The pharmacokinetics of mycophenolate mofetil in renal transplant recipients receiving standard-dose or low-dose cyclosporine, low-dose tacrolimus or low-dose sirolimus: the Symphony pharmacokinetic substudy (original) (raw)
Related papers
2000
has been shown in patients receiving Tc-MMF combination therapy compared with CsA-MMF combination therapy at the same dose of MMF. The aim of this prospective study was to assess the pharmacokinetic/ pharmacodynamic (PK/PD) relationship for MPA in kidney transplant patients receiving low-dose MMF (500 mg twice a day) in combination with Tc. Methods: Adult kidney transplant recipients (n ؍ 51) were included. MPA-PK profiles (blood sampling at 0, 0.5, 1, 2, 4, 6, and 12 h after MMF oral dose) were obtained within the first 2 weeks after transplantation, 3 months after grafting, and at every adverse clinical event [side effect or acute rejection (AR)]. All patients received Tc, MMF (500 mg twice a day), and steroids. Results: Thirty patients (59%) had uneventful outcomes, and 21 patients had 33 episodes of MPA-related side effects; only 3 patients had AR. A total of 78 MPA-PK profiles were obtained. The following PK parameters were increased in the side-effects group compared with the non-side effects group: mean MPA c min , 2.63 ؎ 1.58 vs 1.75 ؎ 0.82 mg/L (P ؍ 0.016); mean c 30 , 10.47 ؎ 6.27 vs 7.66 ؎ 8.95 mg/L (P ؍ 0.009); mean c 60 , 9.67 ؎ 5.42 vs 5.83 ؎ 2.6 mg/L (P ؍ 0.0002); mean area under the MPA time-concentration curve from 0 to 12 h [MPA-AUC (0 -12) ], 48.38 ؎ 18.5 vs 36.04 ؎ 10.82 mg ⅐ h/L (P ؍ 0.0006); mean dose-normalized MPA-AUC, 0.16 ؎ 0.05 vs 0.12 ؎ 0.04 (mg ⅐ h/L)/(mg/m 2 ) (P ؍ 0.0015). For the three AR patients, MPA concentrations obtained at the time of AR revealed MPA c min values of 1.86, 1.76, and 3.83 mg/L, respectively, and MPA-AUC (0 -12) values of 37.7, 24.9, and 104.9 mg ⅐ h/L. The threshold of toxicity was 3 mg/L (sensitivity, 38.7%; specificity, 91.5%) for c min , 8.09 mg/L for maximum MPA concentration during the first hour (sensitivity, 77.8%; specificity, 67.4%), and 37.6 mg ⅐ h/L for MPA-AUC (0 -12) (sensitivity, 83.3%; specificity, 59.6%). Conclusions: These results demonstrate the relationship between plasma MPA concentrations and toxicity. High c min, c 30 , and c 60 values as well as AUC (0 -12) are associated with increased risk for side effects. These values may have an importance in a routine monitoring program.
Transplantation Proceedings, 2007
Introduction. Efficacious prophylaxis of acute rejection episodes (ARE) requires adequate exposure to each component of the immunosuppressive treatment from the first days after renal transplantation. The aim of the present study was to evaluate the correlation between cyclosporine (CsA) and mycophenolic acid (MPA) exposure based upon pharmacokinetics (PK) and pharmacodynamics (PD) and 6-month biopsy-proven acute rejection (BPAR) episodes and chronic allograft nephropathy on 6 month protocol biopsies. Patients and methods. We examined twenty-two first or second de novo renal transplant recipients treated with steroids, Sandimmune Neoral (CsA) and Myfortic (720 mg twice a day). PK (C0, C2, and AUC 0 -12h ) for both drugs were determined on days 7, 90, and 180. Calcineurin activity, interleukin-2 and interferon-␥ synthesis as well as %CEM were tested at days 7 and 180. CsA dosages were adjusted by C2 monitoring. Collected data included: BPAR during the first 6 months and Banff histological parameters on the 6-month protocol biopsies. Results. Eighteen of 22 patients completed 1 year follow-up under treatment. The 6-month BPAR was 18% (4/22). Six-month protocol biopsies in 50% of 14 recipients showed chronic allograft nephropathy 1. At day 7, CsA C2 and AUC median values were 138 ng/mL and 6377 ng ϫ h/mL, while C0 MPA was 1.0 g/mL and AUC ϭ 23.9 g ϫ h/mL. CsA C2 medians at 3 and 6 months were 1468 and 1720 ng/mL. MPA-AUC reached therapeutic targets at 3 months (32.3 g ϫ h/mL) and was 48.3 g ϫ h/mL at 6 months. Patients with BPAR showed lower CsA AUC (P ϭ .06) and a significantly lower baseline inhibition of calcineurin activity (P Ͻ .005) than patients with no BPAR. An increase in mesangial matrix in 6-month protocol biopsies correlated with higher CsA C2 (P ϭ .01). All biomarkers evaluated were significantly inhibited compared with the standard population. Conclusions. When Myfortic is administered together with CsA, it is advisable to begin with higher doses (720 mg ϫ 3 days) to reach adequate PK targets and improve BPAR rates. To prevent chronic allograft nephropathy, lower CsA C2 should be targeted from 3 months.
Clinical Journal of The American Society of Nephrology, 2010
Background and objectives: Adequate early mycophenolic acid (MPA) exposure is an important determinant for effective rejection prophylaxis. This pharmacokinetic study investigated whether an intensified dosing regimen of enteric-coated mycophenolate sodium (EC-MPS) could achieve higher mycophenolic acid (MPA) exposure early after transplantation versus a standard dosing regimen. Design, setting, participants, & measurements: De novo kidney transplant recipients (n ؍ 75) who were treated with basiliximab induction and cyclosporine were randomly assigned to receive EC-MPS as either standard dosing (1440 mg/d; n ؍ 37) or intensified dosing (days 0 through 14: 2880 mg/d; days 15 through 42: 2160 mg/d; followed by 1440 mg/d; n ؍ 38). Full 12-hour pharmacokinetic and pharmacodynamic profiles were taken at six time points during the first 3 months. Exploratory analysis of inosine monophosphate dehydrogenase (IMPDH) activity was also performed for better understanding of the pharmacokinetic-pharmacodynamic relationship between MPA exposure and IMPDH activity in the early posttransplantation period. Preliminary efficacy parameters, safety, and tolerability were assessed. Results: Exposure to MPA was significantly higher on days 3 and 10 after transplantation in the intensified versus standard EC-MPS group, with 52.9 versus 22.2% (P < 0.05) of patients reaching MPA exposure >40 mg/h per L in the first week. The intensified regimen resulted in significantly lower IMPDH activity on day 3 after transplantation, and the overall safety was comparable for both groups. Conclusions: These pharmacokinetic and safety data support further research on the hypothesis that early adequate MPA exposure could improve clinical outcome.
Transplantation Proceedings, 2004
Background: Mycophenolate mofetil (MMF) is widely used in organ transplantation to prevent acute rejection. Because MMF can produce hematologic and/or gastrointestinal toxicity, therapeutic monitoring is becoming mandatory. This study was designed to investigate the relationship between the clinical events and the pharmacokinetics of mycophenolic acid (MPA) in adult renal transplantation. Methods: Thirty-one adult kidney recipients were prospectively included in the study. MPA pharmacokinetic profiles (blood sampling at 0, 0.5, 1, 2, 4, 6, and 12 h after MMF oral dose) were obtained after transplantation (desired creatinine clearance, 40 mL/min), at 3 months after grafting, and at every clinical event (e.g., side effect or rejection). All patients received a 10-day course of anti-thymocyte globulin, cyclosporine, MMF (1 g twice daily), and steroids. Results: We divided the 31 patients into two groups (groups 1 and 2). Ten patients (32%; group 1) had uneventful outcomes, and 21 patients (68%; group 2) presented with MPA-related side effects. For groups 1 and 2, the MPA trough concentrations (C min) were 1.63 ؎ 1.07 and 2.29 ؎ 1.16 mg/L, respectively (P ؍ 0.06), and the areas under the curve (AUCs) for MPA from t 0 to t 12 h (MPA-AUC 0-12h) were 39.80 ؎ 15.29 and 62.10 ؎ 21.07 mg ⅐ h/L, respectively (P ؍ 0.0005, two-sample t-test). Three patients experienced acute graft rejection after the oral MMF dose was reduced because of side effects. In this group, the MPA-C min and MPA-AUC were significantly lower by the time acute rejection occurred (1.00 ؎ 0.45 mg/L and 25.00 ؎ 6.20 mg ⅐ h/L, respectively). At a fixed dose (1 g twice per day), we compared the pharmacokinetic parameters of MPA [C min , the MPA concentration 30 min after the oral dose of MMF (C 30), and AUC] according to the presence or absence of side effects in the two groups. C min and AUC did not differ between the two groups [C min ؍ 2.22 ؎ 1.13 vs 2.17 ؎ 1.13 mg/L (P ؍ 0.9); AUC ؍ 66.82 ؎ 29.87 vs 55.70 ؎ 11.74 mg ⅐ h/L (P ؍ 0.11)]; and C 30 was significantly higher in group 2 than in group 1 (C 30 ؍ 32.99 ؎ 12.59 vs 7.45 ؎ 5.40 mg/L; P <0.0001). Conclusions: Our results demonstrate a pharmacokinetic/pharmacodynamic relationship between MPA and clinical events. At a fixed dose of 2 g/day, a high C 30 is associated with increased risk for side effects. This study suggests that dividing the MMF daily oral dose into more than two divided doses might prevent early MPA toxicity.
Therapeutic Monitoring of Mycophenolate Mofetil in Organ Transplant Recipients
Clinical Pharmacokinetics, 2002
M ycophenolate mofetil (MMF) has become the single most used immunosuppressant in solid-organ transplantation. Despite a well-documented relationship and efficacy (in terms of acute rejection prophylaxis) and exposure to mycophenolic acids (MPA) as measured by area under the curve (AUC), excellent results have been achieved using a fixed-dosage regimen. In the past several years, there has been an increased interest in the utility of monitoring MPA concentrations to both increase efficacy and decrease toxicity, particularly in many current drug minimization protocols.
Nephrology Dialysis Transplantation, 1999
ficant reduction in the rate of biopsy-proven acute rejection during the first 6 months after kidney trans-Background. Combining cyclosporin (CsA) and predplantation [1-3]. The size of the reduction in incidence nisone with mycophenolate mofetil (MMF) results in and severity of acute rejection episodes for patients a significant reduction in the rate of biopsy-proven treated with 2 or 3 g MMF was similar; however, the acute rejection after kidney transplantation. This is 3-g dose was somewhat less well tolerated [1-4]. achieved with a standard daily MMF dosage of 2 or Therefore, the current daily dose recommendation is 3 g. Whether monitoring of the pharmacologically 2 g [5]. active metabolite mycophenolic acid (MPA) will lead Following oral administration MMF is rapidly and to improved safety and efficacy is unclear. essentially completely absorbed and converted to Methods. We monitored MPA trough levels in 18 mycophenolic acid (MPA), the active immunokidney transplant recipients treated with CsA, prednissuppressant [6-7]. The sole metabolite of MPA is the one, and MMF (63 samples) and in 11 patients (31 glucuronide conjugate MPAG, which is pharmacolosamples) treated with prednisone and MMF only, in a gically inactive [6-8]. Although clear conclusions have cross-sectional study. All patients were at least 3 been drawn with regard to clinical efficacy of MMF months after transplantation with stable graft function. [1,3], data confirming the usefulness of monitoring All patients were treated with 2 g MMF for at least 3 MPA concentrations or defining a therapeutic window months and 10 mg prednisone. in terms of plasma MPA concentrations are not avail-Results. The MPA trough levels in the CsA-treated able. So far, the simplicity of fixed dosing (2 g MMF), patients were significantly lower (P<0.0001; Mannwith the exception of dosing by body size at the Whitney) than those in patients on MMF and extremes in adults and in children [9], is recommended prednisone only (mean MPA levels 1.98±0.12 vs for clinical practice [6 ]. Results of clinical trials investi-4.38±0.40 mg/l respectively). gating the potential role of therapeutic drug monitoring Conclusions. Although all patients were treated with in MMF treated transplant recipients are not available an identical MMF dose, a significant difference was so far. found in the MPA trough levels between CsA-vs non-Drug interactions with MMF include decreased CsA-treated patients. This suggests that CsA influences absorption when coadministered with magnesium and the MPA trough level. The level at which CsA affects aluminium hydroxide antacids [5]. Cholestyramine the MPA trough levels is unclear. decreases bioavailability by interfering with the enterohepatic recirculation [10]. MPA is conjugated to the Key words: mycophenolate mofetil; drug monitoring; inactive MPAG [6,7]. CsA is extensively metabolized kidney transplant recipients via the cytochrome P-450 system, an enzyme complex including enzymes that have a role in conjugation [10]. No interaction between CsA and MMF has been reported [10]. Tacrolimus and CsA are believed to be
Transplantation Proceedings, 2005
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 AUC 0 -12 of MPA was determined by the trapezoidal method using four sampling time points: C 0 , C 1 , C 3 , C 5 . Results. While patients on SRL were receiving 0.75 g MMF twice a day, mean AUC 0 -12 and C 0 values of MPA were comparable to those of patients receiving CsA and 1 g MMF twice a day (54.1 Ϯ 17.6 and 3 Ϯ 1.87 vs 51.7 Ϯ 16.7 mg · h/L and 2.76 Ϯ 1.57 mg/L, respectively). On the other hand, 0.5 g MMF twice a day with SRL therapy resulted in AUC 0 -12 and C 0 values of MPA of 32.3 Ϯ 12.6 mg · h/L and 2.32 Ϯ 1.72 mg/L, respectively, whereas, 1 g MMF twice a day with SRL resulted in AUC 0 -12 and C 0 values of MPA of 70.9 Ϯ 19.3 mg · h/L and 4.7 Ϯ 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 AUC 0 -12 of MPA levels comparable to that in patients treated with CsA and MMF 1 g twice a day.