Long‐term dosing patterns of enteric‐coated mycophenolate sodium or mycophenolate mofetil with tacrolimus after renal transplantation

MORE was a four‐yr, prospective, observational study at 40 transplant centers in the US. Data were analyzed to evaluate changes in mycophenolic acid (MPA) dosing over time in 904 de novo kidney transplant recipients receiving enteric‐coated mycophenolate sodium (EC‐MPS, n = 616) or mycophenolate mofetil (MMF, n = 288) with tacrolimus. Induction therapy and steroid treatment were similar in the two subpopulations. The proportion of patients receiving the maximal recommended MPA dose was 80.5%, 43.9%, 39.2%, 34.6%, and 30.1% at baseline and years 1, 2, 3, and 4, respectively. More patients received the maximal recommended MPA dose with EC‐MPS vs. MMF at month 1 (79.2% vs. 71.7%, p = 0.016), month 3 (68.5% vs. 56.9%, p = 0.001), and month 6 (52.9% vs. 44.0%, p = 0.028). Multivariate analysis showed the risk of biopsy‐proven acute rejection, graft loss or death to be similar for EC‐MPS vs. MMF. Estimated glomerular filtration rate (GFR) was similar with EC‐MPS vs. MMF at all time points. There were no significant differences in any category of adverse event between the EC‐MPS and MMF cohorts during follow‐up, including gastrointestinal events. In conclusion, MPA dose was maintained more effectively in the first six months after kidney transplantation using EC‐MPS vs. MMF, without an increase in adverse events.     

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.     

Gastrointestinal side effects in liver transplant recipients taking enteric‐coated mycophenolate sodium vs. mycophenolate mofetil

In the setting of liver transplantation, mycophenolate mofetil (MMF) may be used as an adjuvant therapy for immunosuppression to prevent graft rejection; however, its use may be limited due to severe gastrointestinal (GI) side effects. In contrast, enteric‐coated mycophenolate sodium (EC‐MPS) may be associated with less severe side effects and hence better tolerability. We compared the side effects of EC‐MPS to MMF in liver transplant patients in a de novo study (Study I—randomized, prospective, double‐blinded) and a conversion study (Study II). In both studies, the severity of GI symptoms was assessed at various time points using the Gastrointestinal Symptoms Rating Scale (GSRS) survey, a validated survey of GI symptoms (abdominal pain, reflux, indigestion, diarrhea, and constipation). In Study I, the symptoms of 30 recipients receiving EC‐MPS (n = 15) were compared to 15 recipients receiving MMF. A multivariate analysis of variance (MANOVA) of the total GSRS scores and symptom syndrome subscores revealed no significant difference (p > 0.05) between the two medications over time. A conversion study (Study II) with 29 participants, however, showed that over time, all GI symptoms improved significantly (p < 0.001) when the patients were treated with EC‐MPS instead of MMF.     

A clinical assessment of mycophenolate drug monitoring after liver transplantation

Hwang S, Lee S‐G, Ahn C‐S, Kim K‐H, Moon D‐B, Ha T‐Y, Song G‐W, Jung D‐H, Choi N‐K, Kim K‐W, Yu Y‐D, Park G‐C, Park P‐J, Choi Y‐I. A clinical assessment of mycophenolate drug monitoring after liver transplantation.
Clin Transplant 2010 DOI: 10.1111/j.1399‐0012.2009.01166.x
© 2010 John Wiley & Sons A/S. Abstract: Background: Recent findings have suggested the clinical utility of therapeutic drug monitoring (TDM) in patients treated with mycophenolate mofetil (MMF). Aim: To assess whether routine mycophenolic acid (MPA) TDM is beneficial and how to utilize it. Methods: A series of short‐term prospective studies on TDM for MPA and/or tacrolimus was performed at a large‐volume center. Results: The 673 adult liver transplants were divided into four groups based on immunosuppressive regimens as tacrolimus monotherapy (n = 369), tacrolimus–MMF therapy (n = 270), MMF‐minimal tacrolimus therapy (n = 17), and MMF monotherapy (n = 17). There was a significant difference of tacrolimus concentration between the groups receiving tacrolimus monotherapy and tacrolimus–MMF therapy during the first two yr (at two yr: 8.4 ± 2.7 vs. 6.3 ± 2.6 ng/mL; p ≤ 0.002). MMF‐minimal tacrolimus therapy and MMF monotherapy were applied after first three months and MPA levels ranged from 1.8 to 5.3 μg/mL. Correlation between MMF dosage and MPA concentration showed wide interindividual variations (n = 304, r² = 0.271, p < 0.001), in which r² was fluctuating from 0.056 to 0.213 according to the post‐transplant period over five yr; wide intraindividual variation was also observed during the first two months (n = 12, r² < 0.2, p > 0.195). About 10% of patients were classified as poor MMF absorber and excluded from MMF usage. Mean MPA level leading to successful MMF monotherapy or MMF‐minimal tacrolimus therapy was ≥1.0 μg/mL in 87% and >2.0 μg/mL in 56.5%. Conclusion: MPA TDM‐based MMF dosage adjustment enabled us to administer MMF more confidently than categorical dosing. MPA TDM appears to be a useful tool to cope with the wide pharmacokinetic variability of MMF after liver transplantation.     

Tacrolimus and mycophenolate regimen and subclinical tubulo‐interstitial inflammation in low immunological risk renal transplants

The aim was to evaluate the relationship between maintenance immunosuppression, subclinical tubulo‐interstitial inflammation and interstitial fibrosis/tubular atrophy (IF/TA) in surveillance biopsies performed in low immunological risk renal transplants at two transplant centers. The Barcelona cohort consisted of 109 early and 66 late biopsies in patients receiving high tacrolimus (TAC‐C₀ target at 1‐year 6–10 ng/ml) and reduced MMF dose (500 mg bid at 1‐year). The Oslo cohort consisted of 262 early and 237 late biopsies performed in patients treated with low TAC‐C₀ (target 3–7 ng/ml) and standard MMF dose (750 mg bid). Subclinical inflammation, adjusted for confounders, was associated with low TAC‐C₀ in the early (OR: 0.75, 95% CI: 0.61–0.92; P = 0.006) and late biopsies (OR: 0.69, 95% CI: 0.50–0.95; P = 0.023) from Barcelona. In the Oslo cohort, it was associated with low MMF in early biopsies (OR: 0.90, 95% CI: 0.83–0.98; P = 0.0101) and with low TAC‐C₀ in late biopsies (OR: 0.77, 95% CI: 0.61–0.97; P = 0.0286). MMF dose was significantly reduced in Oslo between early and late biopsies. IF/TA was not associated with TAC‐C₀ or MMF dose in the multivariate analysis. Our data suggest that in TAC‐ and MMF‐based regimens, TAC‐C₀ levels are associated with subclinical inflammation in patients receiving reduced MMF dose.     

Enteric-coated mycophenolate sodium in de novo and maintenance kidney-pancreas transplant recipients

Ricart MJ, Oppenheimer F, Andrés A, Morales JM, Alonso Á, Fernández C, on behalf of the Epi‐trasplante Study, MIDATA Kidney–Pancreas Sub‐study Group. Enteric‐coated mycophenolate sodium in de novo and maintenance kidney–pancreas transplant recipients.
Clin Transplant 2011 DOI: 10.1111/j.1399‐0012.2011.01526.x.
© 2011 John Wiley & Sons A/S. Abstract: Background: Our objective was to describe efficacy and safety of enteric‐coated mycophenolate sodium (EC‐MPS) in de novo and maintenance recipients of kidney–pancreas transplant in the clinical practice. Methods: Observational, multicentre, prospective, 12‐month study. Results: We included 24 de novo and 24 maintenance patients. EC‐MPS mean (±SD) doses at initiation in de novo patients were 1440 ± 0 vs. 1268 ± 263 mg/d at month 12 (M12). Patient and renal graft survival at one yr were 100%, and pancreatic graft survival was 83.3% (two losses owing to technical failure and two owing to rejection). In the maintenance cohort, EC‐MPS was introduced at a median (P25–P75) of 30 (6–71) months after transplant. Baseline doses were 585 ± 310 vs. 704 ± 243 mg/d at M12. In this group, a significant increase in creatinine clearance was observed (65 ± 22 at baseline vs. 74 ± 20 mL/min at M12, p = 0.011). Patient, renal, and pancreatic graft survival were 100%, 95.8%, and 100%, respectively (one kidney graft loss owing to rejection). During follow‐up, one patient from each group discontinued EC‐MPS. Conclusions: The efficacy of EC‐MPS in the clinical practice of kidney–pancreas transplantation is good, with high patient and grafts survival at 12 months, and good safety profile. The maintenance group displayed an improvement in renal function.     

Enteric-coated mycophenolate sodium delivers bioequivalent MPA exposure compared with mycophenolate mofetil

Mycophenolic acid (MPA), the active moiety of mycophenolate mofetil (MMF), is routinely used as an adjunct immunosuppressant therapy in renal transplantation. Although highly effective, MMF therapy is associated with significant gastrointestinal adverse effects. Enteric-coated mycophenolate sodium (EC-MPS) is an advanced formulation delivering MPA. The enteric coat dissolves at pH > 5 allowing for MPA delivery in the small intestine. A single-center, open-label, randomized, three-way crossover study of 24 stable Caucasian renal transplant patients receiving cyclosporine-based immunosuppression, compared the relative bioavailability of two EC-MPS doses (640 and 720 mg) with MMF (1000 mg). Both EC-MPS doses delivered bioequivalent mean MPA exposure (AUC(0-infinity)) compared with 1000 mg MMF: 60.7 microg h/mL for 640 mg EC-MPS, 66.5 microg h/mL for 720 mg EC-MPS, and 63.7 microg h/mL for 1000 mg MMF. Median t(max) was significantly delayed for both EC-MPS doses compared with MMF (2.0 h vs. 0.75 h, respectively; p < 0.01), consistent with a functional enteric coating of EC-MPS. Furthermore, both EC-MPS doses were bioequivalent to 1000 mg MMF for AUC and C(max) for mycophenolic acid glucuronide. All three treatments were well tolerated. The EC-MPS 720 mg dose most closely approximated the MPA exposure of 1000 mg MMF and was selected for subsequent phase III studies.     

Use of enteric‐coated mycophenolate sodium in liver transplant patients with intestinal intolerance caused by mycophenolate mofetil

Abstract: Background: Post‐transplant gastrointestinal (GI) side effects can impair a patient’s quality of life (QoL). This study investigates the improvement in GI side effects and related QoL changes in recipients of liver transplantation (OLT) after converting patients from mycophenolate mofetil (MMF) to enteric‐coated mycophenolate sodium (EC‐MPS). Methods: Thirty‐four patients who underwent OLT and suffered from GI intolerability were included in this study. Infectious causes of GI intolerability were excluded. QoL assessed by the Gastrointestinal Quality of Life Index was evaluated before conversion and at months 3, 6 and 12 post‐conversion. All patients received baseline immunosuppression of one calcineurin inhibitor, MMF, with or without steroids. Patients were converted from MMF to EC‐MPS on an equimolar basis. Paired t‐test was used to assess differences in mean score changes over time. Results: Conversion from MMF to EC‐MPS for GI intolerability post‐OLT shows statistically significant improvement in GI‐related QoL at 3, 6, and 12 months when compared to baseline assessments (p < 0.05 for total mean score); nonetheless, one‐third of patients discontinued EC‐MPS. No rejection episodes, deaths or graft loss were seen during the study period. Conclusion: OLT recipients who develop GI side effects caused by MMF can be safely converted to EC‐MPS with improvement to their QoL.     

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.     

Effect of conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium on maximum tolerated dose and gastrointestinal symptoms following kidney transplantation

Despite the potential tolerability advantage of enteric-coated mycophenolate sodium (EC-MPS), no prospective, randomized trial has evaluated whether conversion from mycophenolate mofetil (MMF) to EC-MPS permits mycophenolic acid dose to be increased or gastrointestinal side-effects to be ameliorated. In a randomized, multicenter, open-label trial, kidney transplant recipients experiencing gastrointestinal side-effects either remained on MMF or switched to an equimolar dose of EC-MPS, adjusted 2 weeks subsequently to target the highest tolerated dose up to 1440 mg/day (EC-MPS) or 2000 mg/day (MMF). Patients were followed up to 12 weeks postrandomization. One hundred and thirty-four patients were randomized. The primary efficacy endpoint, the proportion of patients receiving a higher mycophenolic acid (MPA) dose at week 12 than at randomization, was significantly greater in the EC-MPS arm (32/68, 47.1%) than the MMF arm (10/61, 16.4%; P  < 0.001). At the final visit, 50.0% (34/68) of EC-MPS patients were receiving the maximum recommended dose versus 26.2% (16/61) of MMF patients ( P  = 0.007). Kidney transplant patients receiving reduced-dose MMF because of gastrointestinal side-effects can tolerate a significant increase in MPA dose after conversion to EC-MPS. Patient-reported gastrointestinal outcomes with higher doses of EC-MPS remained at least as good as in MMF-treated controls.     

Long‐term outcomes after cyclosporine or mycophenolate withdrawal in kidney transplantation – results from an aborted trial

Long‐term triple immunosuppressive therapy with cyclosporine (CsA), mycophenolate mofetil (MMF) and prednisolone may be excessively powerful for many transplant recipients. We compared withdrawal of either MMF or CsA in stable kidney transplants on triple immunosuppression. The study was a prospective, randomized, controlled 12‐months trial in stable kidney transplants. The patients who withdrew CsA were given MMF 2 g/d, and CsA troughs were between 75 and 125 ng/mL in MMF withdrawal. Planned inclusion was 298 patients. The study was prematurely aborted after inclusion of 39 patients. Acute rejection rates were 6/20 (30%) in the MMF group compared with 0/19 (0%) in the CsA group (p = 0.02). Time to acute rejections was 4.0–28.7 months after withdrawal. Trough concentrations of mycophenolic acid (MPA) and CsA showed therapeutic levels. The subjects have been observed for eight yr, and of the 28 patients remaining on randomized therapy, the MMF patients preserved graft function better than CsA patients. Death‐censored graft survival was 75% and 95% (p = 0.18) and patient survival was 70% and 68% (p = 0.99) in the MMF and CsA groups, respectively, at the end of long‐term follow‐up. CsA withdrawal was associated with a high rate of acute rejections. Initially, the treatment of acute rejections was successful. However, five of six lost their grafts in the long term.     

Adverse drug reaction driven immunosuppressive drug manipulations: a single-center comparison of enteric-coated mycophenolate sodium vs. mycophenolate mofetil

Abstract: Enteric‐coated mycophenolate sodium (MPS) has been developed to help circumvent the upper gastrointestinal side‐effects of mycophenolic acid by facilitating drug release in the small intestine. Many questions regarding the side‐effect profile of MPS remain. Therefore, the purpose of this study is to review a single‐center’s experience with mycophenolate mofetil (MMF) and MPS. Methods: This retrospective, sequential cohort analysis of de novo renal and pancreas transplants (n = 198) compared MMF 500 mg b.i.d. to MPS 360 mg b.i.d. in conjunction with antibody induction, tacrolimus, and steroids. Results: There were fewer adverse event driven drug manipulations in the MPS group at 90 d (4% MPS vs. 17% MMF) and 180 d (10% MPS vs. 24% MMF, p = 0.006, log‐rank) after transplantation. There was a trend toward fewer GI‐related hospital admissions in the MPS arm (7% MPS vs. 13% MMF, p = 0.18). Allograft outcomes including patient survival, graft survival, acute rejection, serum creatinine, and infection were similar. Conclusion: This single‐center, sequential cohort study demonstrates that MPS is associated with fewer adverse event driven drug manipulations while maintaining similar safety and allograft outcomes.     

Pharmacokinetics of mycophenolic acid, tacrolimus and sirolimus after gastric bypass surgery in end-stage renal disease and transplant patients: a pilot study

Abstract: Background: Promising data regarding the safety and efficacy of gastric bypass surgery (GBS) as an option to address obesity in the transplant population are emerging. The data lack on how GBS may alter the pharmacokinetics (PK) of modern immunosuppression. The objective of this study was to describe the alterations in the PK of modern immunosuppressants and the GBS population. Methods: Data are presented on six subjects who participated in this trial – four were on dialysis and two were renal transplant recipients. Dialysis‐dependent bypass subjects received a single dose of 6 mg of sirolimus, two 4‐mg doses of tacrolimus and two 1000‐mg doses of mycophenolate mofetil (MMF) over the 24‐h study period. Transplant recipients continued their current regimen. Maximum plasma concentration (C_max), time to reach the maximum plasma concentration (T_max) and the area under the plasma concentration vs. time curve (AUC_0–12 and AUC_0–∞ where appropriate) were calculated for tacrolimus, sirolimus, mycophenolic acid (MPA) and mycophenolic acid glucuronide (MPAG). Results: Significant inter‐patient variability in the C_max, T_max and AUC of tacrolimus, sirolimus MPA and MPAG was observed. A notable difference in the AUC:dose ratio for tacrolimus was seen when comparing data with published data in the non‐bypass population. Similar differences in PK were seen with sirolimus, MPA and MPAG. Conclusions: When comparing the PK of sirolimus, tacrolimus, MPA and MPAG to published PK data in the non‐bypass population, significant differences are observed. It is likely that transplant recipients with GBS would need higher doses of tacrolimus, sirolimus and MMF to provide similar exposure to a non‐bypass patient.     

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.     

Pharmacokinetics and pharmacodynamics of mycophenolic acid in stable renal transplant recipients treated with low doses of mycophenolate mofetil

Abstract Suboptimal doses of mycophenolate mofetil (MMF) are frequently employed in renal transplant (Tx) patients, with drug‐related side effects or low weight. The aim of this study was to compare the mycophenolic acid (MPA) pharmacokinetic profile and its pharmacodynamic effect on patients receiving either standard (2 g) or low (1.5 g or 1 g) MMF doses, in order to evaluate the therapeutic efficacy of such low doses in inhibiting IMPDH activity. Twenty‐seven stable renal Tx recipients aged 18‐65 years, with a post‐Tx follow‐up of 38.5 ± 44.8 months (6‐166 months), receiving 1 g (n = 10), 0.75 g (n = 7) and 0.5 g (n = 10) MMF twice a day in association with cyclosporine and prednisone, were included. The control group was made up of untreated healthy volunteers (n = 5). Plasma concentrations of MPA were analyzed by reverse‐phase HPLC. IMPDH activity was determined in lymphocytes by the measurement of ³H release from [2,8‐³H] hypoxantine. The mean value of areas under the concentration‐time curves (AUC_0‐12) of MPA throughout the 12‐h dosing interval in patients treated with 2 g was higher than the corresponding data in patients receiving 1.5 g or 1 g bid, but no statistical differences were observed between the three groups. There was no correlation between MPA‐AUC_0‐12 values and MMF dose (expressed in g/day or g/kg per day). Predose MPA concentrations correlated only weakly with the respective MPA‐AUC_0‐12 values (r² from 0.385 to 0.655), whereas an acceptable correlation was observed between MPA C_max and MPA‐AUC_0‐12 (r² from 0.626 to 0.759) in 2 g, 1.5 g, and 1 g MMF groups. An inverse relationship between MPA concentrations and IMPDH activity was observed. In general, the maximum MPA concentration was achieved from 1 h to 2 h after dosing, and the maximum inhibition of IMPDH was also from 1 h to 2 h after dosing. The evaluation of IMPDH activity demonstrated that there was a significant statistical difference between samples from 0 to 1 h (P = 0.008) and 0 to 2 h (P = 0.04). In conclusion, concentration‐time profiles of renal transplant recipients administered 0.75 g and 0.5 g twice a day are slightly lower than those from the 2 g group, but nor significantly. On the other hand, inhibition of IMPDH activity was comparable in the three groups, indicating considerable interindividual pharmacodynamic variability. Pharmacodynamic monitoring of the degree of immunosuppression and its correlation with MPA plasma concentrations will be assessed further in future studies.     

Monitoring mycophenolate in liver transplant recipients: toward a therapeutic range.

Predose plasma mycophenolic acid (MPA) concentrations measured with a semi-automated enzyme-multiplied immunoassay were related to adverse events (e.g., rejection, leukopenia, infection), drug dose, and clinical status in 147 adult and 63 pediatric liver allograft recipients receiving adjunctive immunosuppression with mycophenolate mofetil (MMF). In 12 of 13 acute rejection episodes, predose MPA levels were below the 1 mg/L cut-off defined using receiver operating characteristic (ROC) curve analysis. The relative risk of developing infection or leukopenia increased more than 3-fold above predose MPA levels of 3 to 4 mg/L. Plasma MPA levels correlated weakly (r2 = 0.081) with MMF dose and the dose / level relationship was variably influenced by age, the indication for MMF, concentrations of serum albumin and creatinine, and comedication with tacrolimus or cyclosporine. The median mycophenolate dose required per unit mycophenolate level was 50% lower in children than in adults. Comparable drug requirements were also decreased by renal dysfunction (by 40 and 43% in adults and children, respectively), and in patients prescribed MMF alone rather than with tacrolimus or cyclosporine. However, in patients with serum albumin less than 35 g/L, MMF dose requirements were higher than in those with normal albumin levels (by 2.1- and 2.6-fold in adults and children, respectively). In adults, 44.7% achieved clinically acceptable therapeutic MPA concentrations at a dose less than 1 g MMF twice daily and only 6.3% required 1.5 g twice daily as suggested by the manufacturer. The immunoassay was a rapid, reliable, and acceptably precise technique in which only 10.8% of measurements were unproductive. In conclusion, our data suggests that MPA predose level monitoring is both clinically- and cost-effective and that a therapeutic range of 1 to 3.5mg/L (by immunoassay) is applicable in liver allograft recipients given adjunctive MMF.     

A comparison of mycophenolate mofetil with mycophenolate sodium in renal transplant recipients on tacrolimus-based treatment

We compared the tolerability and efficacy of mycophenolate mofetil (MMF) versus mycophenolate sodium (MPS) among renal transplant recipients on tacrolimus-based immunosuppression. The 105 patients who underwent kidney transplantation between January 2002 and March 2008 and were treated with steroid, tacrolimus, and a mycophenolic acid compound were enrolled in the study. From patient files we collected on demographics data, donors, immunosuppressive drug doses, biochemical and hematologic parameters, gastrointestinal and hematologic side effects, and kidney function. Fifty-six patients were prescribed MMF and 49 of them were taking MPS. Demographic parameters and pretransplantation dialysis duration were similar between the 2 groups. After the third month, the MPS dose was higher than that of MMF. There were no clinically important differences between the 2 groups, regarding other immunosuppressive drug doses. Gastrointestinal side effects were similar: 42.4% in the MMF versus 44.8% in the MPS group (P = .846). Six patients in the MMF group and 1 patient in the MPS group underwent a switch of the mycophenolic acid therapy due to severe gastrointestinal side effects (P = .183). Biopsy-proven acute rejection was reported in 6 patients on MMF and 7 patients on MPS therapy (P = .768). The log-rank test evaluating a 50% reduction in glomerular filtration rate (GFR) showed no significant difference between the 2 groups (P = .719). No deaths were recorded during the study period; there was only 1 graft loss, which occurred in the MMF group. We did not observe a significant difference in tolerability and efficacy between the 2 widely used mycophenolic acid derivatives. Economic considerations can be an important factor when choosing the drug.     

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.     

Mycophenolate revisited

The patent of mycophenolate mofetil (MMF) has expired, and for enteric‐coated mycophenolate sodium (EC‐MPS), this will happen in 2017. In the twenty years these drugs have been used, they have become extremely popular. In this review, the reasons for the popularity of mycophenolate are discussed, including the benefits compared to azathioprine. MMF and EC‐MPS are therapeutically equivalent. Although neither is considered to be a narrow therapeutic index drug, this should not lead to careless switching between the innovator drug and generic formulations, or between one generic formulation and another. The pipeline of new immunosuppressive drugs is dry, and it is very likely that we will be using mycophenolate for many more years to come as a first‐line immunosuppressive drug in our transplant population. Whether or not the development of donor‐specific anti‐HLA antibodies is related to drug exposure (mycophenolic acid concentrations) remains to be investigated.     

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.