Significance of Mycophenolate Monitoring in Liver Transplant Recipients: Toward the Cut-off Level E. Sarvary, B. Nemes, M. Varga, I. Gaal, K. Monostory, R.M. Langer, D. Gorog, J. Fazakas, L. Kobori, I. Fehervari, and Zs. Gerlei ABSTRACT Mycophenolate mofetil blocks the “de novo” -purine synthesis to reduce the incidence and severity of acute rejection episodes. There has been an increased interest in utility of monitoring mycophenolic acid (MPA) levels, however currently the MPA monitoring is not part of the protocol following liver transplantation. We assessed whether trough MPA monitoring could be advisable in liver transplant patients or not. For this reason MPA levels of 56 liver transplants were measured on 3, 5, 10, 14, 21, 30, 60, and 180 posttransplant days. The optimal cut-off of MPA level (1.73 mg/L) for all (56) and 1.34 mg/L for ciclosporin-treated- and 1.98 mg/L for the tacrolimus-treated transplants were calculated by statistical analysis to reduce the incidence of acute rejection. MPA concentrations of 3 days period before the day of clinical diagnosis acute rejection were well below the cut-off value. Only 3 (16%) out 19 patients with acute rejection had higher MPA levels than the cut-off value on the day of diagnosis of acute rejection. In conclusion, our data suggests that MPA predose level monitoring, especially in the early “filling phase” after transplantation, is applicable in liver allograft recipients given adjunctive MMF, protecting them from the ineffective immunosuppression. W ITH the increasing use of mycophenolic acid (MPA) in solid organ transplantation, the need for more accurate drug dosing has become evident. 1 Mycophenolate mofetil (MMF) has become the single most used immuno- suppressant in solid-organ transplantation. 2 MMF blocks the “de novo” -purine synthesis principally via uncompeti- tive inhibition of inosine monophosphate dehydroge- nase. 3,4,5 The immunological activity of MMF is accom- plished through rapid in vivo hydrolysis to the active form, MPA, which is the active immunosuppressant derived from its 2, 4-morpholino ester, CellCept. 6 An early millestone clinical trial with MMF in renal transplant recipients showed an association of its efficacy with drug exposure (measured as area under the plasma concentration versus time curve) and of a corresponding increase of side effects with drug exposure. 7 This drug was introduced as a drug for which no routine therapeutic drug monitoring (TDM) was considered necessary. 8 Jain et al reported high inter- individual differences in the pharmacokinetic parameters for MPA in liver transplanted patients. 9 This variability exists together with a narrow therapeutic window for MPA. 8 Al- though a concentration-effect relationship has been repeti- tively shown for MPA, most centres have not implemented TDM. 10 According to Hest-R et al, the concentration-controlled MMF dosing is useful in the first month after transplanta- tion. 11 Some studies were designed for TDM of MPA. For example, for the recipients who were on tacrolimus (TAC) therapy, a starting dosage of 2 g/d MMF guaranteed that 76.2% of patients achieved the target therapeutic range of 30 to 60 mg  h/L by day 3, whereas, for ciclosporin (CyA)- treated patients, this amounted to only 51.2% at day 3. 7,11 Over the first 6 weeks of posttransplant period the inter- patient PK variability in liver transplant patients is greater than that in renal or heart transplant patient. 12 Shaw-LM et al. also believed that in order to provide a more comprehensive set of guidelines for the most effective use of MPA therapeutic drug monitoring, further investigations of the relationship From Semmelweis Medical University (E.S., I.G., B.N., M.V., L.K., D.G., I.J.F., F., R.M.L., Zs.G.), Transplantation and Surgical Clinic, Budapest, Hungary; and Hungarian Academy of Sciences (K.M.), Chemical Research Center, Budapest, Hungary. Address correspondence to Dr Eniko Sarvary, PhD, Semmel- weis Medical University, Transplantation and Surgical Clinic, H-1083 Baross str. 23-25, Budapest, Hungary. E-mail: eniko. sarvary@gmail.com © 2012 Published by Elsevier Inc. 0041-1345/–see front matter 360 Park Avenue South, New York, NY 10010-1710 http://dx.doi.org/10.1016/j.transproceed.2012.07.124 Transplantation Proceedings, 44, 2157–2161 (2012) 2157