Abstract

Background. Exposure to mycophenolic acid (MPA), the primary active metabolite of mycophenolate mofetil (MMF), is correlated with therapeutic efficacy of MMF but varies depending on the concomitantly administered immunosuppressive drugs.

Methods. A 3-month pharmacokinetic substudy of the prospective, randomized, multicentre, open-label Symphony study was performed. Eighty-three adult renal transplant patients received standard-dose cyclosporine, MMF 2 g/day and corticosteroids, or daclizumab induction, MMF 2 g/day and corticosteroids plus low-dose cyclosporine, low-dose tacrolimus or low-dose sirolimus. The area under the concentration–time curve (AUC 0–12 ) of MPA and its metabolites between treatment groups was compared. Pharmacokinetic sampling was performed before MMF administration and at 20, 40, 75 min; 2, 3, 6, 8, 10 and 12 h post-dose on Day 7 and Months 1 and 3.

Results. Compared with standard-dose cyclosporine, patients receiving low-dose tacrolimus or low-dose sirolimus had significantly higher AUC 0–12 values for MPA at Day 7 and Month 1 and for free MPA at Day 7, and significantly lower AUC 0–12 values for 7-O-MPA-glucuronide (MPAG) at Month 1 and for acyl-glucuronide at Months 1 and 3 ( P < 0.05). AUC 0–12 of MPA and free MPA was significantly greater with low-dose tacrolimus and low-dose sirolimus than with low-dose cyclosporine in the first month ( P < 0.05). The ratio of MPA to MPAG exposure was significantly higher in the three low-dose groups than in the standard-dose cyclosporine group ( P < 0.05).

Conclusions. Standard- and low-dose cyclosporine reduces the exposure of MPA and free MPA compared to low-dose tacrolimus or low-dose sirolimus in patients given the same dose of MMF.

Introduction

Mycophenolate mofetil (MMF) is a highly effective immunosuppressant that does not adversely affect renal function and has been shown to have a nephroprotective effect in patients with chronic allograft nephropathy [ 1 ]. Consequently, MMF has become an integral component of toxicity-sparing regimens that seek to minimize or eliminate exposure to the nephrotoxic calcineurin inhibitors (CNIs).

MMF itself is not pharmacologically active: once MMF is absorbed, it is metabolized to mycophenolic acid (MPA), the major active metabolite. The pharmacokinetics and pharmacodynamics of MMF have been extensively previously reviewed [ 2 ]. Briefly, MPA is metabolized primarily to the pharmacologically inactive 7-O-MPA-glucuronide (MPAG), and to other minor metabolites, including the pharmacologically active acyl-glucuronide. MPA is eliminated as MPAG, which is excreted renally. Enterohepatic recirculation takes place; in the gut MPAG is deconjugated back into MPA, which is reabsorbed from the colon, producing a second peak in MPA plasma concentration that contributes to ∼40% of overall MPA exposure.

MPA exposure is correlated with therapeutic efficacy. MPA area under the concentration–time curve (AUC) values between 30 and 60 μg h/mL in the early post-transplant period reduces the risk of acute rejections [ 3 ]. When used in combination with cyclosporine in renal transplant recipients, the MPA AUC is correlated conversely with the likelihood of acute rejection [ 4 ]. It is therefore important to achieve optimal MPA exposure in order to optimize the transplant outcome. The large inter- and intra-patient variability of exposure to MPA in transplant recipients is not entirely understood, and many factors may also contribute, including race, renal function, albumin level, delayed graft function, concomitantly administered drugs [ 5 ] and polymorphisms of metabolic enzymes and multidrug resistance proteins [ 6,7 ].

When cyclosporine is coadministered with MMF in transplant patients, the plasma concentration or exposure of MPA is reduced [ 8–12 ] and MPAG concentration increased [ 8 , 12 , 13 ] compared with patients receiving MMF plus tacrolimus [ 8,9 , 13 ], or MMF plus sirolimus [ 10–12 , 14 ]. The differences in MPA concentration between these regimens have been attributed to the pharmacokinetic interaction between MPA and cyclosporine [ 11,12 , 15,16 ].

Daclizumab does not appear to interact with MMF or MPA [ 17 ]. Although corticosteroids were reported to reduce MPA exposure when given at high dosages (16 mg/day) in one study [ 18 ], a clinically or statistically significant relationship between steroid levels and the pharmacokinetics of MPA could not be demonstrated in another [ 5 ]. There are limited published data assessing MPA–sirolimus interactions, and additional studies are needed.

The Symphony study (trial registration: www. clinicaltrials.gov; study number: NCT00231764) compared the safety and efficacy of CNI-sparing regimens with a standard immunosuppression regimen in renal transplant patients [ 19 ]. As part of the overall Symphony study, a substudy was carried out to obtain data on the effect of the different immunosuppression regimens on the pharmacokinetics of MMF. In the Symphony study, long-term maintenance levels of calcineurin inhibitors or sirolimus (low doses) from the day of transplantation were compared with standard-dose cyclosporine. Our intention in this substudy was to assess whether these maintenance drug levels from the day of transplantation correlated with MPA exposure. We hypothesized that standard-dose cyclosporine would have the greatest impact on interaction with MPA exposure, low-dose cyclosporine less impact and tacrolimus/sirolimus the least impact.

Methods

This was a pharmacokinetic substudy conducted during the first 3 months of the Symphony study [ 19 ]. This substudy was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization—Good Clinical Practice Guidelines (ICH−GCP), and with the local ethical committee or institutional review board approval at each centre. All patients provided written informed consent before inclusion in the study. The criteria for patient selection and treatment allocation for the Symphony study have been described in detail elsewhere [ 19 ].

Pharmacokinetic assessments

Pharmacokinetic data were collected on Day 7, and Months 1 and 3 post-transplant. At each visit, 11 blood samples were collected before the first MMF administration of the day and up to 12 h post-dose [pre-dose (time 0)] and at 20, 40 and 75 min; and 2, 3, 4, 6, 8, 10 and 12 h post-dose. MPA, MPAG and acyl-glucuronide plasma levels were determined using high-performance liquid chromatography with UV detection following as previously described [ 20 ] with modification. Free MPA levels were determined using the Centrifree Micropartition® system (Amicon) following the methods of Nowak and Shaw [ 21 ]. Analysis of cyclosporine, tacrolimus and sirolimus exposures is referred to as the ‘third drug’ in this manuscript: whole blood cyclosporine and tacrolimus concentrations were measured using enzyme immunoassay EMIT® methods in a Cobas Mira autoanalyser (Dade-Behring, Palo Alto, CA, USA). Sirolimus levels were determined using high-performance liquid chromatography with tandem mass spectrometry according to the methods described by Brunet et al . [ 22 ]. All measurements were performed at the Laboratory of Pharmacology Hospital Clinic, Barcelona, Spain.

Statistical analyses

The primary objective of the pharmacokinetic substudy was to compare the exposure to MPA, MPAG, free MPA (MPA not bound to serum protein) and acyl-glucuronide, measured as the AUC 0–12 , between treatment groups. The secondary objectives were comparison of the effects of cyclosporine, tacrolimus and sirolimus on MPA maximum plasma concentration ( Cmax ), time to Cmax ( Tmax ) and trough concentration over time, and on the ratio of total MPA to free MPA exposure and the ratio of MPA to MPAG exposure; to find the relationship between selected MPA and MPA metabolite pharmacokinetic parameters at Day 7 and Month 1 with clinical outcomes including biopsy-proven acute rejection (BPAR), gastrointestinal-related adverse events, serum albumin levels and calculated creatinine clearance (using the Cockcroft–Gault formula [ 23 ]) at selected time points; and to find the correlation between MPA and free MPA AUC 0–12 with serum albumin levels and calculated creatinine clearance.

A sample size of 31 evaluable patients [assuming a 25% incidence of non-evaluable patients (defined as profiles with ≥2 adjacent or ≥3 non-adjacent data points missing)] per treatment group was calculated to provide at least 80% power to assure the two-sided significance level of 5% to detect a decrease of 25% in the AUC 0–12 of MPA under cyclosporine treatment. A profile was regarded as non-evaluable and discarded from the analysis if two adjacent or more than two non-adjacent points were missing or if it was considered non-evaluable.

The pharmacokinetic population was defined as all patients who had at least one MPA Cmax and AUC 0−12 value. The AUC 0–12 was calculated using the linear trapezoidal rule. Pre-dose plasma concentration ( C0 ) and Cmax were observed; Tmax was the time point, and Cmax was observed. All MPAG concentrations were expressed as MPA equivalents. For the analysis of pharmacokinetic interactions between drugs, Cmax and AUC 0–12 values for MPA and its metabolites, cyclosporine, tacrolimus and sirolimus were normalized by the dosage of the medication taken prior to blood sampling in the following way:  

formula
The same normalization was carried out for Cmax , unless stated otherwise.

Exploratory descriptive statistical analyses were conducted, using a two-sided test with statistical significance declared for P -values <5% (unless otherwise specified). Treatment comparisons were performed by an ANOVA model with the treatment group, MMF dosage and their interaction as effects. In the case of a significant treatment effect, pairwise comparisons were performed using Wilcoxon rank-sum tests. Univariate correlations between specific pharmacokinetic parameters and clinical outcomes were performed using Spearmann's coefficient of rank correlation as a measure of association. A general linear model was fitted to investigate the relationship between exposure of free MPA at Month 1, drug classes and clinical outcome parameters. All calculations were performed using SAS version 8.2.

Results

A total of 83 patients were enrolled from nine sites in Spain and Belgium; based on prior experience, this sample size was deemed sufficient to address the main question. Patient demographics were broadly similar across the groups at baseline (Table 1 ). The majority of patients were classified as having hypertension (68–94% of patients in each group).

Table 1

Patient demographic characteristics at baseline

 Standard-dose Low-dose Low-dose Low-dose 
 cyclosporine cyclosporine tacrolimus sirolimus 
  ( n = 17)   ( n = 21)   ( n = 20)   ( n = 25)  
Mean (± SD) age (years) 48.2 ± 9.22 49.9 ± 11.56 50.2 ± 14.87 45.7 ± 12.84 
Sex, M/F ( n )  10/7 14/7 14/6 14/11 
Mean (± SD) weight (kg) 64.7 ± 9.82 70.5 ± 14.58 72.0 ± 17.00 70.5 ± 14.82 
Mean (± SD) height (cm) 162.8 ± 11.53 164.3 ± 12.16 167.8 ± 10.83 165.3 ± 8.73 
Mean (± SD) body mass index 24.7 ± 4.63 26.0 ± 4.09 25.2 ± 4.31 25.6 ± 4.58 
Mean (± SD) serum albumin (g/L) 34.9 ± 17.6 36.4 ± 18.3 35.9 ± 20.7 33.6 ± 23.4 
Delayed graft function, yes/no ( n )  4/13 5/16 7/13 5/20 
 Standard-dose Low-dose Low-dose Low-dose 
 cyclosporine cyclosporine tacrolimus sirolimus 
  ( n = 17)   ( n = 21)   ( n = 20)   ( n = 25)  
Mean (± SD) age (years) 48.2 ± 9.22 49.9 ± 11.56 50.2 ± 14.87 45.7 ± 12.84 
Sex, M/F ( n )  10/7 14/7 14/6 14/11 
Mean (± SD) weight (kg) 64.7 ± 9.82 70.5 ± 14.58 72.0 ± 17.00 70.5 ± 14.82 
Mean (± SD) height (cm) 162.8 ± 11.53 164.3 ± 12.16 167.8 ± 10.83 165.3 ± 8.73 
Mean (± SD) body mass index 24.7 ± 4.63 26.0 ± 4.09 25.2 ± 4.31 25.6 ± 4.58 
Mean (± SD) serum albumin (g/L) 34.9 ± 17.6 36.4 ± 18.3 35.9 ± 20.7 33.6 ± 23.4 
Delayed graft function, yes/no ( n )  4/13 5/16 7/13 5/20 

By the end of the third month of treatment, 16 patients had withdrawn from the study. Nine patients were withdrawn because of a lack of pharmacokinetic data at Month 3. Among patients with 3-month measurements, withdrawals were a result of poor treatment compliance (four patients) or treatment failure due to discontinuation of assigned study drugs (three patients).

Study drug received

The MMF mean daily dose across the four treatments was 1680–1946 mg over the first 3 months of treatment. The cyclosporine mean daily dose on Day 7 was 425 mg (±133 mg) in the standard-dose group and 236 mg (±58 mg) in the low-dose group, which decreased to 222 mg (±81 mg) and 183 mg (±79 mg), respectively, by Month 3. These doses corresponded to median trough levels by Day 7, Month 1 and Month 3 of 292 ng/mL, 218 ng/mL and 164 ng/ mL for the standard-dose group, and 75.5 ng/mL, 109 ng/ mL and 80.5 ng/mL for the low-dose group, respectively. During the first 3 months, the tacrolimus and sirolimus mean daily doses were 4.3–5.8 mg and 2.9–3.5 mg, respectively (median trough levels by Day 7, Month 1 and Month 3: 8.1 ng/ mL, 7.7 ng/mL and 7.1 ng/mL, and 4.6 ng/mL, 7.5 ng/mL and 7.8 ng/mL, respectively). The mean actual exposure (AUC 0–12 ) to cyclosporine, tacrolimus or sirolimus as appropriate during the first 3 months in the high-dose cyclosporine, low-dose cyclosporine, tacrolimus and sirolimus groups were 4842.3–9230.7 ng h/mL, 2796.2–3601.6 ng h/mL, 129.3–152.3 μg h/mL and 134.1–160.9 μg h/mL, respectively.

MPA and MPAG metabolite pharmacokinetics

Compared with the standard-dose cyclosporine group, values for dose-normalized exposure to MPA were significantly higher for low-dose cyclosporine, low-dose tacrolimus and low-dose sirolimus groups at Day 7; for low-dose tacrolimus and low-dose sirolimus groups at Month 1 and for low-dose sirolimus at Month 3 (Table 2 ). Patients treated with low-dose tacrolimus or low-dose sirolimus had significantly higher exposure to free MPA compared with standard-dose cyclosporine at Day 7. Compared to the low-dose cyclosporine group, exposure to MPA and free MPA was also significantly greater in the low-dose tacrolimus group at Day 7 and Month 1, and in the low-dose sirolimus group at Month 1. Dose-normalized exposure to MPAG and acyl-glucuronide was significantly lower in patients in the low-dose cyclosporine, low-dose tacrolimus and low-dose sirolimus groups than in the standard-dose cyclosporine group at Month 1, and also at Month 3 for acyl-glucuronide. The difference in exposure to MPAG was also significant at Day 7 for low-dose sirolimus and Month 3 for low-dose tacrolimus (Table 2 ).

Table 2

Geometric mean area under the concentration–time curve from 0 to 12 h (μg h/mL) of MPA, free MPA, MPAG and acyl-glucuronide among four treatment groups of adult renal allograft recipients treated with oral MMF 2 g/day (primary endpoint)

 Standard-dose cyclosporine n Low-dose cyclosporine n Low-dose tacrolimus n Low-dose sirolimus n 
Day 7          
MPA 30.5 (28.9–32.2) 13  43.0 (41.4–44.6) * 17  64.7 (60.5–69.2) *,† 13  52.4 (50.7–54.3) * 21 
Free MPA 1.02 (0.97–1.08) 12 1.12 (1.07–1.17) 17  1.78 (1.67–1.90) *,† 13  1.40 (1.36–1.45) *,† 21 
MPAG 1722.3 (1609.0–1843.7) 13 1192.8 (1130.5–1258.4) 17 1404.1 (1307.3–1508.0) 13  915.58 (872.3–961.0) * 21 
Acyl-glucuronide 17.00 (15.74–18.36) 12 14.60 (13.56–15.72) 17 16.78 (15.43–18.25) 14 9.81 (9.07–10.61) 21 
Creatinine 2.7 (1.4–3.9) 13 2.7 (1.3–4.0) 17 2.6 (1.8—3.5) 14 2.5 (1.5–3.4) 21 
Creatinine clearance 38.7 (28.7–48.8) 13 46.2 (34.4–58.1) 17 42.0 (32.1–51.8) 14 47.0 (39.2–54.9) 21 
Month 1          
MPA 43.4 (41.4–45.5) 12 40.8 (39.3–42.3) 16  69.9 (66.8–73.1) *,† 15  67.5 (65.5–69.7) *,† 22 
Free MPA 1.07 (0.98–1.16) 10 0.93 (0.88–0.99) 15  1.44 (1.37–1.52)  14  1.42 (1.37–1.48)  22 
MPAG 1323.7 (1216.9–1439.9) 12  751.1 (713.5–790.5) * 16  751.9 (717.1–788.3) * 15  695.2 (667.0–724.5) * 22 
Acyl-glucuronide 16.14 (15.11–17.24) 11  9.45 (8.81–10.14) * 15  7.04 (6.46–7.66) * 14  7.09 (6.64–7.57) * 21 
Creatinine 1.6 (1.3–1.9) 13 1.6 (1.1–2.0) 17 1.3 (1.1–1.4) 15 1.4 (1.1–1.7) 22 
Creatinine clearance 48.6 (37.6–59.5) 13 58.0 (49.0–67.1) 17 62.6 (53.7–71.6) 15 67.4 (56.9–77.9) 22 
Month 3          
MPA 54.5 (51.6–57.5) 12 44.3 (42.6–46.1) 18 67.7 (64.9–70.7) 16  83.1 (79.4–86.9) *,† 19 
Free MPA 1.45 (1.35–1.57) 10 1.21 (1.17–1.25) 14 1.43 (1.33–1.53) 14  1.92 (1.80–2.06)  16 
MPAG 1054.5 (997.5–1114.8) 13 702.0 (664.4–741.8) 18  685.2 (639.1–734.6) * 16 758.5 (707.7–812.8) 19 
Acyl-glucuronide 21.36 (19.4–23.5) 12  9.08 (8.49–9.70) * 18  9.42 (8.75–10.14) * 15  11.66 (10.84–12.54) * 17 
Creatinine 1.7 (1.3–2.1) 13 1.5 (1.3–1.7) 18 1.3 (1.1–1.6) 17 1.5 (1.2–1.7) 19 
Creatinine clearance 55.9 (34.7–77.1) 13 61.1 (53.4–68.8) 18 69.2 (55.7–82.7) 17 58.6 (49.4–67.8) 19 
 Standard-dose cyclosporine n Low-dose cyclosporine n Low-dose tacrolimus n Low-dose sirolimus n 
Day 7          
MPA 30.5 (28.9–32.2) 13  43.0 (41.4–44.6) * 17  64.7 (60.5–69.2) *,† 13  52.4 (50.7–54.3) * 21 
Free MPA 1.02 (0.97–1.08) 12 1.12 (1.07–1.17) 17  1.78 (1.67–1.90) *,† 13  1.40 (1.36–1.45) *,† 21 
MPAG 1722.3 (1609.0–1843.7) 13 1192.8 (1130.5–1258.4) 17 1404.1 (1307.3–1508.0) 13  915.58 (872.3–961.0) * 21 
Acyl-glucuronide 17.00 (15.74–18.36) 12 14.60 (13.56–15.72) 17 16.78 (15.43–18.25) 14 9.81 (9.07–10.61) 21 
Creatinine 2.7 (1.4–3.9) 13 2.7 (1.3–4.0) 17 2.6 (1.8—3.5) 14 2.5 (1.5–3.4) 21 
Creatinine clearance 38.7 (28.7–48.8) 13 46.2 (34.4–58.1) 17 42.0 (32.1–51.8) 14 47.0 (39.2–54.9) 21 
Month 1          
MPA 43.4 (41.4–45.5) 12 40.8 (39.3–42.3) 16  69.9 (66.8–73.1) *,† 15  67.5 (65.5–69.7) *,† 22 
Free MPA 1.07 (0.98–1.16) 10 0.93 (0.88–0.99) 15  1.44 (1.37–1.52)  14  1.42 (1.37–1.48)  22 
MPAG 1323.7 (1216.9–1439.9) 12  751.1 (713.5–790.5) * 16  751.9 (717.1–788.3) * 15  695.2 (667.0–724.5) * 22 
Acyl-glucuronide 16.14 (15.11–17.24) 11  9.45 (8.81–10.14) * 15  7.04 (6.46–7.66) * 14  7.09 (6.64–7.57) * 21 
Creatinine 1.6 (1.3–1.9) 13 1.6 (1.1–2.0) 17 1.3 (1.1–1.4) 15 1.4 (1.1–1.7) 22 
Creatinine clearance 48.6 (37.6–59.5) 13 58.0 (49.0–67.1) 17 62.6 (53.7–71.6) 15 67.4 (56.9–77.9) 22 
Month 3          
MPA 54.5 (51.6–57.5) 12 44.3 (42.6–46.1) 18 67.7 (64.9–70.7) 16  83.1 (79.4–86.9) *,† 19 
Free MPA 1.45 (1.35–1.57) 10 1.21 (1.17–1.25) 14 1.43 (1.33–1.53) 14  1.92 (1.80–2.06)  16 
MPAG 1054.5 (997.5–1114.8) 13 702.0 (664.4–741.8) 18  685.2 (639.1–734.6) * 16 758.5 (707.7–812.8) 19 
Acyl-glucuronide 21.36 (19.4–23.5) 12  9.08 (8.49–9.70) * 18  9.42 (8.75–10.14) * 15  11.66 (10.84–12.54) * 17 
Creatinine 1.7 (1.3–2.1) 13 1.5 (1.3–1.7) 18 1.3 (1.1–1.6) 17 1.5 (1.2–1.7) 19 
Creatinine clearance 55.9 (34.7–77.1) 13 61.1 (53.4–68.8) 18 69.2 (55.7–82.7) 17 58.6 (49.4–67.8) 19 

MMF = mycophenolate mofetil; MPA = mycophenolic acid; MPAG = 7-O-MPA-glucuronide.

Values are dose-normalized; the 95% confidence interval limits are reported in parentheses.

*P < 0.05 versus standard-dose cyclosporine; P < 0.05 versus low-dose cyclosporine (between-group comparisons conducted with Wilcoxon rank-sum tests).

Creatinine clearance calculated using the Cockcroft–Gault formula.

Compared with the standard-dose cyclosporine group, MPA Cmax was significantly higher in the low-dose tacrolimus group at Day 7 and Month 1 and in the low-dose sirolimus group at Month 1. MPA trough levels did not differ significantly between the four treatment groups (Table 3 ).

Table 3

Key pharmacokinetic parameters of MPA a among the four treatment groups of adult renal allograft recipients treated with oral MMF 2 g/day (secondary endpoints)

 Standard-dose  Low-dose  Low-dose  Low-dose  
 cyclosporine n cyclosporine n tacrolimus n sirolimus n 
Day 7          
Cmax (μg/mL), mean (95% CI)  9.1 (8.5–9.7) 13 11.8 (11.3–12.4) 17  16.2 (15.1–17.4) * 15 13.2 (12.6–13.8) 21 
Tmax (min) , median (range)  120 (40–240) 13 74 (0–180) 17 75 (20–180) 15 40 (40–180) 21 
Trough level (μg/mL), median (range) b 0.8 (0.0–4.4) 13 1.4 (0.5–24.6) 17 2.1 (1.2–8.1) 15 2.4 (0.6–9.1) 21 
Month 1          
Cmax (μg/mL), mean (95% CI)  17.8 (16.4–19.3) 13 13.9 (13.3–14.4) 16  18.6 (17.2–20.0) * 15  21.5 (20.7–22.5) *,† 22 
Tmax (min) , median (range)  40 (20–720) 13 75 (20–180) 17 40 (20–240) 15 40 (20–720) 22 
Trough level (μg/mL), median (range) b 1.0 (0.0–2.7) 12 1.1 (0.0–2.3) 17 3.5 (0.3–13.1) 15 3.9 (1.3–11.8) 22 
Month 3          
Cmax (μg/mL), mean (95% CI)  20.7 (19.0–22.5) 13 14.6 (13.8–15.4) 18 22.2 (20.7–23.8) 17 20.8 (19.9–21.8) 19 
Tmax (min) , median (range)  75 (20–480) 13 75 (30–245) 18 57.5 (20–720) 16 40 (20–120) 19 
Trough level (μg/mL), median (range) b 0.9 (0.2–4.6) 12 1.6 (0.1–5.6) 18 1.7 (0.4–7.1) 17 4.5 (1.9–10.0) 19 
 Standard-dose  Low-dose  Low-dose  Low-dose  
 cyclosporine n cyclosporine n tacrolimus n sirolimus n 
Day 7          
Cmax (μg/mL), mean (95% CI)  9.1 (8.5–9.7) 13 11.8 (11.3–12.4) 17  16.2 (15.1–17.4) * 15 13.2 (12.6–13.8) 21 
Tmax (min) , median (range)  120 (40–240) 13 74 (0–180) 17 75 (20–180) 15 40 (40–180) 21 
Trough level (μg/mL), median (range) b 0.8 (0.0–4.4) 13 1.4 (0.5–24.6) 17 2.1 (1.2–8.1) 15 2.4 (0.6–9.1) 21 
Month 1          
Cmax (μg/mL), mean (95% CI)  17.8 (16.4–19.3) 13 13.9 (13.3–14.4) 16  18.6 (17.2–20.0) * 15  21.5 (20.7–22.5) *,† 22 
Tmax (min) , median (range)  40 (20–720) 13 75 (20–180) 17 40 (20–240) 15 40 (20–720) 22 
Trough level (μg/mL), median (range) b 1.0 (0.0–2.7) 12 1.1 (0.0–2.3) 17 3.5 (0.3–13.1) 15 3.9 (1.3–11.8) 22 
Month 3          
Cmax (μg/mL), mean (95% CI)  20.7 (19.0–22.5) 13 14.6 (13.8–15.4) 18 22.2 (20.7–23.8) 17 20.8 (19.9–21.8) 19 
Tmax (min) , median (range)  75 (20–480) 13 75 (30–245) 18 57.5 (20–720) 16 40 (20–120) 19 
Trough level (μg/mL), median (range) b 0.9 (0.2–4.6) 12 1.6 (0.1–5.6) 18 1.7 (0.4–7.1) 17 4.5 (1.9–10.0) 19 

Cmax = maximum plasma concentration; MMF = mycophenolate mofetil; MPA = mycophenolic acid; Tmax = time to Cmax .

*P < 0.05 versus standard-dose cyclosporine; P < 0.05 versus low-dose cyclosporine (between-group comparisons conducted with Wilcoxon rank-sum tests).

a To convert minutes to seconds, multiply by 60.

b Patients with a trough level below the assay quantification limit were set to zero.

Cmax values are dose-normalized and are geometric means.

There was no correlation between tacrolimus or sirolimus AUC 0–12 and dose-normalized MPA AUC 0–12 or free MPA AUC 0–12 , or between tacrolimus or sirolimus Cmax and dose-normalized MPA Cmax . Similar analyses with cyclosporine AUC 0–12 values (pooled data from both standard- and low-dose groups) showed no significant interactions with dose-normalized MPA AUC 0–12 or dose-normalized free MPA AUC 0–12 except for weak correlations with dose-normalized MPA AUC 0–12 at Day 7 and Month 1 [Spearman correlation coefficient ( r ) = −0.40 ( P = 0.036) and r = 0.48 ( P = 0.016), respectively] (Figure 1 ). Weak correlations between cyclosporine Cmax and dose-normalized MPA Cmax were also observed at Months 1 and 3 [ r = 0.39 ( P = 0.038) and r = 0.36 ( P = 0.048), respectively], and between cyclosporine Cmax and MPA trough levels at Month 3 [ r = −0.42 ( P = 0.021)].

Fig. 1

Scatter plots showing the correlation between CsA exposure and MPA exposure at ( A ) Day 7, ( B ) Month 1 and ( C ) Month 3 of the study.

Fig. 1

Scatter plots showing the correlation between CsA exposure and MPA exposure at ( A ) Day 7, ( B ) Month 1 and ( C ) Month 3 of the study.

The ratio of MPA to MPAG exposure was significantly higher on Day 7 and Month 1 in patients receiving low-dose cyclosporine, low-dose tacrolimus or low-dose sirolimus than in those receiving standard-dose cyclosporine (Table  4 ), with differences between the standard-dose cyclosporine group and the low-dose tacrolimus and low-dose sirolimus recipients still observed at Month 3 (all P <0.05 versus standard-dose cyclosporine). In contrast, there were no significant between-group differences in the ratio of MPA to free MPA exposure at any time point (data not shown).

Table 4

Ratio of MPA AUC 0–12 : MPAG AUC 0–12 among four treatment groups of adult renal allograft patients receiving MMF 2 g/day

 Standard-dose Low-dose Low-dose Low-dose 
 cyclosporine cyclosporine tacrolimus sirolimus 
Day 7  ( n = 13)   ( n = 17)   ( n = 13)   ( n = 21)  
 Median (range) 0.0156 (0.004–0.070)  0.0319 * (0.016–0.152)   0.0588 * (0.016–0.124)   0.0641 *,† (0.007–0.181)  
Month 1  ( n = 12)   ( n = 17)   ( n = 15)   ( n = 22)  
 Median (range) 0.0368 (0.015–0.075)  0.0477 * (0.028–0.206)   0.0758 *,† (0.051–0.241)   0.1024 *,† (0.033–0.305)  
Month 3  ( n = 12)   ( n = 18)   ( n = 16)   ( n = 19)  
 Median (range) 0.0458 (0.027–0.137) 0.0622 (0.018–0.277)  0.0919 *,† (0.049–0.286)   0.1187 * (0.035–0.499)  
 Standard-dose Low-dose Low-dose Low-dose 
 cyclosporine cyclosporine tacrolimus sirolimus 
Day 7  ( n = 13)   ( n = 17)   ( n = 13)   ( n = 21)  
 Median (range) 0.0156 (0.004–0.070)  0.0319 * (0.016–0.152)   0.0588 * (0.016–0.124)   0.0641 *,† (0.007–0.181)  
Month 1  ( n = 12)   ( n = 17)   ( n = 15)   ( n = 22)  
 Median (range) 0.0368 (0.015–0.075)  0.0477 * (0.028–0.206)   0.0758 *,† (0.051–0.241)   0.1024 *,† (0.033–0.305)  
Month 3  ( n = 12)   ( n = 18)   ( n = 16)   ( n = 19)  
 Median (range) 0.0458 (0.027–0.137) 0.0622 (0.018–0.277)  0.0919 *,† (0.049–0.286)   0.1187 * (0.035–0.499)  

AUC 0–12 = area under the concentration–time curve from 0 to 12 h; MMF = mycophenolate mofetil; MPA = mycophenolic acid; MPAG = 7-O-MPA-glucuronide.

*P < 0.05 versus standard-dose cyclosporine; P < 0.05 versus low-dose cyclosporine (between-group comparisons conducted with Wilcoxon rank-sum tests).

AUC 0–12 values are dose-normalized.

Correlation of MPA and metabolite pharmacokinetics with clinical outcomes

Analyses of the correlation between MPA pharmacokinetic variables and clinical and safety outcomes were conducted in all patients rather than a group-by-group basis. Mean dose-normalized MPA exposure on Day 7 and at Month 1 was not correlated with renal function at Month 3 [the estimated creatinine clearance using the Cockcroft–Gault formula at Month 3 was 26.8–130.8 mL/min (0.45– 2.18 mL/s/1.73 m 2 )]. However, dose-normalized free MPA AUC 0–12 at Day 7 was significantly negatively correlated with estimated creatinine clearance at Day 7 ( r  = −0.475; P < 0.001) and estimated creatinine clearance at Month 3 ( r = −0.436; P = 0.002), but not with estimated creatinine clearance at Month 1 ( r = −0.246; P = 0.07). Neither dose-normalized MPA AUC 0–12 nor free MPA AUC 0–12 values at Month 1 and Month 3 were correlated with serum albumin levels at Month 1 (35–50 g/L) and Month 3 (27–52 g/L), respectively.

Clinical outcomes and safety

No BPAR occurred in this 3-month substudy. Mild-to-moderate treatment-emergent gastrointestinal-related adverse events occurring after Day 7 and Month 1 were reported in 10 and 11 patients, respectively, and included diarrhoea, dyspepsia and vomiting. There was no significant relationship between MPA and acyl-glucuronide exposure or acyl-glucuronide Cmax on Day 7 and Month 1 and the occurrence of gastrointestinal adverse events after 7 days and after 1 month, respectively.

Mild-to-moderate haematological treatment-emergent adverse events occurred in 27 patients during the first 3 months of treatment, including anaemia, leukopenia, lymphadenopathy, nephrogenic anaemia, polycythaemia and thrombocytopenia. One patient suffered from severe leukopenia, which was reported as a serious adverse event.

Discussion

This pharmacokinetic substudy of Symphony was a prospective, longitudinal study with predefined drug target levels, and a relatively high number of patients in comparison with previous studies [ 8 , 10–12 ]. Patients received standard-dose cyclosporine, or daclizumab induction plus low-doses of cyclosporine, tacrolimus or sirolimus, all in addition to MMF and corticosteroids; exposure in the first month post-transplant to MPA and free MPA was generally significantly greater in those patients receiving concomitant low-dose tacrolimus or low-dose sirolimus than in those receiving standard- or low-dose cyclosporine. Although it has been suggested that the lower MPA exposure in the cyclosporine groups may contribute to the inferior clinical outcomes relative to the tacrolimus group in the main Symphony study [ 24 ], this is unlikely to be a major factor. For example, the outcomes in the sirolimus group where MPA exposure was similarly raised were discordant with those in the tacrolimus group [ 19 ]. Moreover, as the low doses of cyclosporine, tacrolimus and sirolimus retain their distinct and different toxicity profiles, it is likely that the MMF and daclizumab-based regimen containing low-dose tacrolimus and corticosteroids provided the best balance of efficacy and toxicity.

The observation of higher exposure to MPA with tacrolimus compared with cyclosporine is consistent with observations made by other groups [ 8,9 ] including paediatric patients [ 25 ]. Similar effects have also been documented when MMF is administered in combination with sirolimus [ 10–12 , 26 ]. A similar trend was apparent at Month 3, although not all differences reached statistical significance. Over the 3-month study period, MPA exposure increased markedly in the standard-dose cyclosporine and low-dose sirolimus groups, consistent with the AUC maturation process known to occur with MPA in the early post-transplantation period [ 27 ], but not in the low-dose cyclosporine and low-dose tacrolimus groups.

MPA trough levels have been reported to be higher in patients receiving MMF and tacrolimus [ 8 ] or sirolimus [ 11 ] than in those receiving MMF and cyclosporine in previous studies, which is consistent with our observations in the early post-transplant period although between-group differences were not significant in our study. In addition, the MPA trough levels were higher in the tacrolimus and sirolimus groups than those in the standard-dose cyclosporine groups by a larger factor than the respective difference between these treatment groups in AUC values. This finding suggests that trough levels cannot be used to estimate change in MPA exposure as expressed by AUC when comparing regimens including cyclosporine to cyclosporine-free regimens.

A strong correlation between cyclosporine exposure (AUC 0–12 ) and dose-normalized MPA exposure could not be demonstrated in our study. We would have expected that with a decrease in cyclosporine exposure, dose-normalized MPA exposure would have increased, because a negative correlation between these variables has been previously demonstrated in a study in paediatric renal transplant recipients, where the Pearson correlation coefficient was ( r2 ) 0.2258 ( P = 0.0220) [ 24 ]. Negative correlations have been reported between cyclosporine C0 values and MPA C0 values in two studies in adult patients [ 9 , 13 ], although these correlations were significant in only one study, and only between 3 and 6 months post-transplant [ 9 ].

As expected, there was no significant correlation between non-dose-normalized tacrolimus or sirolimus exposure and dose-normalized MPA or free MPA exposure up to 3-month treatment ( post hoc analyses). Similarly, there was no significant correlation between pre-dose concentrations of MPA and pre-dose concentrations of tacrolimus [ 9 , 13 ] or MPA level and tacrolimus trough levels [ 28 ] in other studies. Our study results support the current evidence that the differences in MPA exposure between patients receiving MMF plus cyclosporine and MMF plus tacrolimus are attributable to an interaction with cyclosporine [ 15 , 29 ], rather than with tacrolimus or sirolimus.

MPAG exposure was higher in the standard-dose cyclosporine group than in the low-dose cyclosporine group (at Month 1). This could explain, in part, the difference in the ratio of MPA exposure to MPAG exposure between the standard-dose and low-dose cyclosporine groups. Dose-dependent inhibition of the multidrug resistance protein-2 by cyclosporine [ 15,16 ] may be responsible for these different MPAG levels. The greater ratio of MPA exposure to MPAG in patients receiving MMF plus low-dose tacrolimus versus those receiving MMF plus standard-dose cyclosporine reflects changes in the levels of these metabolites that correspond with changes found in other studies, although whether the higher ratio was due to higher MPA or lower MPAG exposure is not clear. Zucker et al. [ 8 ] reported increased MPA and decreased MPAG levels in tacrolimus versus cyclosporine recipients, and Picard et al. [ 12 ] reported lower exposure to MPAG in patients receiving sirolimus and MMF than in those receiving cyclosporine and MMF.

The pharmacokinetics of MMF are altered in patients with impaired renal function [ 3 , 5 , 30 ]. We found a negative correlation between renal function and free MPA exposure, which is consistent with another study by Kuypers and others [ 27 ]. Exposure to total MPA was not correlated with renal function in our study, in contrast with one study [ 9 ], but in agreement with another study that also investigated the pharmacokinetics of MMF plus a low-dose CNI-based regimen [ 27 ]. van Hest et al. have shown that a change in total MPA exposure related to renal function occurs only at creatinine clearance <25 mL/min (0.41 mL/s/1.73 m 2 ) [ 5 ], and more recent results have demonstrated a duality in the effect of renal function on MPA exposure; in patients with moderately impaired renal function, MPA exposure is increased, while in patients with severely impaired renal function MPA clearance is increased, possibly due to an increase in the unbound fraction of MPA, resulting in a decrease in MPA exposure [ 31 ]. These studies may explain the divergence of findings between different studies.

We found no significant correlation between MPA or free MPA exposure and serum albumin levels although the range of albumin concentrations observed was rather small and may have precluded seeing a relationship. However, low serum albumin levels have been shown to be associated with a high percentage of free MPA (where percentage free MPA (%) = [free MPA exposure (mg h/L) / total MPA exposure (mg h/L)] ×100) [ 32 ]. Total MPA levels [ 9 , 28 ] or total MPA exposure [ 5 ] is positively correlated with serum albumin levels.

The relationship between exposure to MPA and acute rejection is already well accepted [ 3 ], but because no patients in our 3-month substudy experienced an acute rejection, examination of this relationship was not possible.

Previous studies have examined the association between MPA pharmacokinetic parameters and gastrointestinal or haematological adverse events. Different studies have produced contradictory results (reviewed by Staatz and Tett [ 2 ]). MPA has usually been the metabolite of interest in these studies. However, we investigated whether acyl-glucuronide exposure was predictive of the occurrence of gastrointestinal adverse events. Acyl-glucuronide is of particular interest because it has a proinflammatory effect in leukocytes [ 33 ], which may mediate the gastrointestinal toxicity associated with MMF. We were not able to find any significant correlation between acyl-glucuronide exposure and Cmax values with the occurrence of gastrointestinal adverse events. These data support another study that examined the relationship between acyl-glucuronide plasma concentration and the incidence of diarrhoea in renal transplant patients receiving MMF and cyclosporine or tacrolimus [ 34 ]. We suggest that it could be the concentration of acyl-glucuronide in the intestinal tract that contributes to this adverse effect, as suggested by overall Symphony study results, where the incidence of diarrhoea was highest in recipients of the tacrolimus-containing regimen [ 19 ].

Although our study provides interesting information on the pharmacokinetics of MPA following MMF administration in combination with maintenance levels of calcineurin inhibitors or sirolimus from the day of transplantation, it does have a number of limitations. As our study recruited a relatively small number of patients coupled with the high interindividual variability, the results presented should be interpreted in this context. In addition, since no acute rejection was reported in our study, it is possible that our results may not be applicable to those with acute rejection. Other limitations of our data included that patients recruited were predominantly Caucasian and that they received organs from deceased donors (unpublished data). Consequently, our data may not be generalizable to other transplant practices where there is a high proportion of living donors or where Blacks represent a significant proportion of the transplant population.

In conclusion, compared with recipients of MMF and standard-dose cyclosporine, patients treated with the same dose of MMF and low-dose tacrolimus or low-dose sirolimus had significantly higher MPA and free MPA exposure and lower MPAG and acyl-glucuronide exposure.

Funding for this study was provided by F. Hoffmann La–Roche Ltd. Editorial assistance was provided by Tracy Harrison and Richard Glover from Wolters Kluwer Health with the financial support of F. Hoffmann La–Roche Ltd. We would also like to acknowledge the support of Susana Traseira and Liliana Ercole from Roche Farma S.A, Spain, for critically reviewing the manuscript. Other investigators from Spain who participated in the Symphony substudy are Dr M. Gonzalez-Molina, Hospital Carlos Haya, Málaga; Dr F. Valdés, Hospital Juan Canalejo, La Coruña; Dr R. Lauzurica, Hospital Germans Trias i Pujol, Badalona; Dr M. Arias, Hospital Universitario Marqués de Valdecilla, Santander.

Conflict of interest statement . J.M.G. has received lecture and consulting fees from F. Hoffmann–La Roche Ltd. H.E. has received consulting fees from Hoffmann–La Roche Ltd, Novartis, Wyeth, Protein Design Lab, Life Cycle Pharma and Astellas and lecture fees from F. Hoffmann–La Roche Ltd and Astellas. R.D.M. has received consulting fees from F. Hoffmann-La Roche Ltd. D.H. has received study grants and speaker honoraria from Roche and Novartis. D.R.K. has received study grants and consultancy fees from Roche. M.A.G. has collaborated with Novartis, Roche and Astellas. J.S.-P. has received speaker honoraria from Roche, Novartis, Astellas and Wyeth. F.O. has received speaker honoraria from F. Hoffmann-La Roche Ltd, Novartis, Astellas, Wyeth and Fresenius. M.B. has no conflict of interest to disclose.

References

1
Gonzalez-Molina
MG
Seron
D
Del Moral
RG
, et al.  . 
Mycophenolate mofetil reduces deterioration of renal function in patients with chronic allograft nephropathy
Transplantation
 , 
2004
, vol. 
77
 (pg. 
215
-
220
)
2
Staatz
CE
Tett
SE
Clinical pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant recipients
Clin Pharmacokinet
 , 
2007
, vol. 
46
 (pg. 
13
-
58
)
3
Shaw
LM
Rosemarie
M
Nowak
I
, et al.  . 
Pharmacokinetics of mycophenolic acid in renal transplant patients with delayed graft function
J Clin Pharmacol
 , 
1998
, vol. 
38
 (pg. 
268
-
275
)
4
van Gelder
T
Hilbrands
LB
Vanrenterghem
Y
, et al.  . 
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
Transplantation
 , 
1999
, vol. 
68
 (pg. 
261
-
266
)
5
van Hest
RM
Mathot
RA
Pescovitz
MD
, et al.  . 
Explaining variability in mycophenolic acid exposure to optimize mycophenolate mofetil dosing: a population pharmacokinetic meta-analysis of mycophenolic acid in renal transplant recipients
J Am Soc Nephrol
 , 
2006
, vol. 
17
 (pg. 
871
-
880
)
6
Kuypers
DRJ
Naesens
M
Vermeire
S
, et al.  . 
The impact of uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) gene promoter region single-nucleotide polymorphisms T-275A and C-2152T on early mycophenolic acid dose-interval exposure in de novo renal allograft recipients
Clin Pharmacol Ther
 , 
2005
, vol. 
78
 (pg. 
351
-
361
)
7
Naesens
M
Kuypers
DRJ
Verbeke
K
, et al.  . 
Multidrug resistance protein 2 genetic polymorphisms influence mycophenolic acid exposure in renal allograft recipients
Transplantation
 , 
2006
, vol. 
82
 (pg. 
1074
-
1084
)
8
Zucker
K
Rosen
A
Tsaroucha
A
, et al.  . 
Unexpected augmentation of mycophenolic acid pharmacokinetics in renal transplant patients receiving tacrolimus and mycophenolate mofetil in combination therapy, and analogous in vitro findings
Transpl Immunol
 , 
1997
, vol. 
5
 (pg. 
225
-
232
)
9
Kuriata-Kordek
M
Boratynska
M
Falkiewicz
K
, et al.  . 
The influence of calcineurin inhibitors on mycophenolic acid pharmacokinetics
Transplant Proc
 , 
2003
, vol. 
35
 (pg. 
2369
-
2371
)
10
Buchler
M
Lebranchu
Y
Beneton
M
, et al.  . 
Higher exposure to mycophenolic acid with sirolimus than with cyclosporine treatment
Clin Pharmacol Ther
 , 
2005
, vol. 
78
 (pg. 
34
-
42
)
11
Cattaneo
D
Merlini
S
Zenoni
S
, et al.  . 
Influence of comedication with sirolimus or cyclosporine on mycophenolic acid pharmacokinetics in kidney transplantation
Am J Transplant
 , 
2005
, vol. 
5
 (pg. 
2937
-
2944
)
12
Picard
N
Premaud
A
Rousseau
A
, et al.  . 
Comparison of the effect of ciclosporin and sirolimus on the pharmacokinetics of mycophenolate in renal transplant patients
Br J Clin Pharmacol
 , 
2006
, vol. 
62
 (pg. 
477
-
484
)
13
Naito
T
Shinno
K
Maeda
T
, et al.  . 
Effects of calcineurin inhibitors on pharmacokinetics of mycophenolic acid and its glucuronide metabolite during the maintenance period following renal transplantation
Biol Pharm Bull
 , 
2006
, vol. 
29
 (pg. 
275
-
280
)
14
El Haggan
W
Ficheux
M
Debruyne
D
, et al.  . 
Pharmacokinetics of mycophenolic acid in kidney transplant patients receiving sirolimus versus cyclosporine
Transplant Proc
 , 
2005
, vol. 
37
 (pg. 
864
-
866
)
15
Hesselink
DA
Van Hest
RM
Mathot
RAA
, et al.  . 
Cyclosporine interacts with mycophenolic acid by inhibiting the multi-drug resistance-associated protein 2
Am J Transplant
 , 
2005
, vol. 
5
 (pg. 
987
-
994
)
16
Kobayashi
M
Saitoh
H
Kobayashi
M
, et al.  . 
Cyclosporin A, but not tacrolimus, inhibits the biliary excretion of mycophenolic acid glucuronide possibly mediated by multidrug resistance-associated protein 2 in rats
J Pharmacol Exp Ther
 , 
2004
, vol. 
309
 (pg. 
1029
-
1035
)
17
Pescovitz
MD
Bumgardner
G
Gaston
RS
, et al.  . 
Pharmacokinetics of daclizumab and mycophenolate mofetil with cyclosporine and steroids in renal transplantation
Clin Transplant
 , 
2003
, vol. 
17
 (pg. 
511
-
517
)
18
Cattaneo
D
Perico
N
Gaspari
F
, et al.  . 
Glucocorticoids interfere with mycophenolate mofetil bioavailability in kidney transplantation
Kidney Int
 , 
2002
, vol. 
62
 (pg. 
1060
-
1067
)
19
Ekberg
H
Tedesco-Silva
H
Demirbas
A
, et al.  . 
Reduced exposure to calcineurin inhibitors in renal transplantation
N Engl J Med
 , 
2007
, vol. 
357
 (pg. 
2562
-
2575
)
20
Brunet
M
Cirera
I
Martorell
J
, et al.  . 
Sequential determination of pharmacokinetics and pharmacodynamics of mycophenolic acid in liver transplant patients treated with mycophenolate mofetil
Transplantation
 , 
2006
, vol. 
81
 (pg. 
541
-
546
)
21
Nowak
I
Shaw
LM
Mycophenolic acid binding to human serum albumin: characterization and relation to pharmacodynamics
Clin Chem
 , 
1995
, vol. 
41
 (pg. 
1011
-
1017
)
22
Brunet
M
Campistol
JM
Diekmann
F
, et al.  . 
T cell function monitoring in stable renal transplant patients treated with sirolimus monotherapy
Mol Diagn Ther
 , 
2007
, vol. 
11
 (pg. 
247
-
256
)
23
Cockcroft
DW
Gault
MH
Prediction of creatinine clearance from serum creatinine
Nephron
 , 
1976
, vol. 
16
 (pg. 
31
-
41
)
24
Ekberg
H
Halloran
P
Reduced exposure to calcineurin inhibitors in renal transplantation
N Engl J Med
 , 
2008
, vol. 
358
 (pg. 
2518
-
2520
)
25
Filler
G
Zimmering
M
Mai
I
Pharmacokinetics of mycophenolate mofetil are influenced by concomitant immunosuppression
Pediatr Nephrol
 , 
2000
, vol. 
14
 (pg. 
100
-
104
)
26
Pescovitz
MD
Vincenti
F
Hart
M
, et al.  . 
Pharmacokinetics, safety, and efficacy of mycophenolate mofetil in combination with sirolimus or ciclosporin in renal transplant patients
Br J Clin Pharmacol
 , 
2007
, vol. 
64
 (pg. 
758
-
771
)
27
Kuypers
DRJ
Vanrenterghem
Y
Squifflet
JP
, et al.  . 
Twelve-month evaluation of the clinical pharmacokinetics of total and free mycophenolic acid and its glucuronide metabolites in renal allograft recipients on low dose tacrolimus in combination with mycophenolate mofetil
Ther Drug Monit
 , 
2003
, vol. 
25
 (pg. 
609
-
622
)
28
Borrows
R
Chusney
G
James
A
, et al.  . 
Determinants of mycophenolic acid levels after renal transplantation
Ther Drug Monit
 , 
2005
, vol. 
27
 (pg. 
442
-
450
)
29
van Gelder
T
Klupp
J
Barten
MJ
, et al.  . 
Comparison of the effects of tacrolimus and cyclosporine on the pharmacokinetics of mycophenolic acid
Ther Drug Monit
 , 
2001
, vol. 
23
 (pg. 
119
-
128
)
30
Kaplan
B
Meier-Kriesche
HU
Friedman
G
, et al.  . 
The effect of renal insufficiency on mycophenolic acid protein binding
J Clin Pharmacol
 , 
1999
, vol. 
39
 (pg. 
715
-
720
)
31
Naesens
M
de Loor
H
Vanrenterghem
Y
, et al.  . 
The impact of renal allograft function on exposure and elimination of mycophenolic acid (MPA) and its metabolite MPA 7-O-glucuronide
Transplantation
 , 
2007
, vol. 
84
 (pg. 
362
-
373
)
32
Atcheson
BA
Taylor
PJ
Kirckpatrick
CM
Free mycophenolic acid should be monitored in renal transplant recipients with hypoalbuminemia
Ther Drug Monit
 , 
2004
, vol. 
26
 (pg. 
284
-
286
)
33
Weiland
E
Shipkova
M
Schellhaas
U
, et al.  . 
Induction of cytokine release by the acyl glucuronide of mycophenolic acid: a link to side effects?
Clin Biochem
 , 
2000
, vol. 
33
 (pg. 
107
-
113
)
34
Heller
T
van Gelder
T
Budde
K
, et al.  . 
Plasma concentrations of mycophenolic acid acyl glucuronide are not associated with diarrhea in renal transplant recipients
Am J Transplant
 , 
2007
, vol. 
7
 (pg. 
1822
-
1831
)

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