Mycophenolic Acid Trough Research Articles

Mycophenolic acid concentrations are associated with cardiac allograft rejection

Background: Mycophenolate mofetil (MMF) therapy decreases the incidence of allograft rejection following solid-organ transplantation. Current dosing strategies of MMF are not routinely adjusted based on mycophenolic acid (MPA) area under the concentration-time curve (AUC), MPA trough, or free MPA (fMPA) AUC values. Methods To determine the clinical significance of MPA concentrations following orthotopic heart transplantation (OHT), we measured pre-dose MPA trough, MPA free fraction, an estimated MPA AUC using an abbreviated sampling schedule, and fMPA AUC in 38 consecutive patients. We measured MPA concentrations using a validated high-performance liquid chromatography method and graded endomyocardial biopsies based on the International Society for Heart and Lung Transplantation (ISHLT) grading system. Results The MPA values for the study group were as follows: MPA trough of 1.2 ± 0.6 μg/ml; MPA free fraction of 1.9 ± 0.4%; MPA AUC of 44.5 ± 16.1 μg/hour/ml; and fMPA AUC of 0.83 ± 0.30 μg/hour/ml. We compared patients with Grade 0 ( n = 22), Grade 1 ( n = 13), or Grade 2/3 ( n = 3). The MPA AUC values were lower in patients with Grade 2/3 than in patients with Grade 0 (26.1 ± 6.6 vs 42.8 ± 14.0 μg/hour/ml, p < 0.08) or Grade 1 rejection (26.1 ± 6.6 vs 51.7 ± 17.5 μg/hour/ml, p < 0.05). The fMPA AUC values were lower in patients with Grade 2/3 than with patients with Grade 0 (0.49 ± 0.11 vs 0.81 ± 0.25 μg/hour/ml, p < 0.05) or Grade 1 (0.49 ± 0.25 vs 0.95 ± 0.34 μg/hour/ml, p < 0.05) rejection. We noted a trend in MPA trough concentrations between patients with Grade 2/3 vs 0 (0.65 ± 0.15 vs 1.20 ± 0.58 μg/ml, p = 0.15) and Grade 1 (0.65 ± 0.15 vs 1.24 ± 0.72 μg/ml, p = 0.14) rejection. Conclusion These preliminary results suggest that lower MPA AUC and fMPA AUC values are associated with cardiac allograft rejection in heart transplant recipients. Individualizing MMF dosing based on MPA determinations may minimize the risk of rejection following OHT.

Mycophenolate mofetil pharmacokinetics in transplant patients receiving cyclosporine or tacrolimus in combination therapy.

Mycophenolate mofetil is a highly effective immunosuppressant drug used in the prophylaxis of organ rejection in combination with cyclosporine or tacrolimus and corticosteroids. The present study is a retrospective data analysis of the routinely estimated mycophenolic acid plasma trough levels in 60 transplant patients (kidney, n = 49; lung, n = 11) receiving mycophenolate mofetil in combination with prednisone and cyclosporine (n = 45) or tacrolimus (n = 15). Coadministration of cyclosporine instead of tacrolimus resulted in a significant increase of median (range) of the ratio of dose-to-concentration 0.92 (0.11-8.33) (n=167) versus 0.38 (0.11-14.28) (n = 66); P < 0.0001. No correlation was seen between mycophenolate mofetil dose and mycophenolic acid trough concentrations. The dose-to-concentration in cyclosporine-treated patients increased significantly (P<0.0001) as the cyclosporine level increased, suggesting a possible interaction between mycophenolate mofetil and cyclosporine. No correlation was seen between dose-to-concentration and tacrolimus blood levels (P x 0.215). Further studies are necessary to investigate this issue.

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.

Effect of adding Mycophenolate mofetil in paediatric renal transplant recipients with chronical cyclosporine nephrotoxicity

Abstract Cyclosporine (CyA) has made a great impact on 1-year al-lograft survival, however, after years, renal function deteriorates, possibly due to chronic toxicity. Recently, Mycophenolate mofetil (MMF) was introduced as a non-nephrotoxic immunosuppressant that might be effective in chronical transplant arteriolopathy. We therefore started MMF at a dose of 600 mg/m2 b. i. d. in 18 pediatric renal transplant recipients (10.8 ± 3.9 (SD) years of age at transplantation, 11/18 with a history of rejections) with biopsy-proven chronic arteriolopathy and other signs of CyA toxicity at a mean follow up time of 6.2 ± 2.7 (range 2.3–11.8) years after transplantation. One month prior to conversion, mean serum creatinine was 171 ± 96 μmmol/1, lower than at the time of conversion (188 ± 100 μmol/1, P= 0.003, paired t-test). At last follow-up (median 13.7 months, range 5.0 to 25.0 months) after conversion, mean serum creatinine decreased significantly to 127 ± 69 μmol/1 (P= 0,0003, paired t-test). The CyA dosage was reduced from a mean of 150 ± 39 mg/m per day to 59 7plusmn; 13 mg/m2 per day in 7 patients, and CyA was discontinued in 11 patients after a median period of nine months (range 1–18 months). After a median period of 21 days, a pharmacokinetic profile was performed in all patients. The mean MMF dose was 1117 ± 319 mg/m2 per day (range 675–1774 mg/m2 per day). The mean Mycophenolic acid (MPA) trough concentration was 4.0 ± 2.0 μg/ml, range 1.4–7.9 μg/ml. Mean 12 h MPA AUC was 70.6 ± 28.1 (range 31.9–127) μg × h/ml. Except for one patient with diarrhea associated with a high AUC, and for one patient with a steroid-sensitive rejection episode after 566 days, no other patient experienced side effects or a rejection episode. Prednisolone was left unaltered at 2–4 mg/m2 per day. We conclude that MMF allows safe reduction of CyA with markedly better graft function, suggesting that chronical CyA-toxicity partially accounts for deteriorating allograft function.

Effect of mycophenolate mofetil on erythropoiesis in stable renal transplant patients is correlated with mycophenolic acid trough levels.

Both mycophenolate mofetil (MMF) and azathioprine (AZA) are immunosuppressive drugs that inhibit purine synthesis. In theory, MMF selectively inhibits lymphocyte proliferation, while AZA has well-known effects on red blood cells and thrombocytes as well. In renal transplant recipients we replaced CsA therapy by MMF in an attempt to reduce the immunosuppressive load 1 year after kidney transplantation. During this study we observed the effect of MMF on haematological parameters such as haemoglobin (Hb), leukocytes, and thrombocytes. One year after kidney transplantation 26 stable patients were converted from cyclosporin A (CsA) to MMF (2 g/day). Thereafter, these patients were tapered twice in their MMF dose from 2 g to 1.5 g (4 months after conversion) and from 1.5 to 1 g (8 months after conversion) per day. The Hb levels, leukocyte and thrombocyte counts, and mycophenolic acid (MPA) trough levels were routinely measured. After conversion from CsA to MMF not only creatinine levels and the number of leukocytes, but also the haemoglobin (Hb) level significantly decreased in 21/26 patients (P=0.0004). In eight patients the Hb level dropped more than 1 mmol/l (=1.61 g/dl). Only in two of eight patients was an explanation for blood loss found. The effect on Hb level did not ameliorate after the first MMF dose reduction to 1.5 g/day. After tapering the MMF dose to 1 g/day, the Hb approached the pre-conversion level. Not only the MMF dose but also the mycophenolic acid (MPA) trough level correlated with the Hb level. After conversion from CsA to MMF 1 year after kidney transplantation, a decrease in Hb level and leukocyte count was observed. The MPA trough level correlated also with the Hb level. The effect on the Hb level was reversible after dose reduction. This finding suggests that MMF exerts a negative effect on erythropoietic cells.

The efficacy of the combination of tacrolimus and mycophenolate mofetil for prevention of acute myocardial rejection is dependent on routine monitoring of mycophenolic acid trough acid levels

The efficacy of the combination of tacrolimus and mycophenolate mofetil for prevention of acute myocardial rejection is dependent on routine monitoring of mycophenolic acid trough acid levels

Combination therapy with tacrolimus and mycophenolate mofetil following cardiac transplantation: importance of mycophenolic acid therapeutic drug monitoring

Background Interest has recently been expressed in tacrolimus and mycophenolate mofetil (MMF), two potent immunosuppressants, for a variety of transplant indications. The efficacy of this combination was assessed as primary therapy following cardiac transplantation. Methods Forty-five patients were enrolled; 15 into Phase I and 30 to Phase II of the study. Intravenous tacrolimus was administered for 2–3 days to all patients prior to conversion to oral therapy; target blood concentrations were 10–15 ng/mL. Treatment also consisted of steroids and MMF. During Phase I, a fixed 2 g/day dose of MMF was given whilst doses were adjusted according to mycophenolic acid (MPA) plasma levels during Phase II (target range 2.5–4.5 μg/mL). Mean follow-up was 696 ± 62 days and 436 ± 88 days for Phases I and II, respectively. Results Phase I: Patient survival was 100%. Rejection was diagnosed in 66.7% of patients (mean number of episodes per patient 1.33 ± 1.18). Retrospective analyses indicated that whereas mean MPA plasma levels >3.0 μg/mL were not associated with rejection, no correlation was found with tacrolimus blood concentrations. Phase II: A survival rate of 96.7% was evident, one patient having died from aspergillosis. Diagnoses of rejection were made in 10.0% of patients (0.10 ± 0.31 episodes per patient) and confounding factors were present in all 3 cases. MPA trough levels were 1.0 ± 0.3 μg/mL at this time. Resolution was apparent following pulse steroid therapy. Steroids were successfully withdrawn from all patients who completed 6 months’ treatment. Conclusions Combination therapy with tacrolimus and MMF is associated with suppression of acute myocardial rejection; however, this is dependent upon routine therapeutic drug monitoring.

Relation of Mycophenolic Acid Trough Levels and Adverse Events in Kidney Allograft Recipients

Relation of Mycophenolic Acid Trough Levels and Adverse Events in Kidney Allograft Recipients

TACROLIMUS AND MMF IN CARDIAC TRANSPLANTATION: IMPORTANCE OF MYCOPHENOLIC ACID DRUG MONITORING

745 Background: Tacrolimus and mycophenolate mofetil (MMF) are both potent immunosuppressants. Interest has recently been expressed in these two agents in a variety of transplant indications. To assess the efficacy of this combination as primary therapy following cardiac transplantation, the following study was undertaken. Methods: 45 patients (pts) were enrolled; 15 into phase I and 30 to phase II of the study. All patients were administered intravenous tacrolimus for a 2-3-day period post-transplant prior to conversion to oral therapy; target blood concentrations were 10-15 ng/mL. Treatment also consisted of steroids and MMF. A fixed dose of 2 g/day MMF was given during phase I whilst MMF doses were adjusted according to mycophenolic acid (MPA) blood levels during phase II (target range 2.5-4.5µg/mL). Mean follow-up was 554±61 days and 305±74 days for phase I and II, respectively. Findings: Phase I. Pt survival was 100%. Acute rejection episodes (ARE) were diagnosed in 66.7% of pts(ARE/pt: 1.33 ± 1.18). Mean MPA blood levels in excess of 3.0µg/mL were associated with freedom from rejection. Phase II. One pt died from aspergillosis resulting in a survival rate of 96.7%. Rejection was evident in 10.0% of pts (ARE/pt: 0.1±0.3); mean MPA trough levels were 1.0+0.3 µg/mL in these 3 pts at the time. All 3 cases resolved following pulse steroid therapy. Steroids were successfully withdrawn from all pts after 6 months treatment. Conclusions: Combination therapy with tacrolimus and MMF is associated with suppression of acute myocardial rejection; this is dependent upon doses of both drugs being adjusted in accordance with their respective target blood concentrations. Routine MPA blood monitoring appears to result in a marked improvement in clinical efficacy. This strategy also allows complete withdrawal of steroids as early as 6 months after HTx.

Long-term Follow-up of Mycophenolic Acid Blood Trough Levels in Graft Recipients with and without a History of Insulin-dependent Diabetes Mellitus IDDM

690 Oral medication is severely hampered by malabsorption. Immunosuppressive oral medication in patients with diabetic gastroparesis can also be affected bearing the risk of under-immunosuppression. Mycophenolate mofetil (MMF) is applied to many immunosuppressive regimen. MMF releases mycophenolic acid(MPA) as the immunosuppressive compound. In this study graft recipients with or without a history of severe diabetes mellitus type I were included. In a cohort of randomly selected type-I diabetics (n=12) with renal or combined renal-pancreas transplantation MPA-trough levels were determined. Simultaneous kidney-pancreas transplantation was performed using the urinary bladder drainage technique. Repeated measurements of MPA trough levels were performed over a period of more than 100 post-operative days. For comparison we also included a cohort of randomly selected non-diabetic renal transplant patients (n=13) who did receive the same immunosuppressive protocol. Repeated blood samples were collected and MPA was measured by means of an EMIT Mycophenolic Acid Assay(Behring Diagnostics, Marburg, Germany). In patients with a history of diabetes mellitus type I (n=12), the median trough levels for MPA was 1,27 µg/ml (maximal levels of 4,08µg/ml; minimal levels of 0, 13 µg/ml). In contrast, in patients without a history of diabetes mellitus type I the median trough levels for MPA was 3, 17 µg/ml (maximal levels of 8,53 µg/ml; minimal levels of 0,57 µg/ml). This difference between both groups was independent of the dosage of MMF (1g or 2g/day). These very preliminary data reveal that MMF pharmacokinetics seem to be affected by previously existing diabetes mellitus. It remains unclear what might cause these differences, but repeated measurements of MPA blood levels are desired in order to control maintenance immunosuppression with MMF.

TACROLIMUS AND MMF IN CARDIAC TRANSPLANTATION: IMPORTANCE OF MYCOPHENOLIC ACID DRUG MONITORING

745 Background: Tacrolimus and mycophenolate mofetil (MMF) are both potent immunosuppressants. Interest has recently been expressed in these two agents in a variety of transplant indications. To assess the efficacy of this combination as primary therapy following cardiac transplantation, the following study was undertaken. Methods: 45 patients (pts) were enrolled; 15 into phase I and 30 to phase II of the study. All patients were administered intravenous tacrolimus for a 2-3-day period post-transplant prior to conversion to oral therapy; target blood concentrations were 10-15 ng/mL. Treatment also consisted of steroids and MMF. A fixed dose of 2 g/day MMF was given during phase I whilst MMF doses were adjusted according to mycophenolic acid (MPA) blood levels during phase II (target range 2.5-4.5 μg/mL). Mean follow-up was 554±61 days and 305±74 days for phase I and II, respectively. Findings: Phase I. Pt survival was 100%. Acute rejection episodes (ARE) were diagnosed in 66.7% of pts (ARE/pt: 1.33 ± 1.18). Mean MPA blood levels in excess of 3.0 μg/mL were associated with freedom from rejection. Phase II. One pt died from aspergillosis resulting in a survival rate of 96.7%. Rejection was evident in 10.0% of pts (ARE/pt: 0.1±0.3); mean MPA trough levels were 1.0+0.3 μg/mL in these 3 pts at the time. All 3 cases resolved following pulse steroid therapy. Steroids were successfully withdrawn from all pts after 6 months treatment.Conclusions: Combination therapy with tacrolimus and MMF is associated with suppression of acute myocardial rejection; this is dependent upon doses of both drugs being adjusted in accordance with their respective target blood concentrations. Routine MPA blood monitoring appears to result in a marked improvement in clinical efficacy. This strategy also allows complete withdrawal of steroids as early as 6 months after HTx.

Long-term Follow-up of Mycophenolic Acid Blood Trough Levels in Graft Recipients with and without a History of Insulin-dependent Diabetes Mellitus IDDM

690 Oral medication is severely hampered by malabsorption. Immunosuppressive oral medication in patients with diabetic gastroparesis can also be affected bearing the risk of under-immunosuppression. Mycophenolate mofetil (MMF) is applied to many immunosuppressive regimen. MMF releases mycophenolic acid(MPA) as the immunosuppressive compound. In this study graft recipients with or without a history of severe diabetes mellitus type I were included. In a cohort of randomly selected type-I diabetics (n=12) with renal or combined renal-pancreas transplantation MPA-trough levels were determined. Simultaneous kidney-pancreas transplantation was performed using the urinary bladder drainage technique. Repeated measurements of MPA trough levels were performed over a period of more than 100 post-operative days. For comparison we also included a cohort of randomly selected non-diabetic renal transplant patients (n=13) who did receive the same immunosuppressive protocol. Repeated blood samples were collected and MPA was measured by means of an EMIT Mycophenolic Acid Assay(Behring Diagnostics, Marburg, Germany). In patients with a history of diabetes mellitus type I (n=12), the median trough levels for MPA was 1,27 μg/ml (maximal levels of 4,08 μg/ml; minimal levels of 0,13 μg/ml). In contrast, in patients without a history of diabetes mellitus type I the median trough levels for MPA was 3,17 μg/ml(maximal levels of 8,53 μg/ml; minimal levels of 0,57 μg/ml). This difference between both groups was independent of the dosage of MMF (1g or 2g/day). These very preliminary data reveal that MMF pharmacokinetics seem to be affected by previously existing diabetes mellitus. It remains unclear what might cause these differences, but repeated measurements of MPA blood levels are desired in order to control maintenance immunosuppression with MMF.

Mycophenolate mofetil in patients with acute renal failure: evidence of metabolite (MPAG) accumulation and removal by dialysis

Abstract Pharmacokinetics of mycophenolic acid (MPA) was analyzed in eight patients with post-transplant acute renal failure. Furthermore, the effect of hemodialysis upon blood levels of MPA and its major metabolite, MPA glucuronide (MPAG), was determined. The mean duration of the posttransplant renal failure was 18 days, but renal function resumed in all patients eventually. The patients were treated with 3 g/day of mycophenolate mofetil for 28 consecutive days combined with cyclosporine A, me-thylprednisolone, and ATG for induction therapy. In all patients, accumulation of MPAG but not of MPA was observed. MPA trough levels were in the range between 0.5 pgiml at day 2 and 2.3 pgiml at the end of the study period. However, this concentration difference did not reach statistical significance. Trough levels of MPAG accumulated, reaching levels as high as 358 μg/ml. However, with increasing recovery of renal function, MPAG levels fell to a median trough concentration of 141 pg/ml. MPAG, but not MPA, could partially be removed from the circulation by hemodialysis treatment.

Mycophenolate mofetil in patients with acute renal failure: evidence of metabolite (MPAG) accumulation and removal by dialysis.

Pharmacokinetics of mycophenolic acid (MPA) was analyzed in eight patients with post-transplant acute renal failure. Furthermore, the effect of hemodialysis upon blood levels of MPA and its major metabolite, MPA glucuronide (MPAG), was determined. The mean duration of the posttransplant renal failure was 18 days, but renal function resumed in all patients eventually. The patients were treated with 3 g/day of mycophenolate mofetil for 28 consecutive days combined with cyclosporine A, methylprednisolone, and ATG for induction therapy. In all patients, accumulation of MPAG but not of MPA was observed. MPA trough levels were in the range between 0.5 microgram/ml at day 2 and 2.3 micrograms/ml at the end of the study period. However, this concentration difference did not reach statistical significance. Trough levels of MPAG accumulated, reaching levels as high as 358 micrograms/ml. However, with increasing recovery of renal function, MPAG levels fell to a median trough concentration of 141 micrograms/ml. MPAG, but not MPA, could partially be removed from the circulation by hemodialysis treatment.