Current target ranges of mycophenolic acid exposure and drug-related adverse events: a 5-year, open-label, prospective, clinical follow-up study in renal allograft recipients.
BACKGROUND
Two recent randomized clinical trials--Fixed Dose Versus Concentration Controlled and the Apomygre--evaluating the benefit of therapeutic drug monitoring of mycophenolate mofetil (MMF) in renal allograft recipients reported conflicting results. In both studies, target mycophenolic acid (MPA) AUC(0-12 h) ranges (ie, values used to guide MMF dosing) were derived from a previous study establishing target MPA AUC(0-12 h) ranges in cyclosporine-treated patients between 30 and 60 mg/L x h(-1). Both studies found an association between MPA exposure and acute rejection. However, only one of the studies found concentration-controlled MMF dosing to be significantly associated with less biopsy-proven acute-rejection episodes compared with fixed dosing. No reduced incidence of MMF-related adverse events (AEs) was observed in either of the 2 trials when MMF concentration-controlled and fixed dosing were compared.


OBJECTIVE
The aim of this study was to assess the clinical utility of target MPA AUC(0-12h) ranges between 30 and 60 mg/L x h(-1) in associating drug exposure with AEs within different time windows after transplantation, thereby identifying patients at increased risk for MMF-related AEs. The effects of single nucleotide polymorphisms (SNPs) of the uridine glucuronosyltransferase 1A9 (UGT1A9) and MRP2 genes (ie, coding for the UGT1A9 and the multidrug resistance protein transporter MRP2)-both involved in MPA metabolism-on stratified MPA exposure were assessed by applying the current advised target MPA AUC(0-12h) ranges.


METHODS
We conducted a 5-year clinical follow-up study in renal allograft recipients in whom MPA exposure was measured at 7 days, 6 weeks, 3 months, 1, 3, and 5 years post transplantation using abbreviated AUC measurements. MMF dose adjustments were based on clinical indications (eg, persistent leukopenia, chronic afebrile diarrhea, BK-polyomavirus infection of the renal allograft). Clinicians were blinded to the results of the AUC measurements.


RESULTS
One hundred white de novo renal allograft recipients (59 men, 41 women; mean [SD] age 51.4 [13.8] years) were included in this study. Ninety-eight patients received a renal allograft from a deceased donor. Significantly more episodes of leukopenia were associated with MPA AUC(0-12h) ranges >60 mg/L x h(-1) (P=0.03). Anemia was also significantly associated with higher MPA exposure ranges (incidence of anemia was 40.8%, 52.2%, and 64.3% for MPA AUC(0-12h) ranges <30, 30-60, and >60 mg/L x h(-1), respectively; P=0.004). Mean MPA AUC(0-12h) was significantly higher in the time window immediately preceding or following leukopenia (mean [SD] 59.7 [31.0] vs 46.5 [26.0] mg/L x h(-1); P=0.004) and anemia (mean [SD] hemoglobin <12 g/L x d(-1): 52.5 [30.0] vs 42.2 [21.2] mg/L x h(-1), P=0.002; hemoglobin <10 g/L x d(-1): 56.2 [32.5] vs 45.6 [24.7] mg/L x h(-1), P=0.005). No association was found between incident episodes. of diarrhea or infection and target MPA AUC(0-12 h) ranges. A significantly higher proportion of MPA AUC(0-12 h) measurements in recipients carrying the UGTIA9 T-275A and/or C-2152T SNP were in the low MPA exposure range (23.7%, 16.6%, and 12.6% for MPA AUC(0-12 h) ranges <30, 30-60, and >60 mg/L x h(-1), respectively; P=0.02).


CONCLUSIONS
Renal allograft recipients suffering from leukopenia or anemia related to MMF could potentially benefit, at least in part, from MMFdose adjustments based on target therapeutic MPA AUC(0-12 h) ranges between 30 and 60 mg/L x h(-1). This study did not find these target MPA AUC(0-12 h) ranges to be of clinical utility in guiding MMF dosing in patients with gastrointestinal or infectious AEs. Larger prospective studies are necessary to examine the risk for MPA underexposure in patients carrying the UGTIA9 T-275A and/or C-2152T SNP.
Kuypers
Dirk R J
DR
Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium. Dirk.Kuypers@uz.kuleuven.ac.be
de Jonge
Hylke
H
Naesens
Maarten
M
de Loor
Henriette
H
Halewijck
Evelyne
E
Dekens
Marc
M
Vanrenterghem
Yves
Y
D000740:Anemia / Q000097:blood / Q000139:chemically induced*; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D005500:Follow-Up Studies; D014453:Glucuronosyltransferase / Q000235:genetics; D006084:Graft Rejection / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007118:Immunoassay; D016030:Kidney Transplantation; D007970:Leukopenia / Q000097:blood / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D009173:Mycophenolic Acid / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D000090264:UDP-Glucuronosyltransferase 1A9
D004247:DNA; D004791:Enzyme Inhibitors; D014453:Glucuronosyltransferase; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009173:Mycophenolic Acid; D000090264:UDP-Glucuronosyltransferase 1A9; C000715087:ABCC2 protein, human; C000715591:UGT1A9 protein, human