Therapeutic Drug Monitoring of Mycophenolic Acid After Lung Transplantation—Is It Clinically Relevant?

Abstract

Mycophenolate mofetil (MMF) is a purine synthesis antagonist frequently used after solid organ transplantation including lung transplantation (LTx) (1). MMF is an inactive prodrug that is converted to its active metabolite mycophenolic acid (MPA) by intestinal, liver, and plasma esterases (2). MMF is normally administered at a fixed dose, and the role of therapeutic drug monitoring (TDM) for MPA in solid organ transplantation remains controversial (3). The aim of this study was to evaluate the role of MPA-TDM in lung transplant recipients. A retrospective analysis in a single center was performed in outpatient stable lung transplant patients receiving triple calcineurin inhibitor (CNI)-based immunosuppression during routine follow-up visits from January 2007 to May 2009. Inclusion criteria for MPA-TDM were clinical suspicion of over- or underdosing or fluctuating drug levels of CNIs. To evaluate clinical outcome, events occurring within 6 months before and after TDM were compared. Blood samples were collected before (C0), and 30 and 120 min (C30 and C120) after the morning dose. A target range of 30 to 60 mg/hr L according to recommended values in renal transplant patients was used (4). Serum concentrations of MPA were measured using reserve-phase high performance liquid chromatography (5, 6). MPA exposure (area under the curve [AUC]) was estimated by 3-point equation according to validated algorithms using the MPA concentration data from predose and at 30- and 120-min levels (7, 8). One hundred twenty-six patients were included. Indications for inclusion centered on recurrent acute rejection episodes (6%) or infections (10%), unexplained leucopenia or anemia (36%), gastrointestinal complaints (12%), and fluctuating CNI (13%). Patient demographics and results are listed in Table 1.TABLE 1: Baseline characteristics of patientsFifty-three patients (42%) had a MPA-AUC outside of 30 to 60 mg/hr L: subtherapeutic AUCs were found in 27% and supratherapeutic AUCs in 15%. Patients taking tacrolimus (44.6 [interquartile range: 35.5–59.4] mg/hr L) demonstrated significantly higher MPA AUCs in comparison with those receiving cyclosporine (vs. 35.4 [26.6–45.8] mg/hr L, P=0.001). C0 levels moderately correlated with AUC (see Figure, Supplemental Digital Content 1,https://links.lww.com/TP/A347). C0 levels were more predictive for MPA AUC in long-term LTx. In the first 6 postoperative months, significantly lower MPA exposure was observed. No significant differences between abnormal MPA-AUCs and incidence of acute rejections, infections, gastrointestinal side effects, or anemia were observed. Leukocytes and hemoglobin increased significantly by median 1.8 Tsd/μL (47 vs. 6.5 Tsd/μL) and 0.1 g/dL (12.3 vs. 12.4 g/dL) 6 months after dose reduction (P=0.035 and P=0.012) in 21 patients. No significant relationships between subtherapeutic MPA AUC and incidence of rejection episodes, cytomegalovirus, respiratory viral, or bacterial infections during the preceding 6 months were observed. In patients with cystic fibrosis (CF), subtherapeutic MPA-AUCs occurred more frequently (38% vs. 24% in non-CF patients, respectively) despite receiving significantly higher doses (29.9 [21.2–39.6] mg/kg/day vs. 21.7 [15.5– 29.0] mg/kg/day, P=0.002). No significant decrease in MPA exposure in patients with proton pump inhibitor (PPI) comedication (40 [29–52] mg/hr L) was observed, when compared with those without PPIs (42 [29–60] mg/hr L). Our results of MMF pharmacokinetics in a large lung transplant population indicate that subtherapeutic MPA levels are frequent in CF patients and early after transplantation. The cause for observed lowered MPA AUCs in the early posttransplant period seems multifactorial. Low serum albumin or increased urea may result in increased plasma clearance along with malabsorption or gastroparesis may explain the pharmacokinetic variation (9). Analysis of genetic polymorphisms in enzymes may also account for supratherapeutic MPA levels. The pharmacokinetics of drugs are altered in CF patients, and the plasma concentrations of many drugs are found to be lower than in individuals without CF (10). Our results regarding drug deposition of MMF in recipients with CF are consistent with those reported by Gerbase et al. (11). The majority of studies in other forms of transplantation similarly demonstrated no significant relationship between clinical outcomes and TDM of MPA (12, 13). In general, MPA monitoring correlated poorly with clinical suspicion of abnormal MMF dosing in our study. Rupprecht et al. (14) have recently shown that concomitant treatment with the PPI pantoprazole significantly decreased MPA in healthy volunteers. In our analysis, there was no significant decrease in MPA exposure in patients with long-term PPI comedication. In conclusion, a substantial clinical benefit of MMF TDM needs to be established. We suggest MPA monitoring in LTx only when dose reduction does not ameliorate side effects. Prospective trials to assess the potential risk of long-term MPA overexposure in LTx are needed. Claudia de Wall Thomas Fuehner Patricia Wehmeier Tobias Welte Jens Gottlieb Department of Respiratory Medicine Medical School Hanover Hanover, Germany