NDT Advance Access originally published online on September 9, 2008
Nephrology Dialysis Transplantation 2008 23(11):3386-3388; doi:10.1093/ndt/gfn497
© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Therapeutic drug monitoring for mycophenolic acid in patients with autoimmune diseases
Brenda C. M. de Winter1 and
Teun van Gelder1,2
1 Department of Hospital Pharmacy
2 Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
Correspondence and offprint requests to: Teun van Gelder, Department of Hospital Pharmacy, Clinical Pharmacology Unit, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands. Tel: +31-10-703-3202; Fax: +31-10-703-2400; E-mail: t.vangelder{at}erasmusmc.nl
Keywords: auto-immune disease; lupus; mycophenolic acid; therapeutic drug monitoring
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Introduction
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Mycophenolate mofetil (MMF, CellCept
®) has become the most
frequently used immunosuppressive drug in kidney transplant
recipients [
1]. Since its approval for the prevention of acute
rejection after kidney transplantation in 1995 in the USA and
in 1996 in Europe, the use of azathioprine has been rapidly
diminishing, giving way to the use of MMF. A second formulation
of mycophenolic acid (MPA), the active metabolite of MMF, has
become available as enteric-coated mycophenolate sodium (EC-MPS,
Myfortic®). Randomized clinical trials have shown that EC-MPS
720 mg b.i.d. is therapeutically equivalent to MMF 1000 mg b.i.d.
with a comparable safety profile [
2,3]. These equimolar doses
of EC-MPS and MMF produce equivalent MPA exposure. The delayed
release formulation, EC-MPS, exhibits more variable pre-dose
MPA concentrations and more variable peak concentrations [
4].
Because of the favourable experience with MMF in transplant recipients, combining good efficacy with relatively few side effects, its use has also been tried in patients with autoimmune diseases [5]. Following case reports and case series of the successful use of MMF, controlled trials have been started [6]. Increasing evidence suggests that MMF can be used not only for the prevention of rejection in solid organ transplant recipients, but also for the treatment of several immunologically mediated (renal) diseases [7].
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Lupus nephritis
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Of the diseases for which MMF may be a first-line drug, systemic
lupus erythematosus or lupus nephritis is the most promising
[
8]. A recent meta-analysis of randomized controlled trials,
published in this journal, showed that MMF not only had higher
efficacy in inducing remission in severe lupus nephritis, but
also caused fewer side effects compared to pulsed cyclophosphamide
[
9]. Also for maintenance therapy in lupus nephritis MMF seems
to be a good alternative to azathioprine [
9]. The upcoming publication
of the results of a large phase III clinical trial (Aspreva
Lupus Management Study, ALMS) should provide us with more comparative
data on the efficacy and safety of MMF as induction and maintenance
therapy in lupus nephritis [
10].
|
ANCA-associated vasculitis
|
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In 2007, Stassen
et al. reported on the use of MMF for induction
of remission in 32 patients with active anti-neutrophil cytoplasmic
antibody (ANCA)-associated vasculitis [
11]. The patients in
this study could not be treated with cyclophosphamide, for varying
reasons. Complete remission was obtained in 25 (78%) patients
and partial remission in 6 (19%) patients. Only one patient
did not respond. Also, other groups found high percentages of
responders on MMF therapy in ANCA-associated vasculitis [
12,13].
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Optimal dosing
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Initially, in patients with lupus nephritis MMF doses of up
to 2 g daily were used. Subsequent dosing regimens started with
1 g MMF/day and titrated on a weekly basis up to a maximum of
3 g/day [
14]. A similar dose escalation is used in the ALMS
trial. It is questionable whether standard dose therapy is the
best way to treat a patient, given the large inter-individual
variability in pharmacokinetics [
15]. In renal transplant patients,
monitoring of MPA exposure to optimize MMF treatment is a heavily
debated topic [
16–19]. Several studies have shown a correlation
between MPA exposure and efficacy [
20]. This is remarkable,
as most renal transplant patients are being treated with three
or sometimes four immunosuppressive drugs in the first months
after transplantation. Apparently exposure to only one (MPA)
of these three or four drugs is so important that it affects
the incidence of acute rejection in these patients. Recently,
a French study showed a reduced incidence of acute rejection
in concentration-controlled MMF-treated renal transplant recipients
compared to treatment with a fixed dose regimen [
21].
Since patients with autoimmune diseases are regularly treated with only one or two immunosuppressive drugs, an adequate MPA exposure may be even more important compared to renal transplant recipients receiving multiple immunosuppressive drugs. Also, in patients treated for autoimmune diseases MPA has highly variable pharmacokinetics, and dose is a poor predictor for MPA exposure [22]. Factors affecting the between-patient variability of MPA have been extensively investigated in transplant patients and are likely the same for lupus patients, as they are drug related [23,24]. Patients with a poor renal function (creatinine clearance <25 mL/min) and patients with low albumin (<32 g/L) are known to have lower MPA exposure. This is explained by the fact that the clearance of MPA depends on its non-protein bound fraction [25]. Hypoalbuminaemia, as well as renal insufficiency, results in a higher free fraction of MPA, and this higher free fraction results in a higher MPA clearance. Other factors influencing MPA pharmacokinetics are listed in Table 1. If in patients with autoimmune diseases MPA exposure can be shown to correlate with either efficacy or toxicity, then therapeutic drug monitoring could contribute to optimize patient care.
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Correlating MPA exposure to clinical outcome
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In this issue of the journal, Neumann
et al. report on the value
of measuring MPA plasma concentrations in patients with autoimmune
diseases [
26]. The study consisted of two parts. In the first
part of the study the correlation between 12-h trough MPA concentrations
and full area under the concentration–time curve (AUC)
of MPA was investigated. Despite a rather weak correlation between
trough and AUC the authors decided to longitudinally monitor
a cohort of patients in the second part of the study, collecting
serial trough values, which were linked to the occurrence of
adverse events and to disease recurrence. Optimal efficacy,
i.e. prevention of recurrence to active disease, was associated
with higher MPA trough concentrations (> 3.0 mg/L). A remarkable
finding is the observation that in this study adverse events
were clustered in patients with a high MPA exposure. This is
in contrast with studies in renal transplant patients, in whom
tolerability was poorly correlated with MPA concentrations.
The authors define the upper threshold of the therapeutic window
based on toxicity. In renal transplant patients, the upper threshold
of the therapeutic window is not based on increased toxicity,
but merely on a lack of further improvement of efficacy above
a certain exposure.
|
Unanswered questions
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Neumann
et al. are careful in the interpretation of their data.
They acknowledge that this is an exploratory study. The therapeutic
window of MPA concentrations between 3.5 and 4.5 mg/L may serve
as a starting point for prospective studies, but is subject
to change. Prospective studies should be adequately powered
to deal with other patient or disease characteristics influencing
the propensity to relapse. Although homogeneous patient populations
would be preferred for establishing correlations between drug
exposure and clinical outcome, in reality patients with lupus
nephritis form rather heterogeneous populations, and we want
to get a better idea of optimal target levels in patients with
a lower or higher risk of relapse. In the study by Neumann
et al., patients were not suffering from the more severe stages
of autoimmune diseases. Obviously, this may have consequences
for optimal target concentrations.
For routine clinical practice, trough concentrations are more practical compared to obtaining a full AUC. Given the poor correlation between trough and AUC, for prospective trials it would be better to use a more robust measurement of MPA exposure than troughs only. As an alternative to the latter abbreviated sampling strategies may be used to accurately estimate AUC. Such abbreviated sampling strategies have been developed for transplant patients [27], but those are not necessarily valid for patients with autoimmune diseases, given the differences in MPA pharmacokinetics between the two patient populations. Indeed, initial studies showed that for lupus patients specifically developed sampling strategies should be used [28].
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What can we do now?
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The data presented should not be considered strong evidence
in favour of MPA monitoring. Nor should their predictions of
a therapeutic window be looked upon as an established guidance
for routine clinical practice. We need more pharmacokinetic/pharmacodynamic
analyses to decide on the value of therapeutic drug monitoring
for MPA in this patient population.
For current patient care, however, even at this moment measurement of MPA plasma concentrations can be of some help. In patients with lupus nephritis in whom MMF is used as induction therapy, one would expect to see a clinical response within a period of 1 month in most patients. If, after 1 month of therapy, in non-responders MPA (trough) plasma concentrations are found to be low (say <2 mg/L), then a dose increase may have favourable effects on the likelihood of reaching remission. However, if in the same patient MPA trough is >4.0 mg/L already, then a further dose increase does not seem to be a good idea, as it may cause toxicity without additional benefit in efficacy. In such patients switching to another agent may be the preferred way to go.
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Conclusion
|
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MMF is an effective immunosuppressive drug, which is increasingly
used in the remission induction and maintenance therapy of lupus
nephritis. Therapeutic drug monitoring may be beneficial considering
the between-patient variability in MPA exposure and the first
indications of a correlation between exposure and efficacy/safety
in patients with autoimmune diseases. Prospective pharmacokinetic/pharmacodynamic
studies are needed to elucidate the true value of dose individualization
for this indication and to identify the subsets of patients
that can benefit from monitoring.
Conflict of interest statement. T.v.G. reports having received consulting fees and grant support from F. Hoffman-La Roche, and lecture fees from F. Hoffman-La Roche, Wyeth and Dade Behring.
(See related article by I. Neumann et al. Association between mycophenolic acid 12-h trough levels and clinical endpoints in patients with autoimmune disease on mycophenolate mofetil. Nephrol Dial Transplant 2008; 23: 3514–3520.)
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Received for publication: 3. 7.08
Accepted in revised form: 8. 8.08
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Introduction
Lupus nephritis