hours after administration, using high-performance liquid chromatography (HPLC). The area under the concentration time curve (AUC) from 0 to 36 hours was calculated using the trapezoidal rule. RESULTS: Mean (+/- SD) AUC for MPA was 55.7 +/- 32.6 mg/L.h for hemodialysis patients and 44.7 +/- 14.7 mg/L.h for peritoneal dialysis patients, which is similar to expected values for subjects with normal renal function. The mean (+/- SD) maximum plasma concentration (Cmax) for MPA was lower than would be expected for subjects with normal renal function (16.01 +/- 10.61 mg/L for hemodialysis, 11.48 +/- 4.98 mg/L for peritoneal dialysis). MPAG clearance was prolonged with AUC approximately five times what would be expected in subjects with normal renal function (1565 +/- 596 mg/L.h for hemodialysis, 1386 +/- 410 mg/L.h for peritoneal dialysis). There was no significant difference for any of the pharmacokinetic parameters between subjects on hemodialysis and those on peritoneal dialysis. Plasma concentrations of MPA and MPAG did not fall significantly during hemodialysis. No MPA was detectable in hemodialysis or peritoneal dialysis fluid, but small amounts of MPAG were detected in hemodialysis fluid in 1 out of 10 subjects and in peritoneal dialysis fluid in 3 out of 10 subjects. CONCLUSIONS: The accumulation of MPAG may be responsible for the poor gastrointestinal tolerance of this drug in dialysis patients and probably limits the maximum dose of MMF that can be tolerated.     

Effect of cyclosporine on mycophenolic acid trough levels in kidney transplant recipients

BACKGROUND: Triple drug treatment consisting of mycophenolate mofetil (MMF), in a standard dose of 2 g daily, combined with cyclosporine (CsA) and prednisone, has become the standard immunosuppressive regimen after kidney transplantation in many centers. The need for therapeutic drug monitoring of mycophenolic acid (MPA) has not yet been established. Several drug interactions with MMF are known. We investigated the influence of CsA withdrawal on MPA trough levels in renal transplant patients. METHODS: Fifty-two patients were treated with 1 g of MMF twice daily, and prednisone and CsA targeted between 125 and 175 ng/ml for 6 months after transplantation. At 6 months after transplantation, 19 patients were randomized for continuation of triple therapy (group A), 19 patients discontinued CsA (group B), and 14 patients discontinued prednisone (group C). We compared 12-hr fasted MPA trough levels at 6 and 9 months after transplantation within and between these groups. RESULTS: MPA trough levels during treatment with CsA, MMF, and prednisone were significantly lower than those during treatment with MMF and prednisone only (group B); median levels were 1.87 mg/L (range: 0.56-5.27) vs. 3.16 mg/L (range: 0.32-7.78), respectively (P=0.002). MPA trough levels in groups A and C did not change between 6 and 9 months after transplantation; group A median levels were 1.87 (range: 0.31-4.32) vs. 1.53 mg/L (range: 0.36-3.70), and group C median levels were 1.62 (range: 0.69-10.34) vs. 1.79 mg/L (range: 0.54-6.00), respectively. At 9 months after transplantation, patients in whom CsA was discontinued had higher MPA trough levels as compared with patients who continued the use of triple therapy (P=0.001) or patients in whom steroids were withdrawn (P=0.014). CONCLUSION: A significant increase of MPA trough levels was found after discontinuation of CsA (6 months after transplantation), resulting in almost a doubling of MPA trough levels at 9 months after transplantation. This resulted in increased MPA levels in patients without CsA as compared to MPA levels in patients continuing triple therapy or discontinuing prednisone.     

Tacrolimus or cyclosporine: which is the better partner for mycophenolate mofetil in heart transplant recipients?

BACKGROUND: The aim of this single-center study was to investigate whether trough level adjusted mycophenolate mofetil (MMF) is more efficacious in combination with tacrolimus (TAC) or cyclosporine (CsA) and to evaluate the impact of either drug on MMF dosage. METHODS: Sixty patients (TAC, n = 30; CsA, n = 30) undergoing heart transplantation were randomized into a prospective, open-label, controlled trial. Immunosuppression consisted of TAC or CsA in combination with MMF and corticosteroids. Target blood trough levels of TAC, CsA, and mycophenolic acid (MPA) were in the range of 10 to 15 ng/mL, 100 to 300 ng/mL, and 1.5 to 4.0 microg/mL, respectively. Acute rejection episodes (ARE); survival data; and adverse events with a special emphasis on infections, diabetes, hypertension, hypercholesterolemia, and the development of graft vessel disease (GVD) were recorded. RESULTS: Baseline characteristics were well balanced. All patients were successfully withdrawn from corticosteroids within 6 months of transplant. Freedom from acute rejection was significantly higher (P = 0.0001) and the incidence of ARE per 100 patient days significantly lower in the TAC-MMF group than in the CsA-MMF group (0.03 vs. 0.15; P = 0.00007). Overall patient survival during follow-up was similar (93% vs. 90%). To achieve the targeted MPA blood levels, a significantly lower dose of MMF was required for TAC versus CsA patients. After a follow-up time of 2 years, the mean GVD score was 1.85 +/- 3.18 in the TAC-MMF group and 3.95 +/- 4.8 in the CsA-MMF group (P = 0.08). CONCLUSIONS: At the selected doses and target levels for TAC and CsA used in this study, trough level adjusted MMF was more efficacious in combination with TAC for prevention of ARE. Furthermore, CsA patients need significantly more MMF to achieve similar MPA levels.     

Mycophenolic acid plasma concentrations in kidney allograft recipients with or without cyclosporin: a cross-sectional study.

BACKGROUND: Combining cyclosporin (CsA) and prednisone with mycophenolate mofetil (MMF) results in a significant reduction in the rate of biopsy-proven acute rejection after kidney transplantation. This is achieved with a standard daily MMF dosage of 2 or 3 g. Whether monitoring of the pharmacologically active metabolite mycophenolic acid (MPA) will lead to improved safety and efficacy is unclear. METHODS: We monitored MPA trough levels in 18 kidney transplant recipients treated with CsA, prednisone, and MMF (63 samples) and in 11 patients (31 samples) treated with prednisone and MMF only, in a cross-sectional study. All patients were at least 3 months after transplantation with stable graft function. All patients were treated with 2 g MMF for at least 3 months and 10 mg prednisone. RESULTS: The MPA trough levels in the CsA-treated patients were significantly lower (P<0.0001; Mann-Whitney) than those in patients on MMF and prednisone only (mean MPA levels 1.98+/-0.12 vs 4.38+/-0.40 mg/l respectively). CONCLUSIONS: Although all patients were treated with an identical MMF dose, a significant difference was found in the MPA trough levels between CsA- vs non-CsA-treated patients. This suggests that CsA influences the MPA trough level. The level at which CsA affects the MPA trough levels is unclear.     

Pharmacokinetics of mycophenolic acid and its glucuronide after a single and multiple oral dose of mycophenolate mofetil in Chinese renal transplantation recipients

PURPOSES: To compare the pharmacokinetic parameters of mycophenolic acid (MPA) and mycophenolic acid glucuronide (MPAG) after single and multiple oral administration of mycophenolate mofetil (MMF) in Chinese renal transplant patients with those of recipients in other countries. METHODS: Twelve Chinese renal transplant patients after an overnight fast received a single 1-g dose of MMF before renal transplantation. Thereafter the patients received 1 g MMF twice a day up to and on the day 12 after renal transplantation. The concentrations of MPA and MPAG were simultaneously measured by RP-HPLC. The concentration-time data were examined with Drug and Statistics pharmacokinetic software. Using paired samples t test (self-contrast) with SPSS statistical software (alpha = 0.05), we compared the pharmacokinetic parameters between single and multiple doses. RESULTS AND DISCUSSIONS: The MPA concentration-time profiles were fitted to a two-compartment open model; MPAG concentration-time profiles were fitted to a single-compartment open model. Compared with the literature reports, the main pharmacokinetic parameters of MPA and MPAG shown by our research revealed some differences. The parent drug MMF was undetectable in plasma during oral administration. A secondary peak of MPA occurred at 6 to 10 hours, which was attributed to enterohepatic recirculation. There was significant variation in MPA and MPAG plasma concentration-time data among subjects. It is suggested that therapeutic drug monitoring should be applied for dosage optimization.     

Pharmacokinetics and variability of mycophenolic acid from enteric-coated mycophenolate sodium compared with mycophenolate mofetil in de novo heart transplant recipients

Sequential pharmacokinetic assessments were performed at five centers within the context of a multicenter, single-blind, randomized clinical trial comparing the efficacy and safety of enteric-coated mycophenolate sodium (EC-MPS, myfortic) and mycophenolate mofetil (MMF, CellCept) in de novo heart transplant recipients. Patients were randomized to either EC-MPS 1080 mg bid or MMF 1500 mg bid, as part of a triple immunosuppressive therapy including cyclosporine microemulsion. Steady-state pharmacokinetic profiles of mycophenolic acid (MPA) and its inactive phenolic glucuronide (MPAG) were assessed at weeks 2, 12, and 52. Pharmacokinetic parameters were evaluated in 32 patients (17 on EC-MPS and 15 on MMF). Dose-normalized peak (C(max,ss)) and area under the curve (AUC(tau,ss)) of MPA and MPAG increased between week 2 and week 12 assessments for both treatments. Comparisons between EC-MPS and MMF showed no statistically significant differences in MPA and MPAG AUC(tau,ss), C(max,ss), and trough (C(min,ss)) values (p-values ranged from 0.225 to 0.990). Consistent with the delayed release characteristics of EC-MPS, C(max,ss) occurred approximately one hour later compared with MMF. Inter-subject coefficients of variation (%CV) for MPA pharmacokinetic parameters of both EC-MPS and MMF were high (37-72% for AUC(tau,ss) at weeks 2 and 12). Also within patients, the pharmacokinetics of MPA varied considerably. Specifically, intra-subject %CVs for MPA AUC(tau,ss), C(max,ss), and C(min,ss) were 28%, 63%, and 34% with EC-MPS and 54%, 139%, and 41% with MMF respectively. These results indicate that a dose of EC-MPS 1080 mg bid in combination with cyclosporine provides adequate systemic MPA exposure in de novo heart transplant patients, comparable with MMF 1500 mg bid. Overall, there is a large inter- and intra-subject variability in MPA pharmacokinetic parameters with both treatments.     

The influence of calcineurin inhibitors on mycophenolic acid pharmacokinetics

Despite the fact that concentrations of mycophenolic acid (MPA) are not routinely measured, accumulating data suggest the usefulness of this monitoring to optimize therapy. The aim of this study was to assess the influence of CsA and tacrolimus on MPA pharmacokinetics. Concentrations of MPA were measured using HPLC. An assay was performed before dose (the C(0)), as well as at 40 minutes and 1, 2, 4, 6, 8, 10, 12 hours after administration of mycophenolate mofetil (MMF). MPA profiles were assessed in 51 patients receiving tacrolimus at a dose of 1.0 g/d and prednisone as well as in 97 patients receiving CsA (2.0 g/d) and prednisone. Significant correlations of MPA levels with serum albumin and GFR were observed in both groups. Women presented with higher levels of MPA than men. C(0) MPA level among the tacrolimus group were significantly higher than those in CsA group: 3.18 +/- 2.21 microg/mL versus 1.68 +/- 1.03 microg/mL (P 相似文献