Pharmacokinetics, safety, and efficacy of mycophenolate mofetil in combination with sirolimus or ciclosporin in renal transplant patients.

AIMS: To compare the pharmacokinetics of mycophenolic acid (MPA) and its metabolite (MPAG) when mycophenolate mofetil (MMF) is administered in combination with sirolimus or ciclosporin (CsA) in renal allograft recipients. Safety and efficacy (biopsy-proven acute rejection (BPAR)) were also assessed. METHODS: Patients (n = 45) were randomized 2 : 1 to receive treatment with sirolimus (n = 30; dosed to maintain trough concentrations of 10-25 ng ml(-1) until week 8, and then 8-15 ng ml(-1) thereafter) or CsA (n = 15; administered as per centre practice) both in combination with daclizumab, oral MMF and corticosteroids. Pharmacokinetic assessments were performed at day 7, week 4, and months 3 and 6 post-transplant. The primary endpoint was the AUC(0,12 h) for MPA and MPAG. The pharmacokinetics of sirolimus were also assessed. RESULTS: MPA exposure was 39-50% lower (month 6 mean AUC(0,12 h) (95%CI): 40.4 (33.8, 47.0) vs. 68.5 (54.9, 82.0) microg ml(-1) h) and MPAG exposure was 25-52% higher (722 (607, 838) vs. 485 (402, 569) microg ml(-1) h at month 6) in the presence of CsA compared with sirolimus across visits. BPAR was 40.0% with sirolimus and 13.3% with CsA. The incidence of hypertension, tremors and hirsutism was higher with CsA than with sirolimus, while the incidence of diarrhoea, hyperlipidaemia and impaired wound closure was higher with sirolimus. No deaths, malignancies or graft losses were reported. CONCLUSIONS: Co-administration of sirolimus with MMF led to greater MPA exposure, but lower MPAG exposure, than co-administration with CsA. As rejection rates were higher in the absence of CsA, further study of calcineurin inhibitor-free regimens is required before general recommendations can be made.

Renal function with cyclosporine C2 monitoring, enteric-coated mycophenolate sodium and basiliximab: a 12-month randomized trial in renal transplant recipients.

BACKGROUND: Cyclosporine exposure, as estimated by the area under the curve (AUC), predicts outcomes in renal transplantation. Cyclosporine concentration at two h post-dose (C(2)) has been shown to be the most reliable, single-point surrogate marker for AUC. The objective of this study was to measure renal function beyond month 2 post-transplant using two different C(2) maintenance targets in combination with enteric-coated mycophenolate sodium (EC-MPS), corticosteroids, and basiliximab induction. METHODS: In this open-label, multicenter trial, renal transplant recipients entered one of two randomized groups at day 61 post-transplant: group A (higher-C(2) range) or group B (lower-C(2) range). RESULTS: Patients (164) were recruited, and 141 patients were entered the randomized groups (group A, n = 66; group B, n = 75). At 12 months, the mean calculated creatinine clearance was significantly greater in group B than in group A (79.2 vs. 71.0 mL/min, p < 0.05). Biopsy-proven acute rejection occurred in 14.7% patients in group B and in 24.2% patients in group A (n.s.). During the 12-month trial, 17.7% patients discontinued EC-MPS because of adverse events. Group B (44.0%) had fewer serious adverse events when compared with group A (62.1%; p = 0.04). Overall patient and graft survival were 99.4% and 95.7% respectively. Among 99 high-risk patients (i.e., African-American race, previous transplant, PRA >35% or >4 HLA mismatches), mean creatinine clearance at 12 months was 65.6 mL/min and biopsy-proven rejection occurred in 20.2% patients. CONCLUSIONS: Low cyclosporine C(2) levels are associated with improved renal function compared with higher C(2) levels when used in conjunction with EC-MPS, steroids and basiliximab induction. EC-MPS with low cyclosporine C(2) levels, corticosteroids and basiliximab provides excellent renal function with good efficacy even in high-risk patients.

12-month safety and efficacy of everolimus with reduced exposure cyclosporine in de novo renal transplant recipients.

The proliferation signal inhibitor everolimus (Certican), has demonstrated efficacy with full-dose cyclosporine (CsA) (Neoral). Two multicenter randomized controlled studies were performed to compare 12-month efficacy and safety of everolimus 1.5 and 3.0 mg/day with reduced-dose CsA. Study 1 enrolled 237 de novo renal allograft recipients, randomizing 222 nonblack patients to either everolimus 1.5 or 3.0 mg/day, with the Neoral) dose guided by C(2) (monitoring of CsA concentration 2 h after dosing). Study 2 had a similar protocol, with basiliximab included, enrolling 256 recipients and randomizing 243 nonblack patients. In Study 1, there was a lower incidence of acute rejection in nonblack patients on 3 mg/day (16.4%) compared with 1.5 mg/day (25.9%), P = 0.08. In Study 2, the inclusion of basiliximab lowered the overall incidence of acute rejection; 14.3% of nonblack patients (3 mg/day) and 13.6% of nonblack patients (1.5 mg/day) had acute rejection by 12 months (P =0.891). Renal function was preserved throughout the study, with no differences observed between groups within studies. Everolimus was well tolerated with no significant differences between doses. Everolimus, in combination with reduced-dose Neoral), demonstrated efficacy and was well tolerated. Basiliximab allows for utilization of lower doses of everolimus with reduced dosing of Neoral).

Therapeutic drug monitoring for everolimus in kidney transplantation using 12-month exposure, efficacy, and safety data.

The aims of the current study were to determine whether therapeutic drug monitoring (TDM) might benefit kidney transplant recipients receiving everolimus, and to establish dosage recommendations when everolimus is used in combination with cyclosporine and corticosteroids. The analysis was based on data from 779 patients enrolled in two 12-month trials. Everolimus trough concentrations >/=3 ng/mL were associated with a reduced incidence in biopsy-proven acute rejection (BPAR) in the first month (p = 0.0001) and the first 6 months (p = 0.0001), and reduced graft loss compared with lower concentrations (4% vs. 20%, respectively). By contrast, cyclosporine in the standard concentration range had no impact on BPAR within the same timeframes. Most patients receiving everolimus 1.5 or 3 mg/d achieved trough concentrations above the therapeutic threshold of 3 ng/mL, regardless of reductions in cyclosporine dose. TDM simulation showed that just two dose adjustments would achieve median everolimus trough values >/=3 ng/mL in 95% of patients during the first 6 months. This investigation indicates that improved efficacy is likely when TDM is considered as an integral component of the immunosuppressive strategy of everolimus.

Everolimus with optimized cyclosporine dosing in renal transplant recipients: 6-month safety and efficacy results of two randomized studies.

Two prospective, randomized studies evaluated everolimus 1.5 vs. 3 mg/day with steroids and low-exposure cyclosporine (CsA) (C2 monitoring) in de novo renal transplant patients. Everolimus dosing was adjusted to maintain a minimum trough level of 3 ng/mL. Study 1 (A2306; n=237) had no induction therapy; in Study 2 (A2307; n=256) basiliximab was administered (Days 0 and 4). The primary endpoint was renal function at 6 months. CsA C2 target levels, initially 1200 ng/mL in Study 1 and 600 ng/mL in Study 2, were tapered over time post-transplant. Median creatinine levels in Study 1 were 133 and 132 micromol/L at 6 months in the 1.5 and 3 mg/day groups, respectively, and 130 micromol/L in both groups in Study 2. Biopsy-proven acute rejection (BPAR) occurred in 25.0% and 15.2% of patients in the 1.5 and 3 mg/day groups in Study 1, and 13.7% and 15.1% in Study 2. Incidence of BPAR was significantly higher in patients with an everolimus trough <3 ng/mL. There were no significant between-group differences in the composite endpoint of BPAR, graft loss or death, nor any significant between-group differences in adverse events in either study. Concentration-controlled everolimus with low-exposure CsA provided effective protection against rejection with good renal function.

Ten-year follow-up in patients with combined heart and kidney transplantation.

BACKGROUND: Combined heart and kidney transplantation has been documented, although data regarding immunosuppression, rejection episodes, and graft or patient survival have not been detailed. We evaluated our experience and more than 10-year outcome with patients selected for combined heart and kidney transplantation. METHODS: Eight patients aged 29 to 59 years were selected for combined heart and kidney transplantation. The indications were end-stage heart disease and underlying renal pathology, or secondary renal insufficiency, or renal failure. Six patients were dialysis dependent before transplantation. There were 7 simultaneous procedures and 1 staged procedure. The heart was transplanted first in all cases. All patients were maintained after transplantation on azathioprine (2 mg x kg(-1) x d(-1)) and whole-blood monoclonal cyclosporine levels at greater than 200 microg/L; prednisone was not decreased to less than 10 mg/d. RESULTS: Seven (87.5%) patients have survived a mean duration of 100.4 months (range, 51-144 months), and each allograft has continued to function. The only death was due to pulmonary emboli and was not related to allograft rejection or failure. Only 4 cardiac and 4 kidney allograft rejections have occurred. Five patients have been free of kidney rejection, 1 patient has been rejection free for more than 8 years, and no patient has had simultaneous rejection. CONCLUSIONS: In select patients, combined heart and kidney transplantation can provide long-term graft function and patient survival. The low rates of rejection support our current approach to immunosuppression. Our experience indicates that end-stage failure of either heart or kidney does not necessarily preclude dual-organ transplantation.