Journal of Postgraduate Medicine Medknow Publications and Staff Society of Seth GS Medical College and KEM Hospital, Mumbai, India ISSN: 0022-3859 EISSN: 0972-2823 Vol. 52, Num. 4, 2006, pp. 243-243

Journal of Postgraduate Medicine, Vol. 52, No. 4, October-December, 2006, pp. 243

Expert's Comments

On the road towards strategic application of therapeutic drug monitoring of mycophenolic acid in renal allograft recipients

Kuypers DR

Department of Nephrology and Renal Transplantation University Hospitals Leuven, Herestraat 49 B-3000 Leuven, Belgium
Correspondence Address:Department of Nephrology and Renal Transplantation University Hospitals Leuven, Herestraat 49 B-3000 Leuven, Belgium Email: dirk.kuypers@uz.kuleuven.be

Code Number: jp06083

The clinical relevance of therapeutic drug monitoring for mycophenolate mofetil (MMF) therapy has been recently examined in three large studies comparing fixed-dosing of MMF to concentration-controlled dosing in renal recipients using different variations of abbreviated exposure measurements (based on non-compartmental and Bayesian kinetic models): The FDCC-study, The Opticept-study and The Apomigre study. While the final outcome of these studies is eagerly awaited, additional data indicate that, most likely, the truth will-as always-lie somewhere in-between: subgroups of patients that are either prone to early (Day 3-7) MPA underexposure or relatively late (from 6-12 weeks onwards) overexposure will most probably benefit from concentration-controlled dosing of MMF but for the majority of recipients a fixed-dose MMF will suffice. The new challenge will be to preemptively identify these patient groups and define the strategic time points that are most crucial for assessing exposure-related efficacy and toxicity. It is already clear that this is not going to be a simple task.[1] A variety of clinical variables that influence MPA exposure are well documented and recently, genetic determinants ( UGT1A9- and MRP2- gene single nucleotide polymorphisms) have been identified which-at least partly- also affect variability in MPA exposure.[2] In order to address these complex issues, reliable drug monitoring tools are needed, constituting a compromise between practical feasibility in terms of costs and work load and clinical usefulness. Because predose trough concentrations of MPA are unreliable in this respect, abbreviated or limited sampling strategies (LSS) provide the least complicated answer to these questions, provided the correct sampling strategy is used for the right patient at the right time.[3] In this month′s issue of JPGM , Fleming et al demonstrate that for this purpose, the established MPA LSS developed for Caucasian recipients are not simply transferable to Indian patients, suggesting that racial and/or geographical factors can influence MPA pharmacokinetics.[4] Indeed, the contribution of MPA enterohepatic recirculation (EHC) to total dose-interval exposure seems not important in Indian recipients and is barely influenced by co-administration of cyclosporine A, a finding that is in disagreement with data from Caucasian and African-American recipients.[5] Genetic and/or environmental factors could account for these differences and will require further study of key enzymes and transport systems involved in MPA metabolism. A detailed comparative pharmacokinetic study of MPA and its metabolites in native Indian and Caucasian patients would be a logical start for trying to elucidate this intriguing finding. Furthermore, the drastic reduction in MPA sampling time from 12 to 6 hours while maintaining a highly accurate prediction of exposure demonstrated in the current study, constitutes an important step towards simplification of concentration-controlled MMF dosing in Indian allograft recipients. The next step will be further shortening of sampling time to four or maybe two hours, thereby reducing costs and workload substantially. Judging from the apparent remarkable lack of MPA EHC in Indian patients, identifying accurate and reproducible shorter LSS should not be too difficult. In the process of developing a practical therapeutic monitoring tool for MMF in Indian transplant recipients, these investigators have added yet another new variable into the equation of variability in MPA exposure, reminding us that we still have a long way to go on this exciting road.

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