Proton Pump Inhibitor Co-medication Reduces Active Drug Exposure in Heart Transplant Recipients Receiving Mycophenolate Mofetil A.O. Doesch, S. Mueller, M. Konstandin, S. Celik, C. Erbel, A. Kristen, L. Frankenstein, A. Koch, P. Ehlermann, C. Zugck, and H.A. Katus ABSTRACT Background. Proton pump inhibitors (PPIs) are often prescribed for gastrointestinal discomfort after heart transplantation. This study investigated the impact of PPI use on mycophenolic acid (MPA) pharmacokinetics in heart transplant recipients receiving mycophenolate mofetil (MMF) in combination with a calcineurin inhibitor (tacrolimus [TAC]/cyclosporine [CsA]) or mammalian target of rapamycin inhibitor (sirolimus/ everolimus). Methods. Abbreviated MPA areas under the curve (AUCs; 0, 30, and 120 minutes after morning intake) were obtained in 19 patients on a PPI (initial examination) and 1 month after PPI discontinuation (follow-up). Mean patient age was 58.2  8.8 years, and mean time after transplantation was 2.3  4.0 years (range, 0.2–13.0 years). Results. At initial examination mean daily MMF dose was 2.2  0.8 g. MMF dose was kept unchanged for the duration of study (P = ns). Mean predose (C0) MPA serum concentrations were insignificantly lower with PPI comedication (2.5  2.2 mg/L vs 2.8  1.7 mg/L; P = .15). Dose-adjusted abbreviated MPA AUCs (adjusted to morning dose) were significantly lower during PPI therapy (45.2  20.3 vs 65.2  38.8 mg · h/L · g [MMF]; P = .02). Conclusions. Patients with PPI comedication during MMF therapy show significantly lower exposure to mycophenolic acid determined by dose-adjusted abbreviated MPA AUCs. Although the clinical relevance of this pharmacokinetic interaction was not determined in this study, MPA drug monitoring by limited sampling strategies might be helpful during changes in antacid comedication in patients on MMF. M ycophenolate mofetil (MMF) has gained widespread acceptance as the immunosuppressant of choice as part of a dual immunosuppressive regimen and has proven to be effective in preventing allograft rejection after heart transplantation (HT). 1 The immunosuppressive drug MMF is the morpholinoethyl ester of the active drug mycophe- nolic acid (MPA). It acts through inhibition of de novo purine synthesis by reversibly inhibiting inosine monophos- phate dehydrogenase (IMPDH), thus preferentially inhib- iting proliferation of T and B lymphocytes. 2 In vitro and in vivo, MPA concentrations exhibit a classic sigmoidal rela- tion to inhibition of IMPDH and suppression of lymphocyte proliferation. 2,3 MPA metabolites undergo enterohepatic recirculation after biliary excretion. MMF pharmacokinet- ics vary widely between patients, and previous studies have demonstrated the feasibility of limited sampling strategies regarding determination of MPA exposure in stable pa- tients after HT. 4 For gastrointestinal discomfort, PPIs are prescribed in a considerable proportion of patients after HT, but the inhibitory effect of PPIs on gastric acid secretion might decrease the elution and hydrolysis of MMF and subsequently diminish its plasma concentration as well as active drug concentration. 5,6 The present study From the Department of Cardiology (O.D., S.M., M.K., S.C., C.E., A.K., L.F., P.E., H.A.K., C.Z.), University of Heidelberg, Heidelberg, Germany; and Department of Cardiovascular Sur- gery (A.K.), University of Heidelberg, Heidelberg, Germany. Address correspondence to Andreas O. Doesch, MD, Mediz- inische Klinik III, Kardiologie, Angiologie, Pulmologie, Im Neuen- heimer Feld 410, 69120 Heidelberg, Germany. E-mail: Andreas. Doesch@med.uni-heidelberg.de © 2010 by Elsevier Inc. All rights reserved. 0041-1345/–see front matter 360 Park Avenue South, New York, NY 10010-1710 doi:10.1016/j.transproceed.2010.09.047 Transplantation Proceedings, 42, 4243– 4246 (2010) 4243