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Articles |
Departments of
1
Kidney and Pancreas Transplantation and
2
Clinical Chemistry, University Hospital Saint Luc, Université Catholique de Louvain, Avenue hippocrate, 10, 1200 Brussels, Belgium.
a Author for correspondence. Fax 32-2-770-78-58;
Michel.Mourad{at}chir.ucl.ac.be
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Methods: Thirty-one adult kidney recipients were prospectively included in the study. MPA pharmacokinetic profiles (blood sampling at 0, 0.5, 1, 2, 4, 6, and 12 h after MMF oral dose) were obtained after transplantation (desired creatinine clearance, 40 mL/min), at 3 months after grafting, and at every clinical event (e.g., side effect or rejection). All patients received a 10-day course of anti-thymocyte globulin, cyclosporine, MMF (1 g twice daily), and steroids.
Results: We divided the 31 patients into two groups (groups 1 and 2). Ten patients (32%; group 1) had uneventful outcomes, and 21 patients (68%; group 2) presented with MPA-related side effects. For groups 1 and 2, the MPA trough concentrations (Cmin) were 1.63 ± 1.07 and 2.29 ± 1.16 mg/L, respectively (P = 0.06), and the areas under the curve (AUCs) for MPA from t0 to t12 h (MPA-AUC0–12h) were 39.80 ± 15.29 and 62.10 ± 21.07 mg · h/L, respectively (P = 0.0005, two-sample t-test). Three patients experienced acute graft rejection after the oral MMF dose was reduced because of side effects. In this group, the MPA-Cmin and MPA-AUC were significantly lower by the time acute rejection occurred (1.00 ± 0.45 mg/L and 25.00 ± 6.20 mg · h/L, respectively). At a fixed dose (1 g twice per day), we compared the pharmacokinetic parameters of MPA [Cmin, the MPA concentration 30 min after the oral dose of MMF (C30), and AUC] according to the presence or absence of side effects in the two groups. Cmin and AUC did not differ between the two groups [Cmin = 2.22 ± 1.13 vs 2.17 ± 1.13 mg/L (P = 0.9); AUC = 66.82 ± 29.87 vs 55.70 ± 11.74 mg · h/L (P = 0.11)]; and C30 was significantly higher in group 2 than in group 1 (C30 = 32.99 ± 12.59 vs 7.45 ± 5.40 mg/L; P <0.0001).
Conclusions: Our results demonstrate a pharmacokinetic/pharmacodynamic relationship between MPA and clinical events. At a fixed dose of 2 g/day, a high C30 is associated with increased risk for side effects. This study suggests that dividing the MMF daily oral dose into more than two divided doses might prevent early MPA toxicity.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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MPA can cause toxicity, mainly of hematologic and/or gastrointestinal nature (1)(2)(3)(6). Some pharmacokinetic/pharmacodynamic (PK/PD) relationships have already been reported (6)(7). Patients with low areas under the curve for MPA (MPA-AUC) appear to be at high risk for experiencing graft rejection (7), whereas high-target AUC concentrations can increase toxicity (6). Considerable individual variability in pharmacokinetic (PK) parameters has been observed in adult and pediatric kidney recipients (8). In view of individual variability, toxicity, and the PK/PD relationship, therapeutic drug monitoring using different analytical methods, such as HPLC (9) or the Emit® assay (Dade-Behring) (10), is becoming mandatory. To optimize clinical results, we have introduced into our practice MPA therapeutic drug monitoring using the Emit methodology, which offers the opportunity to determine both MPA and the M-2 active metabolite. With this method, the immunoassay better reflects the total immunosuppressive effect of MMF than HPLC (11). Our preliminary results with the Emit assay confirm the previously reported satisfactory analytical performance (12).
To gain insight into the safety of using MMF, this prospective study was designed to further investigate the relationship between clinical events (side effects and rejection) and the MPA PK parameters in adult kidney patients receiving cyclosporine-based quadruple immunosuppression in conjunction with a fixed MMF dose (2 g/day).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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immunosuppression
All patients received a quadruple immunosuppressive regimen. A
10-day course of anti-thymocyte globulin induction therapy (ATG
Fresenius, 4
mg · kg-1 · day-1)
was used in combination with cyclosporine
(Neoral®, 5–10
mg · kg-1 · day-1)
in two divided doses and steroids tapered down to 5 mg by 3 months.
Neoral administration was controlled by cyclosporine whole-blood,
trough-concentration monitoring using the AxSYM methodology (Abbott)
and was adjusted to a target therapeutic window of 120–150 µg/L
during the first 3 months after transplantation and 100–120 µg/L
thereafter. MMF (CellCept; Roche) was administrated twice daily at a
fixed dose of 2 g/day, starting at the first morning after
transplantation. The oral MMF dose was adjusted according to drug
tolerance and related side effects.
study design and pk assessments
A total of 93 MPA PK profiles were analyzed. MPA (PK) profiles
were systematically obtained at steady state, early after
transplantation, ideally when creatinine clearance reached 40 mL/min,
and at 3 months after transplantation. Profiles were also obtained when
suspected MMF-related side effects or rejection occurred. Each PK
profile consisted of blood samples (n = 7) obtained in EDTA tubes
at trough (predose) concentrations
(Cmin) and at 30 min
(C30) and at 1
(C60), 2, 4, 6 and 12 h after the
morning MMF dose. All plasma samples were stored at -18 °C during
the study period after blood centrifugation for 5 min at
2500g. Samples were analyzed retrospectively using a
semiautomated immunoassay based on the Emit on the Cobas Mira Plus
analyzer. Hematological side effects were defined according to the
following criteria: white blood cells <3 x
101
/µL, hemoglobin <70 g/L, and platelets
<100 x 101
/µL. For upper abdominal
complaints, an esophagogastroduodenoscopy was performed. In case of
diarrhea, a bacteriologic examination of stools was considered. The MPA
AUCs from t0 to
t12 h (AUC0–12)
were calculated at steady state using the linear trapezoidal rule up to
the last measured plasma concentration drawn 12 h after drug
administration, according to the following equation:
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statistical methods
JMP 3.2 (SAS Institute) and Excel 97 (Microsoft) were used for
statistics, calculations, and graphic interfaces. To compare the
Cmin and AUC between patients
experiencing and not experiencing side effects, we used the two-sided
t-test for comparison of means. For other comparisons, a
paired t-test was used. Outliers were eliminated with the
box-plot if statistical evidence or other reasonable evidence was
present. The normality of the distribution was checked with the
Kolmogorov-Smirnoff test. If the normality assumption of populations
could not be made (P <0.05), logarithmic transformation or
inverse original values were used, outliers were eliminated, and
normality was again verified. Even when normality could not be achieved
this way, we kept the results from parametric tests. When we compared
these results with those obtained with the Wilcoxon signed-rank test,
no difference could be detected. The reported P values are
those of P >|t| (i.e., the probability of
obtaining a greater absolute t value by chance alone if
there is no difference between pairs or sample means). This is the
P for observed significance of the two-tailed
t-test. The alpha concentration was set at 0.05 for all
analyses.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, 42% of patients experienced a reduction of the daily
MMF dose because of side effects.
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Of the 31 patients, 10 did not experience side effects. In the remaining 21 patients, 25 episodes of side effects occurred during the study evaluation up to the third posttransplantation month. Side effects included 15 episodes of leukopenia, 7 of severe anemia, 1 of diarrhea, 1 episode of esophagitis, and 1 episode of thrombocytopenia. At a fixed dose of 2 g/day, one patient presented with acute rejection (borderline according to Banff classification) with a below-therapeutic cyclosporine trough concentration (66 µg/L, as measured by the AxSYM). Three rejection episodes occurred in three other patients when the MMF dose was reduced because of side effects (leukopenia). In these patients, cyclosporine trough concentrations were within therapeutic range (mean, 116 µg/L as measured by the AxSYM).
relationships between mpa serum concentrations and clinical events
The mean plasma Cmin and AUC
obtained from patients who demonstrated either MMF toxicity or
biopsy-confirmed acute rejection and from patients who presented with
no side effects are shown in Table 2
. Both the Cmin and AUC were
increased in the group of patients who experienced side effects
compared with the patients who had uneventful outcomes, but the
increase was statistically significant only for AUC (62.10 ±
21.07 vs 39.80 ± 15.29 mg · h/L; P =
0.0005). In the group of patients who experienced biopsy-confirmed
acute rejection, the Cmin and AUC were
lower than in the patients with uneventful outcomes, but the number of
samples did not allow statistical comparisons.
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mpa plasma trough concentrations and auc evolution over time
The Cmin and AUC for the early
posttransplantation period and at 3 months after transplantation are
compared in Table 3
. Both the Cmin and AUC in
patients receiving a fixed dose (1 g twice a day) displayed a
progressive increase during the first 3 months after transplantation.
Nevertheless, only the AUC values are statistically significantly
different between these two periods (P = 0.01). This is
probably because the small data set for the trough concentrations lacks
sufficient statistical power.
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pk profiles analysis
Individual MPA plasma concentration profiles in patients receiving
1 g of MMF twice a day are represented on Fig. 1
. Individual variability occurred mainly during the early
postdose period. MPA concentrations at 30 min displayed the
largest variability. When individual MPA plasma-concentration profiles
(0–12 h) are considered according to the occurrence of side effects,
high and low C30 profiles will be
obtained. Fig. 2
represents the mean MPA concentration (with SD) at each time
point of the PK profiles in the groups that did or did not experience
side effects. The comparison of mean
Cmin,
C30, and AUC according to the
occurrence of side effects are represented in Table 4
. As shown, the peak MPA concentration
(C30) correlates better than
Cmin and AUC with side effects in
patients receiving 1 g twice a day (P <0.0001; Table 4
).
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correlations between Cmin,
C30, C60,AND AUC
The correlations among Cmin,
C30,
C60, and AUC0–12
h are shown in Fig. 3
. The data used are those collected from PK profiles obtained
during the entire study period, including both the early and 3-month
posttransplant profiles, regardless of whether the patients received
two 1-g doses a day or less. The linear correlation coefficients were
0.62, 0.77, and 0.68, respectively.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Data from a Japanese study in which MMF was administered at doses of 1, 2, 3 or 4 g/day showed an increase of MPA-AUC with dose (7). In patients with low MPA-AUCs, acute rejection was more frequent than in those with high MPA-AUCs. The same study demonstrated the relatively poorer predictive value of the Cmin compared with AUC (7). In the Randomized Concentration Controlled Study (RCCT) on the safety and efficacy of MMF, the technical (13) and clinical (6) aspects of which were published recently, the authors clearly demonstrated that both the MPA-Cmin and MPA-AUC are associated with the incidence of acute rejection but not with side effects.
In our study, both the MPA-Cmin and MPA-AUC were higher in patients who presented with side effects than in those with uneventful outcomes; however, only MPA-AUC reached statistical significance. Moreover, at a fixed dose (2 g/day), the MPA concentration at 30 min (MPA-C30) was significantly associated with an increased risk of side effects. High MPA-C30 values would explain the occurrence of side effects in patients with MPA-AUCs within nontoxic limits. In contrast, the RCCT study showed that MMF safety is related more to the oral dose than to the MPA PK parameters [Cmin, maximum concentration (Cmax), and AUC]. However, it should be mentioned that in the RCCT study, there was a distinct preponderance of gastrointestinal side effects compared with other MMF-related adverse events, such as hematologic disorders. Furthermore, the withdrawal rate from the RCCT study was related to oral dose only for gastrointestinal side effects and not for all adverse events. These three trials of the safety and/or efficacy of MMF differ from each other by their design: the controlled variable in the Japanese study was the oral dose, whereas it was the target AUC in the RCCT trial and the drug tolerance at a fixed dose the current prospective study.
As indicated in experimental studies in rats (14), MMF is stable in artificial digestive fluid, whereas it is rapidly hydrolyzed to MPA by esterase in plasma and tissue homogenates. The conversion rate is higher in liver homogenates than in plasma, and is higher in plasma than in the small-intestine epithelial cells. On the basis of our results, we would suggest that the rate at which MMF is hydrolyzed by epithelial cells, plasma esterases, or both varies among individual patients and that patients in whom MMF is hydrolyzed more rapidly would thus be exposed to early toxic concentrations of MPA after oral administration of MMF. From a practical point of view, these results would postulate the beneficial effect of dividing the oral daily dose of MMF (2 g/day) into more than two doses to avoid early toxic concentrations of MPA. We think that this latter administration modality should be tested on the basis of a prospective clinical trial.
Therapeutic MMF monitoring should take into account factors that may
affect MMF absorption, MPA metabolism, and the MPA free-fraction
rate. The use of antacids decreases both the MPA-AUC and
MPA-Cmax by decreasing MMF absorption
(15). The intake of food also influences the PK of MMF,
decreasing the MPA-Cmax by 
25%,
without affecting MPA-AUC (15). An increase in
MPA-Cmin and MPA-AUC when tacrolimus
is used in conjunction with MMF has been already reported
(16). In addition, the MPAG-AUC is lower in patients
receiving tacrolimus in combination with MMF than in patients
receiving cyclosporine in combination with MMF at the same dose of 2
g/day. Recently, it has been demonstrated that cyclosporine affects the
MPA-Cmin, which is lower in patients
receiving cyclosporine than in patients not receiving cyclosporine at
the same MMF dose, showing less interindividual variation
(17). Metabolic interactions among cyclosporine, tacrolimus,
and MMF are still not clearly understood. These interactions are
probably not attributable to the hydrolysis of MMF, which is extremely
rapid and almost totally achieved by esterases, but could be related to
a possible inhibitory effect of tacrolimus on MPA metabolism or to
acceleration of MPA metabolism by cyclosporine.
Human serum albumin, high concentrations of the primary glucuronide metabolite of MPA (MPAG), and high doses of sodium salicylate significantly affect albumin MPA binding (18). Because early acute renal dysfunction after transplantation (i.e., acute tubular necrosis) is a frequent complication and renal function remains poor during the first days after grafting, a study of PK parameters is of particular interest during this period. Previous studies showed an accumulation of MPAG related to renal dysfunction (19), leading to an increase in the MPA free fraction, presumably by a competitive displacement mechanism. Special care was taken in our prospective study regarding fasting, concomitant medication, and renal function to avoid interference with determining PK parameters.
At a fixed dose (2 g/day), the MPA-AUC 0–12 h displays a progressive significant increase during the first 3 months after transplantation, suggesting a change in the MPA PK during this period. There was also a tendency for trough concentrations to rise over time, up to the third month, but the results were not statistically significant. These changes have been described previously in adult (6) and pediatric (20) renal transplant populations and are of multifactorial origin. The increase in MPA-AUC is the result of a decrease in MPA clearance and metabolism, which is supported by the fact that MPA free fraction decreases over time (20). Factors influencing MPA metabolism may include protein binding (21), changes in enterohepatic recirculation, and induction of hepatic glucuronyl transferase activity by glucocorticoids (22), which are usually taken at high doses early after transplantation and tapered off thereafter.
In conclusion, analysis of MPA plasma concentrations in adult kidney transplant recipients treated with a fixed dose of oral MMF (2 g/day) revealed a PK/PD relationship for MPA in this prospective study of drug tolerance. Early plasma concentrations, especially at 30 min after the oral dose, seem to correlate better than MPA-AUC0–12 h with side effects. These results would suggest a beneficial effect of dividing the oral dose into more than two daily doses. Moreover, additional studies are needed to confirm the role of both Cmin and the early MPA concentration (at 30 min) in predicting the safety and efficacy in daily practice for selected patients.
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Acknowledgments |
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Footnotes |
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
) and not experiencing (
) side
effects.