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   

The pharmacokinetic-pharmacodynamic relationship for total and free mycophenolic Acid in pediatric renal transplant recipients: a report of the german study group on mycophenolate mofetil therapy

It is currently being debated whether pharmacokinetic monitoring of mycophenolic acid (MPA), the active constituent of mycophenolate mofetil (MMF), can optimize MMF therapy after organ transplantation. This open-label longitudinal study in pediatric renal transplant recipients was designed to investigate the pharmacokinetic (PK)/pharmacodynamic relationship of total and free MPA and to establish PK values for the assessment of an individual's MPA PK parameters. Fifty-four children, aged 2.2 to 17.8 yr, on an immunosuppressive triple regimen consisting of cyclosporin A, prednisone, and MMF (600 mg/m(2) body surface area twice daily) were investigated 1 wk and 3 wk (initial phase) and 3 mo and 6 mo (stable phase) after renal transplantation. MPA was measured by reverse phase HPLC, free MPA by HPLC after separation by ultrafiltration. There was an association between the risk of acute rejection episodes and MPA-AUC(0-12) values or MPA predose levels; by receiver operating characteristic analysis, an AUC(0-12) of 33.8 mg x h/L in the initial phase posttransplant had a diagnostic sensitivity of 75% and a diagnostic specificity of 64% for discrimination of patients with acute rejections. The respective discrimination threshold for the MPA predose concentration was 1.2 mg/L with a sensitivity of 83% and a specificity of 64%. In contrast, high free, but not total, MPA-AUC(0-12) values were associated with an increased risk of the MMF-related side effects leukopenia and/or infections. These data indicate that therapeutic drug monitoring of MPA has the potential for optimization of MMF efficacy in this patient population by steering patients away from the low values of MPA PK variables that are associated with an increased rejection risk. For the assessment of the toxic risk of MMF regarding leukopenia and/or infections, measurement of free MPA appears to be more appropriate.     

Randomized crossover study to assess the inter‐ and intrasubject variability of morning mycophenolic acid concentrations from enteric‐coated mycophenolate sodium and mycophenolate mofetil in stable renal transplant recipients

Tedesco‐Silva H, Felipe CR, Park SI, Pinheiro‐Machado PG, Garcia R, Slade A, Schmouder R, Medina‐Pestana JO. Randomized crossover study to assess the inter‐ and intrasubject variability of morning mycophenolic acid concentrations from enteric‐coated mycophenolate sodium and mycophenolate mofetil in stable renal transplant recipients.
Clin Transplant 2010: 24: E116–E123.
© 2009 John Wiley & Sons A/S. Abstract: The delayed release of mycophenolic acid (MPA) from enteric‐coated mycophenolate sodium (EC‐MPS, myfortic^®) may have an impact on the variability of MPA trough (C_{0 h}) levels. A randomized, two‐period crossover study was performed in 24 maintenance renal transplants to evaluate the inter‐ and intrasubject variability of MPA predose levels from EC‐MPS and mycophenolate mofetil (MMF, CellCept^®), both in combination with cyclosporine. Patients received EC‐MPS (720 mg b.i.d.) and MMF (1000 mg b.i.d.) for a period of 21 d each. MPA plasma levels were measured over the final seven consecutive days at ?1, 0, 1, 2, and 3 h after the morning MPA dose. Intersubject coefficients of variation (%CV) for MPA troughs were 47.5% (95% CI, 34.1–80.3) and 54.4% (40.0–86.8) for EC‐MPS and MMF, respectively; intrasubject %CVs were 62.7% (55.1–72.9) and 42.8% (37.9–49.2). High MPA C_{0 h} levels >10 μg/mL were rarely observed with both EC‐MPS (1.8%) and MMF (0.6%). Mean MPA area under the curve (AUC)_{0–3 h} was comparable between treatments, while MPA C_{0 h} was on average 46% higher with EC‐MPS. In conclusion, predose MPA trough level monitoring appears of limited value during EC‐MPS and MMF therapy given the large intrasubject variability in MPA C_{0 h} levels with both treatments.     

Pharmacokinetic evaluation of mycophenolic acid profiles during the period immediately following an orthotopic liver transplant

BACKGROUND: Area under the curve (AUC) limited sampling strategies have been proposed to improve the efficiency of mycophenolic acid (MPA), treatment of the transplanted patient. Our objective was to develop a model in the initial phase of the transplantation that explains the variability in the pharmacokinetic behavior of MPA in the immediate posttransplant period, following treatment with mycophenolate mofetil (MMF) in adult liver transplantation. METHODS: One hundred ten pharmacokinetic simplified sampling profiles were collected, including four samples over a 6-hour postdose interval, in over 60 patients treated with cyclosporine or tacrolimus, MMF, and steroids, combining Daclizumab in more than a third of the patients. For an enzyme-multiplied immunoassay technique method was established for MPA estimates. The correlation between the AUC and the plasma concentration points was established using a multiple linear regression with various equations for three different pharmacokinetic groups. RESULTS: The maximum mean values of MPA AUC and predose concentration (C0h) (20.8 +/- 11.8 and 2.3 +/- 1.8, respectively) were reached on the third day. The single sample showing the greatest correlation with the MPA AUC was the one collected after 3 hours (r(2) = 0.575); 59.1% of profiles displayed a single peak with more than half showing a tmax >/= 3 hours. CONCLUSIONS: This profile analysis during the first few weeks highlighted the problems in determining therapeutic targets. Profiles showing a double peak revealed the marked influence of the enterohepatic cycle on MPA concentrations during the initial phase.     

Proton pump inhibitor co-medication reduces active drug exposure in heart transplant recipients receiving mycophenolate mofetil

Background

Proton pump inhibitors (PPIs) are often prescribed for gastrointestinal discomfort after heart transplantation. This study investigated the impact of PPI use on mycophenolic acid (MPA) pharmacokinetics in heart transplant recipients receiving mycophenolate mofetil (MMF) in combination with a calcineurin inhibitor (tacrolimus [TAC]/cyclosporine [CsA]) or mammalian target of rapamycin inhibitor (sirolimus/everolimus).

Methods

Abbreviated MPA areas under the curve (AUCs; 0, 30, and 120 minutes after morning intake) were obtained in 19 patients on a PPI (initial examination) and 1 month after PPI discontinuation (follow-up). Mean patient age was 58.2 ± 8.8 years, and mean time after transplantation was 2.3 ± 4.0 years (range, 0.2–13.0 years).

Results

At initial examination mean daily MMF dose was 2.2 ± 0.8 g. MMF dose was kept unchanged for the duration of study (P = ns). Mean predose (C0) MPA serum concentrations were insignificantly lower with PPI comedication (2.5 ± 2.2 mg/L vs 2.8 ± 1.7 mg/L; P = .15). Dose-adjusted abbreviated MPA AUCs (adjusted to morning dose) were significantly lower during PPI therapy (45.2 ± 20.3 vs 65.2 ± 38.8 mg · h/L · g [MMF]; P = .02).

Conclusions

Patients with PPI comedication during MMF therapy show significantly lower exposure to mycophenolic acid determined by dose-adjusted abbreviated MPA AUCs. Although the clinical relevance of this pharmacokinetic interaction was not determined in this study, MPA drug monitoring by limited sampling strategies might be helpful during changes in antacid comedication in patients on MMF.     

Long-term results of mycophenolate mofetil as part of immunosuppressive induction therapy after liver transplantation

BACKGROUND: The addition of mycophenolate mofetil (MMF) to the induction protocol resulted in a lower incidence of rejection episodes. However, the question whether MMF should be administered in combination with tacrolimus or cyclosporine has not been answered yet. In our study, we report on the long-term results of triple induction therapy after orthotopic liver transplantation (OLT), consisting of MMF and low-dose corticosteroids, in combination with either tacrolimus or cyclosporine. METHODS: Between March 1996 and April 1997, 120 consecutive patients, who underwent OLT at our institution, were enrolled in this study. Of these patients, 80 received triple induction therapy consisting of cyclosporine and MMF (40) or tacrolimus and MMF (40), in combination with low-dose corticosteroids, whereas the remaining 40 patients served as 'MMF-free' control group receiving dual induction therapy with tacrolimus and corticosteroids. Besides the eight-yr follow-up of patient and graft survival, clinical data were also reviewed for episodes of rejection and infection. Additionally, the early post-operative pharmacokinetics of mycophenolic acid (MPA, immunological active metabolite of MMF) were evaluated. RESULTS: Long-term results provided higher patient and graft survival after tacrolimus/MMF-based induction therapy than after cyclosporine/MMF-based induction therapy. However, the tacrolimus-based control protocol yielded similar results and, therefore, no significantly superior effect was observed when MMF was added. The same observation was made for incidence of rejection and infection episodes. AUC and C(max) of MPA increased in combination with tacrolimus compared with cyclosporine. CONCLUSIONS: Although pharmacological synergy between tacrolimus and MMF was observed, MMF showed no significant beneficial effects in the immunosuppressive induction protocol, neither in combination with tacrolimus nor with cyclosporine.     

Pharmacokinetics of mycophenolic acid in kidney transplant patients receiving sirolimus versus cyclosporine

INTRODUCTION: Mycophenolic acid (MPA) pharmacokinetics exhibit large variability in transplant recipients and may be altered due to concurrent immunosuppressants. Little is known about the influence of sirolimus (SRL) on MPA pharmacokinetics in kidney transplant patients. METHODS: We studied the areas under concentration-time curves (AUC) for MPA in 15 patients receiving immunosuppression combining SRL with mycophenolate mofetil (MMF). The pharmacokinetic measurements were performed in all patients using three MMF dosing regimens (0.5 g twice a day, 0.75 g twice a day, 1 g twice a day). Similar blood AUC profiles were also sampled from 12 patients treated with a fixed dose of MMF 1 g twice a day and cyclosporine (CsA). MPA was measured using HPLC; the AUC0-12 of MPA was determined by the trapezoidal method using four sampling time points: C0, C1, C3, C5. RESULTS: While patients on SRL were receiving 0.75 g MMF twice a day, mean AUC0-12 and C0 values of MPA were comparable to those of patients receiving CsA and 1 g MMF twice a day (54.1 +/- 17.6 and 3 +/- 1.87 vs 51.7 +/- 16.7 mg.h/L and 2.76 +/- 1.57 mg/L, respectively). On the other hand, 0.5 g MMF twice a day with SRL therapy resulted in AUC0-12 and C0 values of MPA of 32.3 +/- 12.6 mg.h/L and 2.32 +/- 1.72 mg/L, respectively, whereas, 1 g MMF twice a day with SRL resulted in AUC0-12 and C0 values of MPA of 70.9 +/- 19.3 mg.h/L and 4.7 +/- 2.44 mg/L, respectively. CONCLUSIONS: These findings demonstrate that MPA exposure in the presence of SRL is higher than that with CsA. It appears that the MMF dose should be reduced to 0.75 g twice a day in patients receiving SRL to obtain AUC0-12 of MPA levels comparable to that in patients treated with CsA and MMF 1 g twice a day.     

Primary immunosuppression with tacrolimus and low-dose mycophenolate mofetil in renal transplant recipients

Both tacrolimus and mycophenolate mofetil (MMF) are potent immunosuppressive agents used in combination for prevention of acute rejection in renal transplantation. We studied the efficacy and safety of tacrolimus/MMF-based primary immunosuppression as well as their pharmacokinetics (PK) in Chinese renal transplant recipients. Oral tacrolimus was initiated at about 0.2 mg/kg/d, dose which was adjusted to achieve target trough levels of 10 to 20 ng/mL at 3 months and 5 to 10 ng/mL thereafter. The patients also received MMF (0.5 g bid) and prednisolone. PK profiles were studied at 1 week, and 1, 3, and 6 months posttransplant. Blood samples were taken at 0 (predose), 20, 40, 60, 75, and 90 minutes and 2, 4, 6, 8, 10, and 12 hours postdose for each profile. Plasma MPA and whole blood tacrolimus levels were determined by HPLC and EMIT methods respectively. Eight patients were studied with mean follow-up of 16.1 +/- 2.4 months. One patient (12.5%) experienced a borderline acute rejection episode. Both 1-year graft and patient survival rates were 100%. Posttransplant diabetes, diarrhea, and hand tremor occurred in 12.5%, 12.5%, and 37.5%, respectively. No patient had an opportunistic infection. Tacrolimus trough concentrations showed a fair correlation with AUC(0-12h) (R(2) = 0.587). Mean MPA AUC values at 1, 3, and 6 months were 40.5 +/- 9.4, 44.4 +/- 17.3, and 57.2 +/- 20.7 mug*h/mL, respectively (P = .0486, n = 7). In conclusion, primary immunosuppression with tacrolimus, low-dose MMF (0.5 g bid), and prednisolone is effective and safe with adequate systemic MPA exposure in renal transplant recipients.     

Pharmacokinetics help optimizing mycophenolate mofetil dosing in kidney transplant patients

BACKGROUND: Mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), is now routinely used as immunosuppressant in solid organ transplantation in a fixed daily dose regimen (2 g/d) in association with cyclosporine (CsA) and steroids. However, no correlation has been shown between fixed MMF dose and clinical outcome. METHODS: Here we examined the possibility of optimizing MMF dosing by drug pharmacokinetic monitoring in 46 stable kidney transplant recipients. MPA plasma concentration profiles were measured by a reverse-phase high-performance liquid chromatography method 6-9 months after transplantation and related with routine laboratory analysis tests. Since MPA is extensively bound to serum albumin and only the free fraction is pharmacologically active, in a subgroup of 23 patients free plasma MPA was also determined. RESULTS: Despite a comparable MMF dose, a large interindividual variability in both MPA area under the curve (AUC) from 0 to 12 h (range 10.1-99.8 microg/mL. h) and in trough levels (range 0.24-7.04 microg/mL) was found. Patients with AUC >40 microg/mL. h showed a better (p<0.05) renal function than patients with lower AUC (creatinine clearance 85.7+/-23.2 versus 64.5+/-17.5 mL/min), despite no difference in CsA dose, CsA AUC and blood CsA trough level. The percentage of free plasma MPA but not total MPA correlated with the red blood cell and leukocyte count. CONCLUSIONS: Therapeutic MMF drug monitoring might contribute to a better management of kidney transplant recipient with the goal of optimizing drug dosing and limiting the risk of MMF-related toxicity.     

A randomized long-term trial of tacrolimus and sirolimus versus tacrolimus and mycophenolate mofetil versus cyclosporine (NEORAL) and sirolimus in renal transplantation. I. Drug interactions and rejection at one year

BACKGROUND: To reduce long-term nephrotoxic calcineurin inhibitor dosage, adjunctive sirolimus or mycophenolate mofetil (MMF) was used in a 150-patient, randomized, three-armed trial in cadaveric or human leukocyte antigen non-identical living-donor first renal transplant recipients (n=50/group). METHODS: Group A received tacrolimus and sirolimus. Target tacrolimus trough levels postoperatively were 10, 8, and 6 ng/mL at 1 month, 6 months, and 1 year, respectively. Group B received tacrolimus and MMF. Target tacrolimus trough levels were 10 and 8 ng/mL at 1 month and 1 year, with a targeted dose of MMF of 1 g twice daily. Group C received cyclosporine A (CsA) (Neoral, Novartis, Basel, Switzerland) and sirolimus with target CsA trough levels of 225 and 175 ng/mL at 1 month and 1 year. Maintenance sirolimus target trough levels were 8 ng/mL in groups A and C. Each group received daclizumab induction and methylprednisolone maintenance. This first of two companion 1-year reports details demographics, drug-dosing interactions, and rejection. RESULTS: There were no notable differences in group demographics, but a somewhat less favorable course occurred in group C, despite higher bioavailability of sirolimus in group C versus group A (P<0.001). Acute rejection rates were lower in groups A (4%) and B (4%) combined versus group C (14%) (P=0.03). Histopathologic findings were supported by comparing perioperative with 1-year postoperative protocol biopsies. CONCLUSIONS: This 1-year interim analysis indicates that a decreasing dosage of tacrolimus with either adjunctive sirolimus or MMF may optimize future graft survival versus a less favorable outcome using a similar algorithm with CsA and sirolimus.     

The impact of renal allograft function on exposure and elimination of mycophenolic acid (MPA) and its metabolite MPA 7-O-glucuronide

BACKGROUND: Previous studies have shown that total-body clearance of mycophenolic acid (MPA) is increased and total MPA exposure decreased in renal allograft recipients with severe renal dysfunction. In contrast to these studies, other studies have associated renal impairment with higher MPA exposure. The reason for these inconsistencies is not clear. METHODS: In 120 renal allograft recipients with stable graft function and treated with a combination of mycophenolate mofetil, tacrolimus, and corticosteroids, clinical determinants of exposure to total MPA and its glucuronide metabolite MPA 7-O-glucuronide (MPAG) were investigated in a multivariate regression model at 3 (n=118) and 12 (n=63) months after transplantation. RESULTS: Almost 50% of total MPA exposure could be explained by the final model, in which proteinuria, glomerular filtration rate, diabetes mellitus, and the mycophenolate mofetil dose were independent determinants of total MPA exposure. Lower glomerular filtration rate (GFR) was independently associated with higher MPA exposure both at 3 and 12 months after transplantation. GFR, alanine aminotransferase, and serum albumin levels and mycophenolate mofetil dose explained 69% of total MPAG exposure variability. CONCLUSION: In stable renal recipients, total MPA exposure negatively associates with renal function, through accumulation of both MPA and MPAG in patients with moderately reduced renal allograft function. This is in contrast to severe graft dysfunction, where MPA clearance is higher due to increased free fraction of MPA, as shown in previous studies. The duality in the effect of graft function on MPA pharmacokinetics is of clinical importance, adjusting mycophenolate mofetil dose according to renal function might help to avoid side effects and improve efficacy.     

Pharmacokinetic and Pharmacodynamic Comparison of Enteric-Coated Mycophenolate Sodium and Mycophenolate Mofetil in Maintenance Renal Transplant Patients

The aim of this single-center crossover substudy was to assess pharmacokinetics and pharmacodynamics [inosine 5'-monophosphate dehydrogenase (IMPDH) activity] of enteric-coated mycophenolate sodium (EC-MPS) and mycophenolate mofetil (MMF) at steady-state conditions. Stable maintenance renal transplant patients on 1 g MMF b.i.d. participating in a double-blind, multicenter study, were randomized to receive EC-MPS (720 mg b.i.d.) or continue receiving MMF (1000 mg b.i.d.) for 12 months. Thereafter, all patients (n = 18) received 720 mg EC-MPS b.i.d. Area under the plasma mycophenolic acid (MPA) concentration-time curve with EC-MPS (57.4 +/- 15.0 microg h/mL) fulfilled bioequivalence criteria (geometric mean 0.98 (90% CI: 0.87-1.11) compared to MMF (58.4 +/- 14.1 microg h/mL). Consistent with the delayed release characteristics of EC-MPS, peak MPA concentration (geometric mean 0.89; 90% CI: 0.70-1.13) occurred approximately 0.5 h later (p < 0.05) and predose MPA levels (geometric mean 2.10; 90% CI: 1.51-2.91) were higher and more variable, not fulfilling bioequivalence criteria. IMPDH activity inversely followed MPA concentrations and was inhibited to a similar degree (approximately 85%) by both formulations. The calculated value for 50% IMPDH inhibition was identical for both drugs. In conclusion, equimolar doses of EC-MPS and MMF produce equivalent MPA exposure, while the delayed release formulation of EC-MPS exhibits more variable predose levels and T(max). Overall, IMPDH activity reflected MPA pharmacokinetics.     

Individualized Mycophenolate Mofetil Dosing Based on Drug Exposure Significantly Improves Patient Outcomes After Renal Transplantation

Efficacy and safety of mycophenolate mofetil (MMF) may be optimized with individualized doses based on therapeutic monitoring of its active metabolite, mycophenolic acid (MPA). In this 12-month study, 137 renal allograft recipients from 11 French centers receiving basiliximab, cyclosporine A, MMF and corticosteroids were randomized to receive either concentration-controlled doses or fixed-dose MMF. A novel Bayesian estimator of MPA AUC based on three-point sampling was used to individualize doses on posttransplant days 7 and 14 and months 1, 3 and 6. The primary endpoint was treatment failure (death, graft loss, acute rejection and MMF discontinuation). Data from 65 patients/group were analyzed. At month 12, the concentration-controlled group had fewer treatment failures (p = 0.03) and acute rejection episodes (p = 0.01) with no differences in adverse event frequency. The MMF dose was higher in the concentration-controlled group at day 14 (p < 0.0001), month 1 (p < 0.0001) and month 3 (p < 0.01), as were median AUCs on day 14 (33.7 vs. 27.1 mg*h/L; p = 0.0001) and at month 1 (45.0 vs. 30.9 mg*h/L; p < 0.0001). Therapeutic MPA monitoring using a limited sampling strategy can reduce the risk of treatment failure and acute rejection in renal allograft recipients 12 months posttransplant with no increase in adverse events.     

Mycophenolic acid trough levels after kidney transplantation in a cyclosporine‐free protocol

Abstract Twenty‐seven stable kidney transplant recipients treated with cyclosporine and prednisone were converted to mycophenolate mofetil (MMF) and prednisone 1 year after transplantation. After conversion the patients were treated with a standard daily dose of 1 g MMF b.i.d. and 10 mg prednisone for 4 months. Thereafter, two MMF dose reductions were performed with a 4‐month interval. Mycophenolic acid (MPA) trough levels were measured at regular intervals. A relation was found between MPA trough levels and MMF dose. The median MPA trough level for patients treated with 1 g MMF b. i. d. was 4.3 μg/ml (0.95‐15.5) and 3.0 μg/ml (0.73‐7.8) for patients treated with 750 mg b. i. d. (P = 0.0002). The MPA trough levels further decreased from 3.0 to 2.3 μg/ml (0.6‐6.63) in patients treated with 500 mg MMF b. i. d. (P = 0.01). Dose reduction of MMF from 1 g to 750 mg b.i.d. could be performed without acute rejections. A further dose reduction to 500 mg b.i.d. elicited 3 rejections. Patients experiencing an acute rejection had a median MPA trough level of 2.3 μg/ml (1.26‐3.38) compared to 3.8 μg/ml (1.48‐6.52) in patients without an acute rejection (P = 0.25). We conclude that there is a significant relation between MPA trough levels and MMF dose. MPA trough levels were not predictive of rejection in the present study.     

Pediatric aspects of therapeutic drug monitoring of mycophenolic acid in renal transplantation

Mycophenolate mofetil (MMF) is widely used for maintenance immunosuppressive therapy in pediatric renal and heart transplant recipients. Children undergo developmental changes (ontogeny) of drug disposition, which may affect drug metabolism of the active compound mycophenolic acid (MPA). Therefore, a detailed characterization of MPA pharmacokinetics and pharmacodynamics in this patient population is required. In general, the overall efficacy and tolerability of MMF in pediatric patients appear to be comparable with those in adults, except for a higher prevalence of gastrointestinal adverse effects in children younger than 6 years. The currently recommended dose in pediatric patients with concomitant cyclosporine is 1200 mg/m² per day in 2 divided doses; the recommended MMF dose with concomitant tacrolimus or without a concurrent calcineurin inhibitor is 900 mg/m² per day in 2 divided doses. Recent data suggest that fixed MMF dosing results in MPA underexposure (MPA-area under the concentration-time curve (AUC_0-12), <30 mg × h/L) early posttransplant in approximately 60% of patients. To achieve adequate MPA exposure in most patients, an initial MMF dose of 1800 mg/m² per day with concomitant cyclosporine and 1200 mg/m² per day with concomitant tacrolimus for the first 2 to 4 weeks posttransplant has been suggested. As in adults, there is an approximately 10-fold variability in dose-normalized MPA-AUC_0-12 values between pediatric patients after renal transplantation, strengthening the argument for concentration-controlled dosing of the drug. Although the clinical utility of therapeutic drug monitoring of MPA for graft outcome and patient survival is still controversial, potential indications are the avoidance of underimmunosuppression, particularly in patients with high immunologic risk in the initial period posttransplant, in patients who are treated with protocols that explore the possibilities of calcineurin inhibitor minimization, withdrawal or even complete avoidance, and steroid withdrawal or avoidance regimens that might also benefit from intensified therapeutic drug monitoring of MPA. An additional indication especially in adolescent patients is the monitoring of drug adherence. Therapeutic drug monitoring of MPA in pediatric solid organ transplantation using limited sampling strategies is preferable over drug dosing based on trough level monitoring only. Several validated pediatric limited sampling strategies are available. Clearly, more research is required to determine whether pediatric patients will benefit from therapeutic drug monitoring of MPA for long-term maintenance immunosuppression with MMF.     

Significance of Mycophenolate Monitoring in Liver Transplant Recipients: Toward the Cut-off Level

Mycophenolate mofetil blocks the "de novo" -purine synthesis to reduce the incidence and severity of acute rejection episodes. There has been an increased interest in utility of monitoring mycophenolic acid (MPA) levels, however currently the MPA monitoring is not part of the protocol following liver transplantation. We assessed whether trough MPA monitoring could be advisable in liver transplant patients or not. For this reason MPA levels of 56 liver transplants were measured on 3, 5, 10, 14, 21, 30, 60, and 180 posttransplant days. The optimal cut-off of MPA level (≥1.73 mg/L) for all (56) and ≥1.34 mg/L for ciclosporin-treated- and ≥1.98 mg/L for the tacrolimus-treated transplants were calculated by statistical analysis to reduce the incidence of acute rejection. MPA concentrations of 3 days period before the day of clinical diagnosis acute rejection were well below the cut-off value. Only 3 (16%) out 19 patients with acute rejection had higher MPA levels than the cut-off value on the day of diagnosis of acute rejection. In conclusion, our data suggests that MPA predose level monitoring, especially in the early "filling phase" after transplantation, is applicable in liver allograft recipients given adjunctive MMF, protecting them from the ineffective immunosuppression.     

Mycophenolic acid trough level monitoring: relevance in acute and chronic graft versus host disease and its relation with albumin

Hiwarkar P, Shaw BE, Tredger JM, Brown NW, Kulkarni S, Saso R, Evans S, Treleaven J, Davies FE, Ethell ME, Morgan GJ, Potter MN. Mycophenolic acid trough level monitoring: relevance in acute and chronic graft versus host disease and its relation with albumin.
Clin Transplant 2011: 25: 222–227. © 2010 John Wiley & Sons A/S. Abstract: Mycophenolate mofetil (MMF) is used to treat acute and chronic graft versus host disease (GvHD). There is scant evidence in the literature about mycophenolic acid (MPA) trough level monitoring in GvHD. We therefore reviewed 32 patients treated with MMF for acute (n = 19) or chronic GvHD (n = 13). Twelve (63%) of 19 patients with acute GvHD and nine (69%) of 13 with chronic GvHD showed a good response. In all 21 patients who responded to MMF, their mean total MPA levels were therapeutic (1–3.5 mg/L), whereas five of 11 patients who did not respond had sub‐therapeutic mean MPA levels (p = 0.002). Sixteen (66%) of 24 steroid refractory or dependent patients responded to MMF. Associations between the mean total MPA level for each patient and the corresponding mean serum albumin concentration showed therapeutic mean total MPA levels for all 23 patients with mean albumin ≥31 g/L but sub‐therapeutic mean total MPA levels in five of nine patients with mean albumin <31 g/L (p = 0.0006). In conclusion, MMF is efficacious in steroid refractory and dependent acute or chronic GvHD with statistically significant correlation between therapeutic plasma total MPA trough levels and clinical response. Serum albumin levels should be taken into account when considering MMF dose adjustments.     

Conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in maintenance renal transplant recipients receiving tacrolimus: clinical, pharmacokinetic, and pharmacodynamic outcomes

BACKGROUND: Mycophenolic acid (MPA) pharmacokinetics using the mycophenolate mofetil (MMF) formulation are known to differ between patients receiving tacrolimus or cyclosporine, but only limited data exist concerning concomitant use of tacrolimus and enteric-coated mycophenolate sodium (EC-MPS). METHODS: In this six-month, multicenter, open-label, single-arm trial, 63 maintenance renal transplant patients receiving tacrolimus were converted from mycophenolate mofetil (MMF) to EC-MPS. RESULTS: MPA concentration-time profiles in 21 patients showed that MPA exposure was similar with MMF or EC-MPS (mean area under the curve 39.9+/-11.6 microg x h/mL versus 43.7+/-17.4 microg x h/mL at day 14 post-conversion). Median time to peak concentration was 0.5 hr with MMF and 1.5 hr with EC-MPS. Inosine monophosphate dehydrogenase (IMPDH) activity was almost identical: area under the enzyme activity time curve (AEC) was 124.2+/-32.0 nmol x h/mg prot/h with MMF and 130.3+/-36.6 nmol x h/mg prot/h with EC-MPS at 14 days post-conversion; average daytime IMPDH activity was 10.3+/-2.7 nmol/h/mg protein and 10.9+/-2.7 nmol/h/mg protein, respectively. Maximal daytime inhibition of IMPDH activity was 67% with MMF and 62% with EC-MPS at day 14. One patient (1.6%) experienced mild biopsy-proven acute rejection. No graft losses or deaths occurred. Renal function remained stable (mean calculated creatinine clearance 70.6+/-26.8 mL/min with MMF and 68.8+/-25.4 mL/min six months post-conversion). Adverse events or infections with a suspected relation to EC-MPS occurred in 12 patients (19%). Four patients discontinued EC-MPS due to adverse events or infections. CONCLUSIONS: MMF and EC-MPS are associated with similar MPA exposure and equivalent pharmacodynamic effect. Conversion of tacrolimus-treated maintenance renal transplant patients from MMF to EC-MPS is safe and well-tolerated and does not compromise therapeutic efficacy.     

Long‐term outcomes in African American kidney transplant recipients under contemporary immunosuppression: a four‐yr analysis of the Mycophenolic acid Observational REnal transplant (MORE) study

Mycophenolic acid Observational REnal transplant (MORE) was a prospective, observational study of de novo kidney transplant patients receiving mycophenolic acid (MPA). Four‐yr data on 904 patients receiving tacrolimus and enteric‐coated mycophenolate sodium (EC‐MPS) or mycophenolate mofetil (MMF) were analyzed to evaluate immunosuppression and graft outcomes in African American (AA, n = 218) vs. non‐AA (n = 686) patients. Mean tacrolimus dose was higher in AA vs. non‐AA patients but mean tacrolimus trough concentration was similar. Use of the recommended MPA dose in AA patients decreased from 78.9% at baseline to 33.1% at year 3. More AA patients received the recommended MPA dose with EC‐MPS than MMF at month 6 (56.2% vs. 35.7%, p = 0.016) and month 36 (46.6% vs. 16.7%, p = 0.029), with no safety penalty. Significantly, more AA patients received corticosteroids than non‐AA patients. Biopsy‐proven acute rejection was higher in AA vs. non‐AA patients (18.9% vs. 10.7%, p = 0.003), as was graft loss (10.9% vs. 4.4%, p = 0.003); differences were confirmed by Cox regression analysis. Patient survival was similar. Estimated GFR was comparable in AA vs. non‐AA patients. Kidney allograft survival remains lower for AA vs. non‐AA recipients even under the current standard of care.     

Sequential determination of pharmacokinetics and pharmacodynamics of mycophenolic acid in liver transplant patients treated with mycophenolate mofetil

BACKGROUND: In liver transplantation, mycophenolate mofetil (MMF) is habitually administered using fixed doses. We assessed whether mycophenolic acid (MPA) monitoring could be advisable in liver transplant patients. METHODS: In 15 liver transplant patients receiving tacrolimus, daclizumab and MMF (1 g bid, orally), we determined the 12-hour plasma MPA pharmacokinetic profile after one dose of MMF at days 6, 10, and 16, and months 3 and 6. The inhibitory capacity of serum MPA on proliferation of CEM cells, a cell line insensitive to other immunosuppressants, was also determined. RESULTS: A large interindividual variability in MPA profiles was observed at any time. Regardless of a gradual increase in individual MPA AUC and C(0) over time following transplantation, a substantial proportion of patients had these parameters below the ranges recommended in other organ transplantations throughout the study. When MPA AUC and C(0) were within the recommended ranges, CEM proliferation was inhibited by almost all serum samples, but when these pharmacokinetic parameters were below the recommended ranges, CEM proliferation was very variable and, therefore, unpredictable. No relationship between MPA pharmacokinetics and the efficacy of MMF could be established (only one patient developed rejection), probably due to the concomitant administration of tacrolimus and daclizumab. Gastrointestinal symptoms were the only adverse events with a significant relationship with MPA levels. CONCLUSIONS: During the first postoperative months, exposure to MPA is low in a considerable proportion of liver transplant patients receiving MMF at a fixed dose of 1 g bid. MPA monitoring appears necessary in these patients.