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Year : 2006  |  Volume : 52  |  Issue : 4  |  Page : 244

Population-specific limited sampling strategies for therapeutic drug monitoring of mycophenolic acid

Department of Hospital Pharmacy, Clinical Pharmacology Unit, Erasmus MC, Rotterdam, Netherlands

Correspondence Address:
Reinier M van Hest
Department of Hospital Pharmacy, Clinical Pharmacology Unit, Erasmus MC, Rotterdam
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Source of Support: None, Conflict of Interest: None

PMID: 17191354

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How to cite this article:
van Hest RM. Population-specific limited sampling strategies for therapeutic drug monitoring of mycophenolic acid. J Postgrad Med 2006;52:244

How to cite this URL:
van Hest RM. Population-specific limited sampling strategies for therapeutic drug monitoring of mycophenolic acid. J Postgrad Med [serial online] 2006 [cited 2023 Jun 4];52:244. Available from:

Therapeutic drug monitoring (TDM) of the immunosuppressive agent mycophenolic acid (MPA), which is the active compound of the prodrug mycophenolate mofetil (MMF), is increasingly being advocated. The most important reason for the shift from standard dose therapy to individualized therapy in renal transplant recipients is that the risk for acute rejection is minimized with MPA area-under-the-concentration-time curve (AUC 0-12 ) values between 30 and 60 mg*h/L, while the currently recommended fixed MMF dose of 2g bid produces MPA AUC 0-12 values in the range of 10 to 100 mg*h/L.[1] MMF dose increases in those patients with low exposure and dose decreases in those with high exposure, is likely to optimize MMF therapy.[1]

An important disadvantage of TDM with measurement of full AUC 0-12 is that at least eight MPA concentration-time samples need to be drawn covering the total 12h dosing interval. This is costly, time-consuming, inconvenient for the patient and not feasible in an outpatient clinic setting. A suitable alternative is estimation of full MPA AUC 0-12 by a limited sampling strategy (LSS). Several LSS have been proposed for MPA in Caucasian renal transplant recipients, mostly consisting of three or four samples drawn during the first 2-6h of a dosing interval. However, these LSS may not be applicable in other ethnic groups. This idea is fuelled by the remark of Fleming et al[2] in this issue of The Journal that several LSS developed in Caucasian transplant patients did not perform well in their population of Indian renal transplant recipients. Unfortunately, the authors do not provide data that show that the currently available LSS are insufficient in other ethnic populations. Nevertheless, it is plausible that there is a need for population-specific LSS to ensure practical and reliable estimation of full AUC 0-12 in every patient for TDM of MPA and Fleming et al[2] present such an LSS for Indian renal transplant patients. Their LSS consists of 10 samples over the first six hours of a dosing interval, thereby halving the time needed to determine a full AUC 0-12 . This is already a big improvement, but the required 10 samples cannot exactly be called "limited".

First, for optimal convenience, an LSS should be sought that does not include more than four samples over a 2h period. Second, because cyclosporine interacts with MPA,[3] it is unlikely that the same LSS will perform well in both patients treated with and patients treated without cyclosporine. In addition, the pharmacokinetics of MPA change over time after renal transplantation. The MPA AUC 0-12 is lower in the immediate posttransplant phase (first six months) compared with the period thereafter despite a fixed dose.[4] It is therefore of importance that separate LSS are developed specific for the applied immunosuppressive regimen and specific for the period after transplantation. Third, it is known that when the evaluation of the performance of a strategy is based on the same data as it was derived from, biased results could be produced.[5] This may in theory lead to false decisions about the adjustment of the MMF dose. Consequently, the LSS should be validated with a separate data set, which is independent from the data set used to develop the LSS.

The valuable work of Fleming et al[2] in developing LSS specific for the Indian renal transplant population deserves continuation to indeed make sure that full MPA AUC 0-12 can be reliably estimated in every patient in a way that is both valid and convenient for the patient and the doctor.

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1.Van Gelder T, Meur YL, Shaw LM, Oellerich M, Denofrio D, Holt C, et al . Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006;28:145-54.  Back to cited text no. 1    
2.Fleming DH, Mathew BS, John GT, Chandy SJ, Manivannan J, Jeyaseelan V. A six hour extrapolated sampling strategy for monitoring mycophenolic acid in renal transplant patients in the Indian subcontinent. J Postgrad Med 2006;52:248-52.  Back to cited text no. 2    
3.Hesselink DA, Van Hest RM, Mathot RA, Bonthuis F, Weimar W, de Bruin RW, et al . Cyclosporine interacts with mycophenolic acid by inhibiting the multidrug resistance-associated protein 2. Am J Transplant 2005;5:987-94.  Back to cited text no. 3    
4.Shaw LM, Korecka M, Venkataramanan R, Goldberg L, Bloom R, Brayman KL. Mycophenolic acid pharmacodynamics and pharmacokinetics provide a basis for rational monitoring strategies. Am J Transplant 2003;3:534-42.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]
5.David OJ, Johnston A. Limited sampling strategies for estimating cyclosporin area under the concentration-time curve: Review of current algorithms. Ther Drug Monit 2001;23:100-14.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]

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Online since 12th February '04
2004 - Journal of Postgraduate Medicine
Official Publication of the Staff Society of the Seth GS Medical College and KEM Hospital, Mumbai, India
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