Mycophenolic acid plasma concentrations in kidney allograft recipients with or without cyclosporin: a cross-sectional study.

BACKGROUND: Combining cyclosporin (CsA) and prednisone with mycophenolate mofetil (MMF) results in a significant reduction in the rate of biopsy-proven acute rejection after kidney transplantation. This is achieved with a standard daily MMF dosage of 2 or 3 g. Whether monitoring of the pharmacologically active metabolite mycophenolic acid (MPA) will lead to improved safety and efficacy is unclear. METHODS: We monitored MPA trough levels in 18 kidney transplant recipients treated with CsA, prednisone, and MMF (63 samples) and in 11 patients (31 samples) treated with prednisone and MMF only, in a cross-sectional study. All patients were at least 3 months after transplantation with stable graft function. All patients were treated with 2 g MMF for at least 3 months and 10 mg prednisone. RESULTS: The MPA trough levels in the CsA-treated patients were significantly lower (P<0.0001; Mann-Whitney) than those in patients on MMF and prednisone only (mean MPA levels 1.98+/-0.12 vs 4.38+/-0.40 mg/l respectively). CONCLUSIONS: Although all patients were treated with an identical MMF dose, a significant difference was found in the MPA trough levels between CsA- vs non-CsA-treated patients. This suggests that CsA influences the MPA trough level. The level at which CsA affects the MPA trough levels is unclear.     

Mycophenolic Acid Trough Level Measurements and Clinical Outcomes in Kidney Transplantation Recipients on a Fixed Dose (1.5 g/d) of Mycophenolate Mofetil in Korea

Background

Mycophenolate mofetil (MMF) is routinely used at a fixed dose, but several factors interact to alter the blood level of mycophenolic acid (MPA), resulting in toxicity or treatment failure.

Methods

From January 2007 to December 2008, 85 kidney transplantation patients were given a fixed dose of 1.5 g/d of MMF in 12-hour intervals. MPA trough levels were measured on postoperative 1 week, 1 month, 3 months, 6 months, and 12 months.

Results

Mean age of patients was 41 years. Thirty five cases were deceased donor kidney transplantations and 50 were living donor kidney transplantations. Mean trough levels of MPA were 1.04 μg/mL, 1.09 μg/mL, 1.28 μg/mL, 1.83 μg/mL, and 1.69 μg/mL at postoperative 1 week, 1 month, 3 months, 6 months, and 12 months, respectively. Mean trough levels of the subgroup of patients taking cyclosporine were 0.82 μg/mL, 0.94 μg/mL, 1.01 μg/mL, 1.56 μg/mL, and 1.46 μg/mL (n = 36). Mean trough levels of the subgroup of patients taking tacrolimus were 1.19 μg/mL, 1.21 μg/mL, 1.56 μg/mL, 2.13 μg/mL, and 2.20 μg/mL (n = 49). At 12 months, 31% of all patients experienced one or more opportunistic infections. Eight patients (9.4%) had cytomegalovirus infections, 14 patients (16.5%) had polyomavirus infections, and four patients (4.7%) had parvovirus infections. Ten patients (11.8%) experienced biopsy-proven acute rejection during the follow-up period.

Conclusion

Mean MPA trough levels of patients on 1.5 g/d of MMF reached 1.0 μg/mL within 1 week. Thirty one percent of patients experienced opportunistic infections, and 11.8% of patients had biopsy-proven acute rejections.     

Dosing of MMF in combination with tacrolimus for steroiD-resistant vascular rejection in pediatric renal allografts

Abstract SteroiD-resistant vascular rejection was treated in seven adolescent renal allograft recipients using the combination of mycopheno-late mofetil (MMF) and tacrolimus (FK506). Since there are no published pediatric dose recommendations for MMF using this combination, trough concentrations and pharmacokinetic profiles were used for therapeutic drug monitoring. In order to keep the mycophenolic acid (MPA) concentrations between 2–5 μg/ml, mean MMF doses were reduced from 600 to 250 mg/m² b. i. d. Apparent clearance of MPA decreased from 5 to 1 ml/min per kg within 2 weeks. Pharmacokinetic monitoring revealed substantial variability among patients of both MMF and FK506. The MPA dose ranged from 178 to 1008 mg/m² per day to achieve an area under the curve (AUC) of 59.9 μg × h/ml ± 10.5 SD (range 49–65 μg). FK506 dose ranged from 1.3 to 8.8 mg/m² per day to achieve an AUC of 116 ng × h/ml ± 27 SD (range 83–145). We recommend adjusting MMF doses using therapeutic drug monitoring.     

Effect of cyclosporine on mycophenolic acid trough levels in kidney transplant recipients

BACKGROUND: Triple drug treatment consisting of mycophenolate mofetil (MMF), in a standard dose of 2 g daily, combined with cyclosporine (CsA) and prednisone, has become the standard immunosuppressive regimen after kidney transplantation in many centers. The need for therapeutic drug monitoring of mycophenolic acid (MPA) has not yet been established. Several drug interactions with MMF are known. We investigated the influence of CsA withdrawal on MPA trough levels in renal transplant patients. METHODS: Fifty-two patients were treated with 1 g of MMF twice daily, and prednisone and CsA targeted between 125 and 175 ng/ml for 6 months after transplantation. At 6 months after transplantation, 19 patients were randomized for continuation of triple therapy (group A), 19 patients discontinued CsA (group B), and 14 patients discontinued prednisone (group C). We compared 12-hr fasted MPA trough levels at 6 and 9 months after transplantation within and between these groups. RESULTS: MPA trough levels during treatment with CsA, MMF, and prednisone were significantly lower than those during treatment with MMF and prednisone only (group B); median levels were 1.87 mg/L (range: 0.56-5.27) vs. 3.16 mg/L (range: 0.32-7.78), respectively (P=0.002). MPA trough levels in groups A and C did not change between 6 and 9 months after transplantation; group A median levels were 1.87 (range: 0.31-4.32) vs. 1.53 mg/L (range: 0.36-3.70), and group C median levels were 1.62 (range: 0.69-10.34) vs. 1.79 mg/L (range: 0.54-6.00), respectively. At 9 months after transplantation, patients in whom CsA was discontinued had higher MPA trough levels as compared with patients who continued the use of triple therapy (P=0.001) or patients in whom steroids were withdrawn (P=0.014). CONCLUSION: A significant increase of MPA trough levels was found after discontinuation of CsA (6 months after transplantation), resulting in almost a doubling of MPA trough levels at 9 months after transplantation. This resulted in increased MPA levels in patients without CsA as compared to MPA levels in patients continuing triple therapy or discontinuing prednisone.     

Lack of Correlation Between MMF Dose and MPA Level in Pediatric and Young Adult Cardiac Transplant Patients: Does the MPA Level Matter?1

To determine the correlation between mycophenolate mofetil (MMF) dose and mycophenolic acid (MPA) level as well as its impact on rejection among young cardiac transplant recipients (OHT), trough concentrations of MPA and its metabolite, mycophenolic acid glucuronide (MPAG), were measured following MMF doses of 1200 mg/m2/d (max 3000 mg/d). Corresponding endomyocardial biopsy (EMB) grades and calcineurin inhibitor levels were recorded with simultaneous MPA/MPAG levels. Correlation coefficients were derived between MMF dose and MPA/MPAG levels. Contingency analysis evaluated the relation between MPA level and EMB score. Twenty-six patients (median age 15.4 years) had 120 MPA/MPAG levels measured. Average MMF dose was 1208.8 mg/m2/d with median MPA and MPAG concentrations: 2.1 (therapeutic: 1.0-3.5 microg/mL) and 48 microg/mL (reference range: 35-100 microg/mL), respectively. Only 50% of patients consistently achieved therapeutic levels with standard dosing. No correlation was found between MMF dose and MPA/MPAG levels. In the presence of therapeutic calcineurin inhibition, EMB grade > or = 2 occurred more with MPA concentrations < 2.5 microg/mL (p = 0.01). In young OHT patients, MMF dose does not correlate with MPA/MPAG levels, and standard MMF dosing fails to consistently achieve 'therapeutic' MPA concentrations. An MPA trough level < 2.5 microg/mL was more frequently associated with EMB grade > or = 2. Concentration rather than dose-driven management is a more prudent strategy when using MMF.     

Inadequate Mycophenolic Acid Exposure and Acute Rejection in Kidney Transplantation

Introduction

The clinical utility of predose levels of mycophenolic acid (MPA) monitoring among patients treated with mycophenolate mofetil (MMF) has been questioned. The aim of this study was to evaluate the impact of adequate MPA levels in the incidence of acute rejection episodes among a cohort of kidney transplant recipients.

Material and Methods

In this retrospective study of 314 consecutive cases treated with tacrolimus, MMF, and steroids, evaluated 12-hour trough MPA samples during the first week as well as at 1, 3, 6, and 12 months as median values.

Results

During the first week, the median values of MPA were 1.6 μg/mL (p25-75 0.7-2.7 μg/mL) on mean doses of 1.84 ± 0.38 g/d. The incidence of acute rejection was 28%. The mean MPA levels during the first week were significantly lower among patients who developed rejection than in nonrejectors (1.5 ± 0.1 vs 2.1 ± 0.1 μg/mL; P < .001). There were no significant differences in trough tacrolimus levels between rejectors and nonrejectors (11.2 ± 0.4 vs 11.6 ± 1.2 μg/mL; P < .78). Logistic regression analysis showed that one of the predictive factors of acute rejection was a 12-hour trough MPA <1.6 μg/mL (relative risk [RR] 2.6; CI [confidence interval] 95% 1.6-4.3; P < .001).

Conclusions

Adequate MPA exposure is important to prevent acute rejection. Taking into account that the routine measurement of the area under the curve of MPA is impractical, at least the follow-up of trough MPA levels may help in the management of renal transplant recipients.     

Randomized crossover study to assess the inter‐ and intrasubject variability of morning mycophenolic acid concentrations from enteric‐coated mycophenolate sodium and mycophenolate mofetil in stable renal transplant recipients

Tedesco‐Silva H, Felipe CR, Park SI, Pinheiro‐Machado PG, Garcia R, Slade A, Schmouder R, Medina‐Pestana JO. Randomized crossover study to assess the inter‐ and intrasubject variability of morning mycophenolic acid concentrations from enteric‐coated mycophenolate sodium and mycophenolate mofetil in stable renal transplant recipients.
Clin Transplant 2010: 24: E116–E123.
© 2009 John Wiley & Sons A/S. Abstract: The delayed release of mycophenolic acid (MPA) from enteric‐coated mycophenolate sodium (EC‐MPS, myfortic^®) may have an impact on the variability of MPA trough (C_{0 h}) levels. A randomized, two‐period crossover study was performed in 24 maintenance renal transplants to evaluate the inter‐ and intrasubject variability of MPA predose levels from EC‐MPS and mycophenolate mofetil (MMF, CellCept^®), both in combination with cyclosporine. Patients received EC‐MPS (720 mg b.i.d.) and MMF (1000 mg b.i.d.) for a period of 21 d each. MPA plasma levels were measured over the final seven consecutive days at ?1, 0, 1, 2, and 3 h after the morning MPA dose. Intersubject coefficients of variation (%CV) for MPA troughs were 47.5% (95% CI, 34.1–80.3) and 54.4% (40.0–86.8) for EC‐MPS and MMF, respectively; intrasubject %CVs were 62.7% (55.1–72.9) and 42.8% (37.9–49.2). High MPA C_{0 h} levels >10 μg/mL were rarely observed with both EC‐MPS (1.8%) and MMF (0.6%). Mean MPA area under the curve (AUC)_{0–3 h} was comparable between treatments, while MPA C_{0 h} was on average 46% higher with EC‐MPS. In conclusion, predose MPA trough level monitoring appears of limited value during EC‐MPS and MMF therapy given the large intrasubject variability in MPA C_{0 h} levels with both treatments.     

Mycophenolic acid trough level monitoring: relevance in acute and chronic graft versus host disease and its relation with albumin

Hiwarkar P, Shaw BE, Tredger JM, Brown NW, Kulkarni S, Saso R, Evans S, Treleaven J, Davies FE, Ethell ME, Morgan GJ, Potter MN. Mycophenolic acid trough level monitoring: relevance in acute and chronic graft versus host disease and its relation with albumin.
Clin Transplant 2011: 25: 222–227. © 2010 John Wiley & Sons A/S. Abstract: Mycophenolate mofetil (MMF) is used to treat acute and chronic graft versus host disease (GvHD). There is scant evidence in the literature about mycophenolic acid (MPA) trough level monitoring in GvHD. We therefore reviewed 32 patients treated with MMF for acute (n = 19) or chronic GvHD (n = 13). Twelve (63%) of 19 patients with acute GvHD and nine (69%) of 13 with chronic GvHD showed a good response. In all 21 patients who responded to MMF, their mean total MPA levels were therapeutic (1–3.5 mg/L), whereas five of 11 patients who did not respond had sub‐therapeutic mean MPA levels (p = 0.002). Sixteen (66%) of 24 steroid refractory or dependent patients responded to MMF. Associations between the mean total MPA level for each patient and the corresponding mean serum albumin concentration showed therapeutic mean total MPA levels for all 23 patients with mean albumin ≥31 g/L but sub‐therapeutic mean total MPA levels in five of nine patients with mean albumin <31 g/L (p = 0.0006). In conclusion, MMF is efficacious in steroid refractory and dependent acute or chronic GvHD with statistically significant correlation between therapeutic plasma total MPA trough levels and clinical response. Serum albumin levels should be taken into account when considering MMF dose adjustments.     

Graft Outcome and Mycophenolic Acid Trough Level Monitoring in Kidney Transplantation

Background

Large inter- and intrapatient variabilities have been observed in the pharmacokinetics of mycophenolic acid (MPA). As a consequence, the efficacy and safety of mycophenolate mofetil (MMF) may be optimized with individualized doses based on therapeutic drug monitoring.

Materials and Methods

In this retrospective study we analyzed; 7536 12-hour trough MPA samples obtained during the first year posttransplantation among 314 kidney recipients treated with tacrolimus, MMF, and corticosteroids.

Results

Despite taking similar MMF doses, patients with delayed graft function (DGF) showed lower 12-hour trough MPA levels than patients without DGF 1.4 ± 0.1 vs 2.1 ± 0.1 μg/mL; P = .001). There was a significant correlation between 12-hour trough MPA levels and creatinine clearance (r = .32; P < .001). Logistic regression analysis showed that creatinine clearance was a predictive factor of adequate 12-hour trough MPA levels (>1.6 μg/mL) at 7 days posttransplantation. Twelve-hour trough MPA levels at 7 days posttransplantation were lower among patients who developed an acute rejecton episode (1.5 ± 0.1 vs 2.1 ± 0.1 μg/mL; P < .001), whereas those with gastrointestinal side effects showed high levels (4.1 ± 0.5 μg/mL).

Conclusions

In patients with delayed or poor graft function, MMF doses greater than 2 g/d may be necessary to achieve adequate MPA levels. Therapeutic drug monitoring of MPA may be useful to prevent acute rejection episodes or toxicity.     

A randomized double-blind, multicenter plasma concentration controlled study of the safety and efficacy of oral mycophenolate mofetil for the prevention of acute rejection after kidney transplantation.

BACKGROUND: Adding a fixed dose of 1 g b.i.d. of mycophenolate mofetil (MMF) to an immunosuppressive regimen consisting of cyclosporine and prednisone results in a 50% reduction in the incidence of acute rejection after kidney transplantation. This study was designed to investigate the relationship between pharmacokinetic data (mycophenolic acid area under the curve; MPA AUC) and the prevention of rejection after kidney transplantation. METHODS: A total of 154 adult recipients of a primary or secondary cadaveric kidney graft were randomly allocated, in this double-blind trial, to receive MMF treatment aimed at three predefined target MPA AUC values (16.1, 32.2, and 60.6 microg x hr/ml). During the first 6 months after transplantation, plasma samples for nine AUCs were collected. After analysis of the samples, a coded dose adjustment advice was generated using a Bayesian algorithm, maintaining the double blinding. Immunosuppressive therapy further consisted of cyclosporine and prednisone. The primary end point of this study was the occurrence of biopsy-proven acute rejection within the 6-month study period. RESULTS: A total of 150 patients were eligible for analysis. Although after day 21, the mean MMF dose was reduced, the mean MPA AUC gradually increased and target MPA AUC values were exceeded in all three groups. The incidences of biopsy-proven acute rejection in the low, intermediate, and high target MPA AUC groups were 14 of 51 (27.5%), 7 of 47 (14.9%), and 6 of 52 (11.5%), respectively. The incidences of premature withdrawal from the study due to adverse events in the three groups were 4 of 51 (7.8%), 11 of 47 (23.4%), and 23 of 52 (44.2%), respectively. Logistic regression analysis showed a highly statistically significant relationship between median ln(MPA AUC) and the occurrence of a biopsy-proven rejection (P<0.001). The logistic regression using median ln(Cpredose) was also statistically significant for this relationship (P=0.01), whereas it was not when using mean MMF dose (P=0.082). In contrast, the logistic regression using mean MMF dose for comparison of patients who successfully completed the study versus patients experiencing premature withdrawal due to adverse events was highly significant (P<0.001), whereas this was not significant when using median ln(Cpredose) (P=0.512) or median ln(MPA AUC) (P=0.434). CONCLUSION: MPA Cpredose and MPA AUC are significantly related to the incidence of biopsy-proven rejection after kidney transplantation, whereas MMF dose is significantly related to the occurrence of adverse events.     

Pharmacokinetics of intravenous mycophenolate mofetil after allogeneic blood stem cell transplantation

BACKGROUND: Mycophenolate mofetil (MMF) has shown synergistic effects in combination with cyclosporin A (CsA) in prevention of acute graft versus host disease (GvHD) after allogeneic blood stem cell transplantation (BSCT) in preclinical animal models. After having measured low plasma levels of the active metabolite mycophenolic acid (MPA) in recipients of allogeneic blood stem cell transplants after oral administration of MMF, we initiated a phase I/II study evaluating different dose levels of the intravenous (i.v.) formulation together with standard dose CsA. METHODS: A total of 15 patients received i.v. MMF in two split doses for 21 d after allogeneic BSCT from related (n=9) and unrelated (n=6) donors. Total daily doses of 25, 28, 31 and 34 mg/kg were investigated in 3-5 patients at each dose level. Plasma concentrations of MPA and its metabolite mycophenolic acid glucuronide (MPAG) were measured by high-performance liquid chromatography (HPLC). RESULTS: Mean trough blood levels of MPA ranged between 68.8 and 340 ng/mL with a median of 146.7 ng/mL. The mean MPA AUC0-12 h after first dose ranged between 19349+/-5087 ng * h/mL and 25705+/-3042 ng * h/mL and correlated with the dose level of MMF. The incidence of acute GvHD>grade I was 40%. No dose limiting toxicities were observed. CONCLUSIONS: The application of i.v. MMF is safe at a weight-adjusted dose between 25 and 34 mg/kg after allogeneic BSCT. The measured trough blood levels of MPA in patients after BSCT were ten times lower than in healthy volunteers. The toxicity induced by the conditioning therapy seems to negatively influence the pharmacokinetic behavior of MMF, MPA and MPAG.     

Pharmacokinetics of mycophenolate mofetil are influenced by concomitant immunosuppression

The recommended dosage for mycophenolate mofetil (MMF) in combination with cyclosporin (CyA) for pediatric kidney transplant recipients is 600 mg/m² twice daily (b.i.d.). We recently published pharmacokinetic (PK) profiles of MMF in combination with tacrolimus (FK506): in order to keep the mycophenolic acid (MPA) pre-dose trough concentration between 2 and 5 μg/ml and to avoid side effects, mean MMF doses were reduced to 300 mg/m² b.i.d.. In order to investigate whether this striking difference was due to alterations of MPA clearance by CyA or FK506, we analyzed PK profiles from 13 patients who received MMF without CyA or FK506, and compared these data with 14 patients who received a combination of MMF and FK506 and 15 patients who received MMF and CyA. Mean area under the curve (AUC) in all PK profiles was 61.9±23.8 μg×h/ml. Although the AUCs did not differ between the groups, the dose per square meter was significantly lower in patients receiving concomitant FK506 compared with CyA, and the dose-normalized AUC was significantly higher. The MMF doses were 1,158±301 mg/m² per day in the CyA group, 555±289 mg/m² per day in the tacrolimus group, and 866±401 mg/m² per day in the group without concomitant calcineurin inhibitor treatment. The apparent clearance of MPA is reduced in combination with tacrolimus. The reason for this remains unknown. There was a trend towards lower dose-normalized AUCs in the CyA group compared with the group without calcineurin inhibitor treatment. We conclude that concomitant medication alters the clearance of MPA. It is noteworthy that there was substantial interindividual variation, despite the rather marked differences between the groups, and therefore we recommend starting MMF in combination with CyA at a dose of 600 mg/m² b.i.d., in combination with tacrolimus at a dose of 300 mg/m² b.i.d., and without a calcineurin inhibitor at a dose of 500 mg/m² b.i.d., and adjusting doses using therapeutic drug monitoring of MPA. Received: 2 September 1998 / Revised: 7 January 1999 / Accepted: 7 January 1999     

Long-term follow-up of pediatric transplant recipients: mycophenolic acid trough levels are not a good indicator for long-term graft function

Abstract: Background: Mycophenolate mofetil (MMF) has the potential of decreasing acute rejection episodes early following renal transplantation. Pharmocokinetic monitoring of mycophenolic acid (MPA) trough levels is performed by many centers. MMF has also proved successful in improving long‐term graft function in patients with chronic allograft nephropathy (CAN). However, no data for long‐term monitoring of MPA in children have yet been published. Methods: MMF therapy with a dose of 600 mg/m² twice daily was initiated in 42 children (median age 9.4 yr, range 1.4–15.1) after a median period of 3.8 yr (range 1.0–10.6) post‐transplantation – according to significant increases in serum creatinine. CAN was diagnosed by renal biopsy and the amount of fibrosis was quantified with PicroSiriusRed staining. MMF therapy was combined with ciclosporin A and prednisolone. MPA‐C0‐levels, measured by high‐pressure liquid chromatography, were tested every 3 months. In 12 children a full MPA area under the curve concentration (AUC) was measured. The glomerular filtration rate (GFR) was calculated at the start of MMF therapy and 2 yr later. Results: After initiation of MMF, the calculated GFR did not decrease further in 22 children and mean GFR remained stable for 2 yr in the whole study group. There was a significant correlation between MPA levels 75 min after administration and the full AUC (r = 0.94, p < 0.001) but no correlation between trough levels and AUC (r = ?0.07, p > 0.05). The mean MPA trough level was 2.8 ± 1.3 ng/mL. The intra‐individual coefficient of variation was 2.6 ± 1.4. There was no correlation between mean MPA trough levels and GFR development after 2 yr (r = 0.03, p > 0.05). In children with an MPA level below 1.2 mg/L (n = 5), the mean GFR decline was no different to those with a higher level (p > 0.05). Conclusions: Drug monitoring of MPA trough levels had no impact on long‐term graft function in kidney recipients. MPA levels taken 75 min after administration showed a high correlation with MPA‐AUC whereas C0‐levels did not correlate. The value of C75 drug measurements for monitoring renal allograft survival will have to be judged in future studies.     

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

Cyclosporine (CyA) has made a great impact on 1-year allograft 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 μmol/l, lower than at the time of conversion (188 ± 100 μmol/l, 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/l (P = 0,0003, paired t-test). The CyA dosage was reduced from a mean of 150 ± 39 mg/m2 per day to 59 ± 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. Received: 20 April 1999 Revised: 9 January 2000 Accepted: 15 March 2000     

Mycophenolic acid levels in pediatric heart transplant recipients receiving mycophenolate mofetil.

BACKGROUND: Mycophenolate mofetil (MMF) is an immunosuppressive agent that has shown promise in adult patients who have undergone heart transplantation. There have been a number of studies of the pharmacokinetics of MMF in adult solid organ transplant recipients, but there is very little information in the pediatric population. The purpose of this study was to review our experience with MMF dosing and the role of mycophenolic acid (MPA) levels for therapeutic drug monitoring in a population of pediatric heart transplant recipients. METHODS: Data were obtained by review of the pediatric heart transplant database between November 1, 1997 and October 15, 1998. The data included all serum trough MPA levels, patient age, weight, height, indication for and dose of MMF, other medications, and details of all episodes of graft rejection. RESULTS: Forty-four patients (27 males) had a total of 128 serum trough MPA levels. Median age at transplant was 2.7 years (7 days to 18.4 years), and at time of review was 6.3 years (29 days to 23.5 years). MMF treatment was used for induction in 18 patients, induction and rejection in 23 patients and graft vasculopathy in 3 patients. Dosing by body surface area (mg/m(2)), age and interval from transplantation were all independently associated with MPA level. There was a trend toward requiring higher doses to achieve desired levels (>3 ng/ml) in younger patients. The average dose to achieve desired levels was higher in the immediate post-transplant period. There was a trend that MPA levels for a given dose were higher in patients on concurrent tacrolimus therapy. CONCLUSIONS: (1) There is marked individual variation in pharmacokinetics of MMF in pediatric patients; (2) dosing by body surface area may be advantageous; (3) higher MMF doses may be required at younger ages and in the early period after transplantation; (4) lower MMF doses may be required with concurrent tacrolimus therapy; and (5) serum trough MPA levels may relate to efficacy. Therefore, therapeutic drug monitoring of serum trough MPA levels may be required for individualized MMF dosing in pediatric cases.     

Daclizumab induction and maintenance steroid-free immunosuppression with mycophenolate mofetil and tacrolimus to prevent acute rejection of hepatic allografts

Steroid-free immunosuppressive regimens reduce corticosteroid-related side effects in liver transplant recipients although their efficacy is very variable. We evaluated the efficacy and safety of a steroid-free regimen in a 6-month, open-label, multicenter, pilot study, which involved 102 liver transplant patients treated with daclizumab (2 mg/kg within 6 h following transplant and 1 mg/kg on day 7), mycophenolate mofetil (MMF, 1 g b.i.d) and tacrolimus (trough levels of 5-15 ng/ml in the first month and 5-10 ng/ml thereafter). One intra-operative dose of methylprednisolone was administered. At 6 months, the acute rejection rate was 9.8%, and patient and graft survival rates were 96% and 95%, respectively. Acute rejection rates were similar for hepatitis C-positive patients (8.6%) and hepatitis C-negative patients (10.4%). Infections occurred in 22% of patients; most cases were considered mild or moderate. Post-transplantation hypertension and diabetes mellitus developed in 37% and 14% of patients, respectively, during the study period, but were markedly less frequent (8% and 6%, respectively) at 6 months. Hypercholesterolemia was observed in only 2% of patients. In conclusion, the steroid-free immunosuppressive regimen of daclizumab, MMF, and tacrolimus effectively prevents acute rejection after liver transplantation without decreasing safety.     

Randomized, International Study of Cyclosporine Microemulsion Absorption Profiling in Renal Transplantation with Basiliximab Immunoprophylaxis

Increasing information suggests that absorption profiling may be superior to trough level monitoring for optimal concentration control of cyclosporine microemulsion (Neoral^TM) therapy, and that CsA exposure early post‐transplant may correlate significantly with reduced risk of acute graft rejection. This randomized, prospective, multicenter international concentration‐controlled study was conducted in 21 renal transplant centers in 8 countries to test and compare the clinical feasibility, functionality, accuracy, precision and prediction of rejection by cyclosporine microemulsion absorption profiling to conventional trough‐level drug monitoring. Primary or second renal allograft recipients treated with basiliximab, cyclosporine microemulsion and prednisone immunosuppression were randomized to two study groups in which cyclosporine microemulsion therapy was monitored using a multipointalgorithm or by trough levels. The two study arms were comparable in terms of baseline characteristics, treatment and clinical outcomes. Treatment failure, consisting of acute rejection, graft loss or death, occurred with equal incidence in the two groups (30% and 33%, respectively). Diagnostic feasibility, measured as the proportion of samples obtained within the designated time window, was marginally lower in area under the time‐concentration curve (AUC) than in trough groups, but the therapeutic accuracy and precision were comparable or superior in the AUC group. Cox regression analysis performed across study groups showed a highly significant correlation between the predicted probability of acute rejection and cyclosporine (CsA) exposure measured by AUC over the entire 12‐h dosage interval (AUC[0–12]) (p = 0.0068), AUC over the first 4 h of the 12‐h dosage interval (AUC[0–4]) (p = 0.0014) or 2 h post‐dose (C2) CsA level (p = 0.0027). Day 3 dose‐ and weight‐corrected C2 values (EMIT equivalent) separated patients into low (< 200 μg/L/mg/kg dose), intermediate (200–350 μg/L/mg/kg dose) and high absorber categories (> 350 μg/L/mg/kg dose), defining those at greatest risk. Within these categories, C2 values above approximately 1500 μg/L by day 3 post‐transplant were associated with the lowest predicted probability of rejection. Comparable analysis by Cox regression using C0 levels did notreach statistical significance. Absorption profiling is a feasible, accurate and precise method for monitoring cyclosporine microemulsion therapy in clinical practice and, as shown in the companion article, may be simplified by the use of single‐point C2 concentrations which accurately predict individual AUC[0–4] exposure levels. Both cyclosporine microemulsion relative absorption (i.e. dose‐ and weight‐corrected exposure) and CsA exposure (measured by predicted AUC or C2 levels) are closely correlated with the risk of rejection, and define patients at high and low risk of acute graft rejection. Trough (C0) levels are not closely correlated with either CsA exposure or rejection risk, and should not be considered reliable for monitoring cyclosporine microemulsion therapy.     

The use of mycophenolate mofetil suspension in pediatric renal allograft recipients

Mycophenolate mofetil (MMF) is widely used to prevent acute rejection in adults after renal, cardiac, and liver transplantation. This study investigated the safety, tolerability, and pharmacokinetics of MMF suspension in pediatric renal allograft recipients. One hundred renal allograft recipients were enrolled into three age groups (33 patients, 3 months to <6 years; 34 patients, 6 to <12 years; 33 patients, 12 to 18 years). Patients received MMF 600 mg/m² b.i.d. concomitantly with cyclosporine and corticosteroids with or without antilymphocyte antibody induction. One year after transplantation, patient and graft survival (including death) were 98% and 93%, respectively. Twenty-five patients (25%) experienced a biopsy-proven (Banff grade borderline or higher) or presumptive acute rejection within the first 6 months post-transplantation. Analysis of pharmacokinetic parameters for mycophenolic acid (MPA) and mycophenolic acid glucuronide showed no clinically significant differences among the age groups. The dosing regimen of MMF 600 mg/m² b.i.d. achieved the targeted early post-transplantation MPA 12-h area under concentration-time curve (AUC_0–12) of 27.2 μg h per ml. Adverse events had similar frequencies among the age groups (with the exception of diarrhea, leukopenia, sepsis, and anemia, which were more frequent in the <6 years age group) and led to withdrawal of MMF in about 10% of patients. Administration of MMF 600 mg/m² b.i.d. is effective in prevention of acute rejection, provides predictable pharmacokinetics, and is associated with an acceptable safety profile in pediatric renal transplant recipients. Received: 7 May 2001 / Revised: 16 July 2001 / Accepted: 16 July 2001     

Correlation Between Mycophenolic Acid Blood Level and Renal Dysfunction in Stable Liver Transplant Recipients Receiving Mycophenolate Monotherapy

Purpose

Mycophenolate mofetil (MMF) is frequently used after liver transplantation (OLT). Mycophenolic acid (MPA) metabolites are eliminated primarily via the kidneys. If renal function declines, clearance is significantly impaired. The aim of this study was to reveal the renal function-dependent changes of MPA level in stable adult OLT recipients receiving MMF monotherapy.

Methods

Sixty-five OLT recipients were selected from our OLT database of >3500 cases. All had undergone MMF monotherapy with a daily MMF dose of 1000 mg or 1500 mg for more than 2 years, primarily because they could not tolerate calcineurin inhibitors. Their clinical profiles, including MPA therapeutic drug monitoring (TDM) and renal function, were analyzed as a cross-sectional study.

Results

For the group treated with 1000 mg MMF (n = 40), the 12-hour MPA trough level was 1.20 ± 0.35 μg/mL with serum creatinine (Cr) level ≤1.4 mg/dL in 13 patients; it was 2.78 ± 1.19 μg/mL with Cr >1.4 mg/dL in 16 patients not undergoing hemodialysis and 3.83 ± 0.87 μg/mL in 11 patients undergoing hemodialysis (P < .001). For the group treated with 1500 mg MMF (n = 25), the MPA trough level was 2.23 ± 0.99 μg/mL with Cr ≤1.4 mg/dL in 6 patients; it was 2.81 ± 0.99 μg/mL with Cr >1.4 mg/dL in 18 patients not undergoing hemodialysis and 3.5 μg/mL in 1 patient undergoing hemodialysis (P = .21).

Conclusions

Considering the potential therapeutic range of MPA, the suggested MMF dosage for Korean adult OLT recipients requiring hemodialysis may be set around 1000 mg per day. We suggest adjusting the MMF dosage on an individualized basis according to the results of MPA TDM, particularly for patients with markedly impaired renal function.