Age-dependency of mycophenolate mofetil dosing in combination with tacrolimus after pediatric renal transplantation

BACKGROUND: Dosing of mycophenolate mofetil (MMF) must be lower in combination therapy with Tacrolimus (Tac) than with Cyclosporine. One study with mostly adolescent recipients recommended an MMF dose of 250 mg/m2 BID. Because this dose resulted in low area-under-the-curve (AUC) in our infant population, we retrospectively analyzed all available pharmacokinetic (PK) profiles in pediatric renal transplant patients on MMF plus Tac therapy to propose appropriate MMF dosing in pediatric patients of all ages. PATIENTS AND METHODS: Forty-four PK profiles were performed in 27 patients (median age, 11.6 years; range, 1.8-20.7 years). The investigations were performed at a median of 299 days (range, 24-3424) after transplantation. Ten patients were converted to Tac plus MMF, all others received this as primary therapy. For patients with repeated measurements, we calculated the average AUC and doses. We used first-order PK modeling to calculate the doses for a mycophenolic acid (MPA) AUC of 60 ug*h/mL and a Tac AUC of 150 ng*h/mL. RESULTS: The mean Tac dose was 2.6 +/- 1.2 mg/m2/d or 0.086 +/- 0.038 mg/kg/d, resulting in an average AUC of 120.6 +/- 30.4 ng*h/mL. The MMF dose was not normally distributed; the median dose was 549 mg/m2/d (range, 146-1413) and the median MPA AUC was 49.8 ug*h/mL (range, 26.7-156.0). The mean dose for a Tac AUC of 150 ng*h/mL was 3.50 +/- 1.77 mg/m2/d (0.117 +/- 0.058 mg/kg) and was independent of age or time after transplantation. By contrast, we found a negative relationship between the dose per m2 (r2 = 0.29; P = 0.0038) or per kg (r2 = 0.58; P < .0001) required for an MPA AUC of 60 ug*h/mL and patient age. Converted and primary patients behaved identically. The dosing requirement decreased from 500 mg/m2 BID in 2-year-old patients to 250 mg/m2 in adolescents. There was substantial interpatient variability of 44%. CONCLUSIONS: Higher MMF doses are required for young children. Our data suggest a starting dose for infants of 500 mg/m2 BID, with PK monitoring of MPA due to substantial interpatient variability.     

Combination therapy with tacrolimus and mycophenolate mofetil: effects of early and late minimization of mycophenolate mofetil after renal transplant

The objectives of the study were: (i) to compare the efficacy and safety of minimizing mycophenolate mofetil (MMF) early (30 d) or late (90 d) after renal transplantation, when used in combination with tacrolimus; (ii) to retrospectively investigate factors associated with early, acute rejections and (iii) to investigate the pharmacokinetic interaction between tacrolimus and diltiazem. A prospective, randomized, multicenter, open-label study was conducted in 124 de novo kidney transplant recipients. Efficacy and safety outcomes were assessed for 180 d after transplantation and subjects were followed-up for a mean duration of 5.1 yr. The efficacy and safety outcomes were comparable whether the dose of MMF was minimized early or late. The incidence of early, acute rejection episodes was higher for recipients who were younger, received a graft from an unrelated donor or failed to achieve adequate tacrolimus concentrations (trough > 10 ng/mL) in the first seven d after transplant. Concomitant use of diltiazem had a tacrolimus-sparing effect in some subjects. Based on these results, we support the achievement of a high target tacrolimus concentration within the first week after renal transplant and suggest that early minimization of MMF can be achieved when used in combination with tacrolimus.     

Randomized trial of tacrolimus (Prograf) in combination with azathioprine or mycophenolate mofetil versus cyclosporine (Neoral) with mycophenolate mofetil after cadaveric kidney transplantation

BACKGROUND: Our clinical trial was designed to investigate the optimal combination of immunosuppressants for renal transplantation. METHODS: A randomized three-arm, parallel group, open label, prospective study was performed at 15 North American centers to compare three immunosuppressive regimens: tacrolimus + azathioprine (AZA) versus cyclosporine (Neoral) + mycophenolate mofetil (MMF) versus tacrolimus + MMF. All patients were first cadaveric kidney transplants receiving the same maintenance corticosteroid regimen. Only patients with delayed graft function (32%) received antilymphocyte induction. A total of 223 patients were randomized, transplanted, and followed for 1 year. RESULTS: There were no significant differences in baseline demography between the three treatment groups. At 1 year the results are as follows: acute rejection 17% (95% confidence interval 9%, 26%) in tacrolimus + AZA; 20% (confidence interval 11%, 29%) in cyclosporine + MMF; and 15% (confidence interval 7%, 24%) in tacrolimus + MMF. The incidence of steroid resistant rejection requiring antilymphocyte therapy was 12% in the tacrolimus + AZA group, 11% in the cyclosporine + MMF group, and 4% in the tacrolimus + MMF group. There were no significant differences in overall patient or graft survival. Tacrolimus-treated patients had a lower incidence of hyperlipidemia through 6 months posttransplant. The incidence of posttransplant diabetes mellitus requiring insulin was 14% in the tacrolimus + AZA group, 7% in the cyclosporine + MMF and 7% in the tacrolimus + MMF groups. CONCLUSIONS: All regimens yielded similar acute rejection rates and graft survival, but the tacrolimus + MMF regimen was associated with the lowest rate of steroid resistant rejection requiring antilymphocyte therapy.     

Lung transplants with tacrolimus and mycophenolate mofetil: a review

Traditionally, immunosuppressive maintenance therapy in solid organ transplantation has consisted of cyclosporine (CsA), azathioprine, and prednisone. However, lung transplant recipients are far more frequently affected by acute rejection, especially during the first 6 months after the transplantation, than patients with other transplanted organs. Further, they display a greater risk for chronic transplant dysfunction and ultimate graft loss. Bronchiolitis obliterans syndrome (BOS) is the major cause of morbidity and mortality among long-term survivors after lung transplantation. Acute pulmonary allograft rejection has been identified as the major risk factor for the development of BOS. Based on favourable results in kidney, liver, and heart transplantation, tacrolimus and mycophenolate mofetil have been used as primary prophylaxis and as rescue therapy for recurrent or persistent acute rejection and BOS. A secondary indication is CsA toxicity. This review focuses on reported results of the combination of tacrolimus and mycophenolate mofetil in lung transplantation. These new immunosuppressive drugs have markedly improved the efficacy profiles without additional detrimental toxicities, and appear to be a safe alternative to CsA and azathioprine in patients following lung transplantation. However, at present, BOS is not influenced by these new drugs. The optimal long-term immunosuppressive regimen remains to be established.     

Randomized comparative trial of mizoribine versus mycophenolate mofetil in combination with tacrolimus for living donor renal transplantation

Background

Mizoribine (MZR) was approved in 1984 in Japan for the suppression of rejection in renal transplantation with an approved administration dosage of 1–3 mg/kg/day. The action of MZR resembles that of mycophenolate mofetil (MMF), but MZR dosing is markedly lower than that of MMF. To examine whether higher dosing of MZR could obtain efficacy similar to MMF in renal transplantation, we conducted a comparative study of MZR and MMF using a high daily dose of MZR.

Methods

A prospective, randomized comparative study of MZR versus MMF using tacrolimus (FK) and steroids as the base was conducted in 35 patients who had undergone living-donor renal transplantation (ABO-incompatible patients were not included) at 8 institutions in Japan between July 2005 and June 2007. Starting doses were 12 mg/kg/day for MZR and 2 g/day for MMF. Dosages of FK and steroids were set according to the protocol of each institution.

Results

Patient and graft survival rate at 1 year after transplantation was 100 % in each group, with no significant difference in rejection rate apparent between groups. Adverse events found in both groups were characteristic, frequently involving infection and digestive organ disorder in the MMF group and elevated uric acid levels in the MZR group.

Conclusions

Based on these results, MZR and MMF are considered almost equivalent in terms of efficacy and safety.     

The use of daclizumab as induction therapy in combination with tacrolimus and mycophenolate mofetil in recipients with previous transplants

Clinical trials using daclizumab as induction therapy in combination with tacrolimus (TAC) and mycophenolate mofetil (MMF) have been shown to reduce the incidence of acute rejection episodes in solid organ transplantation. In an attempt to obtain a low rejection rate we proceeded with the use of daclizumab as induction therapy, in combination with TAC and MMF for recipients with previous transplants. In this study, we analyzed patients who received previous transplants, treated with the above immunosuppressive regimen. Group A consisted of four patients with previous liver transplants, group B consisted of 16 recipients with previous kidney transplants and group C consisted of three patients with previous simultaneous pancreas-kidney transplants. All patients underwent cadaveric kidney transplants except one patient in group B, who underwent a pancreas transplant. At 12 months, patient and graft survival for all groups was 100 and 100%, respectively. Acute rejection rate was 0% for group A, 12.5% for group B, and 0% for group C. Daclizumab induction therapy is effective for patients with previous transplants and does not appear to increase the risk of acute rejection.     

Five-year results of renal transplantation on immunosuppressive triple therapy with mycophenolate mofetil

Mycophenolate mofetil (MMF) combined with cyclosporine and prednisolone significantly lowers acute rejection frequency in the early post-renal transplantation phase. To date only registry data with very high transplant numbers have shown that MMF significantly influences long-term outcome. A comparative retrospective analysis of the 5-yr results with MMF in a single transplant center was thus undertaken vs. other standard immunosuppressive regimens. The results of 1579 renal transplantations were grouped by treatment modality, subjected to Kaplan-Meier analysis, and compared using the log rank test. Both the total population and subgroups showed a non-significant trend towards better graft survival with MMF, evident at 2 yr and persisting for 5 yr. Extrapolation indicates that on combination therapy with MMF vs. azathioprine, approximately 10% more patients will be alive at 10 yr with a functional graft.     

Heart transplantation under cyclosporine or tacrolimus combined with mycophenolate mofetil or everolimus

Objective

In this study, we examined whether cyclosporine was effective when combined with everolimus in clinical heart transplantation (HT).

Patients and Methods

From August 2004 to July 2007, 108 adult patients underwent primary HT. The main exclusion criteria were: donors >60 years; cold ischemia times >6 hours; recipients of multiorgan transplantation or a previous transplantation; and panel-reactive antibodies ≥25%. The cyclosporine plus everolimus regimen (group CE, n = 32) was suggested first; upon refusal or if the recipient or donor was positive for hepatitis B surface antigen or PCR + hepatitis C infection, then patient was randomly assigned to success cyclosporine plus mycophenolate mofetil (MMF; group CM, n = 24) or tacrolimus plus MMF (group TM, n = 25). All patients underwent similar operative procedures and postoperative care with protocol endomyocardial biopsies.

Results

No 30-day mortality was noted in any group. The efficacy failure rates were 3%, 25%, and 16% in groups CE, CM, and TM, respectively (P = .04 between groups CE and CM). The 1-year survivals were 96.7% ± 18.1%, 89.7% ± 29.8%, and 81.0% ± 35.5% for groups CE, CM, and TM, respectively (P = .04 between groups CE and TM). The 3-year survival rates were 91.9% ± 28.3%, 79.8% ± 46.0%, and 81.0% ± 35.5% in groups CE, CM, and TM, respectively.

Conclusions

The 3 immunosuppressive regimens offered good efficacy after HT. The cyclosporine plus everolimus regimen showed a significantly better result with less efficacy failure (compared with cyclosporine plus MMF: 3% vs 25%) and better 1-year survival compared with tacrolimus plus MMF: 96.7% vs 81.0%.     

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.     

Randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 6 months

BACKGROUND: This is the first report of a randomized, multicenter, clinical trial comparing the combination of sirolimus or mycophenolate mofetil (MMF) with tacrolimus-based immunosuppression in kidney transplantation. Results at 6 months of follow-up are presented. METHODS: Before transplantation, patients were randomized to receive tacrolimus plus corticosteroids with sirolimus (n=185) or MMF (n=176). The primary endpoint of the study was the incidence of biopsy-confirmed acute rejection. Patient and graft survival, renal function, and composite endpoints also were evaluated. Safety was assessed by monitoring laboratory parameters and adverse events. RESULTS: By 6 months of follow-up, the incidence of biopsy-confirmed acute rejection was similar in both treatment groups (13.0% tacrolimus+sirolimus vs. 11.4% tacrolimus+MMF; P=0.64 log-rank). Patient survival (97.3% tacrolimus+sirolimus vs. 97.7% tacrolimus+MMF) and graft survival (93.0% tacrolimus+sirolimus vs. 95.5% tacrolimus+MMF) were equivalent (P=0.53, overall survival log-rank). There was a significantly higher incidence of study drug discontinuation in patients receiving sirolimus (21.1% vs. 10.8%; P=0.008). Renal function was significantly better in the MMF-treatment group (serum creatinine 1.44+/-0.45 mg/dL vs. 1.77+/-1.42 mg/dL; P=0.018). Hyperlipidemia was significantly more prevalent in the sirolimus-treatment group. Diastolic blood pressure was significantly higher in sirolimus-treated patients. There were significantly more leukopenia and gastrointestinal adverse events in the MMF-treatment group. The incidence of posttransplant diabetes mellitus was 7.6% in the sirolimus group and 7.7% in the MMF group. CONCLUSION: Tacrolimus is equally effective in renal transplantation when combined with sirolimus or MMF. The tacrolimus-MMF combination may be superior in terms of improved renal function and improved cardiovascular risk factors including hyperlipidemia and hypertension.     

Comparison of steroid avoidance in tacrolimus/mycophenolate mofetil and tacrolimus/sirolimus combination in kidney transplantation monitored by surveillance biopsy

BACKGROUND: Chronic steroid therapy in kidney transplantation has myriad side effects and steroid avoidance has become feasible. This prospective study compared the safety and efficacy of steroid avoidance in tacrolimus (TAC)/mycophenolate mofetil (MMF) and TAC/sirolimus (SRL) combinations in kidney transplantation. METHODS: In all, 150 kidney recipients were analyzed: 75 each in TAC/MMF and TAC/SRL groups. The primary endpoint was acute rejection. Surveillance biopsies were completed to analyze subclinical acute rejection (SCAR) and chronic allograft nephropathy (CAN). Acute rejection and SCAR were treated by methylprednisolone. Two-year patient and graft survival, renal function, and adverse effects were monitored. RESULTS: Acute rejection was seen in 12% of TAC/MMF and 8% of TAC/SRL patients. Two-year actuarial patient survival was 95% and 97%, and graft survival 90% and 90% in TAC/MMF and TAC/SRL groups, respectively. Surveillance biopsy showed cumulative incidence of SCAR was 27 % in TAC/MMF and 16 % in TAC/SRL groups at 2 years (P = 0.04). Overall, 33% of recipients in TAC/MMF and 20% in TAC/SRL received methylprednisolone for acute rejection/SCAR. Moderate/severe CAN was 10% in TAC/SRL group and 22% in TAC/MMF group(P = 0.06). New-onset diabetes mellitus (NODM) was 4% each in both groups. All recipients remain free of maintenance steroid therapy. CONCLUSIONS: Steroid avoidance in tacrolimus-based immunosuppression with MMF or SRL provides equivalent 2-year patient and graft survival with a low incidence of acute rejection and NODM. SCAR and CAN are lower in TAC/SRL compared to TAC/MMF group. The impact of decreased SCAR and CAN in TAC/SRL group on longer-term graft survival and function is to be evaluated.     

Clinical outcome of heart transplant recipients receiving tacrolimus with or without mycophenolate mofetil

Tacrolimus (TAC) is a calcineurin inhibitor that is used for cardiac allograft rejection. Efficacy and safety data of a combined TAC/mycophenolate mofetil (MMF) therapy in comparison with a TAC/cortisone therapy in heart recipients are lacking. We analysed the clinical outcome of 41 patients who received TAC in combination with MMF (TMF group) and of 41 patients who received TAC in combination with cortisone (TCO group). Outcomes were serum creatinine levels, cardiac rejections, cytomegalovirus infections, graft vasculopathy, malignancy rates and two-yr survival. Baseline characteristics were comparable in the two study groups. During follow-up, serum creatinine levels decreased slightly in the TMF group (p=0.039) but not in the TCO group. Compared with the TMF group, more clinically proven cardiac rejections which needed a cortisone bolus and more severe rejections that needed lymphoablative therapy with OKT occurred in the TCO group (p=0.001 and 0.04, respectively). In contrast, significantly more cytomegalovirus (CMV) infections occurred in the TMF group compared with the TCO group (p=0.01). The number of patients with graft vasculopathy as well as malignancy rates and overall survival did not differ significantly between the two study groups. The introduction of MMF was associated with an improvement of renal function and a more efficient immunosuppressive therapy. However, this treatment strategy also had led to a higher CMV infection rate compared with cortisone. Consequently, no general recommendation can be given at present whether TAC should be combined with MMF or with cortisone in heart transplant recipients.     

Five years of steroid sparing in renal transplantation with tacrolimus and mycophenolate mofetil

Steroid sparing with tacrolimus and mycophenolate mofetil (MMF) is associated with good short-term renal transplant outcomes. However, late allograft dysfunction and failure remain concerns. In this study, 101 consecutive patients underwent renal transplantation with tacrolimus, MMF, and 7 days of corticosteroids only. After a median follow-up of 51 months (range 36-62), overall patient survival is 97%, and overall survival with graft function is 91%. The acute rejection rate at 12 months was 19%. Late rejection was uncommon, with only three further episodes beyond 12 months. Graft function was stable during the study, with a mean creatinine of 140 micromol/L and mean estimated creatinine clearance of 57 ml/min at the end of follow-up. Six patients developed posttransplant diabetes mellitus (three cases beyond 12 months). This steroid avoidance regimen is associated with excellent medium-term patient and graft outcomes, and a low incidence of side effects.