PMID- 18498916
OWN - NLM
STAT- MEDLINE
DCOM- 20081118
LR  - 20211203
IS  - 0149-2918 (Print)
IS  - 0149-2918 (Linking)
VI  - 30
IP  - 4
DP  - 2008 Apr
TI  - 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.
PG  - 673-83
AB  - 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.
FAU - Kuypers, Dirk R J
AU  - Kuypers DR
AD  - Department of Nephrology and Renal Transplantation, University Hospitals Leuven, 
      Leuven, Belgium. Dirk.Kuypers@uz.kuleuven.ac.be
FAU - de Jonge, Hylke
AU  - de Jonge H
FAU - Naesens, Maarten
AU  - Naesens M
FAU - de Loor, Henriette
AU  - de Loor H
FAU - Halewijck, Evelyne
AU  - Halewijck E
FAU - Dekens, Marc
AU  - Dekens M
FAU - Vanrenterghem, Yves
AU  - Vanrenterghem Y
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Randomized Controlled Trial
PL  - United States
TA  - Clin Ther
JT  - Clinical therapeutics
JID - 7706726
RN  - 0 (ABCC2 protein, human)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Multidrug Resistance-Associated Protein 2)
RN  - 0 (Multidrug Resistance-Associated Proteins)
RN  - 0 (UGT1A9 protein, human)
RN  - 9007-49-2 (DNA)
RN  - EC 2.4.1.17 (Glucuronosyltransferase)
RN  - EC 2.4.1.17 (UDP-Glucuronosyltransferase 1A9)
RN  - HU9DX48N0T (Mycophenolic Acid)
SB  - IM
MH  - Anemia/blood/*chemically induced
MH  - Chromatography, High Pressure Liquid
MH  - DNA/genetics
MH  - Drug Resistance, Multiple/genetics
MH  - Enzyme Inhibitors/*administration & dosage/adverse effects/pharmacokinetics
MH  - Female
MH  - Follow-Up Studies
MH  - Glucuronosyltransferase/genetics
MH  - Graft Rejection/*drug therapy/metabolism
MH  - Humans
MH  - Immunoassay
MH  - *Kidney Transplantation
MH  - Leukopenia/blood/*chemically induced
MH  - Male
MH  - Middle Aged
MH  - Multidrug Resistance-Associated Protein 2
MH  - Multidrug Resistance-Associated Proteins/genetics
MH  - Mycophenolic Acid/*administration & dosage/adverse effects/pharmacokinetics
MH  - Polymerase Chain Reaction
MH  - Polymorphism, Single Nucleotide
MH  - Prospective Studies
MH  - Time Factors
MH  - Treatment Outcome
MH  - UDP-Glucuronosyltransferase 1A9
EDAT- 2008/05/24 09:00
MHDA- 2008/11/19 09:00
CRDT- 2008/05/24 09:00
PHST- 2008/02/20 00:00 [accepted]
PHST- 2008/05/24 09:00 [pubmed]
PHST- 2008/11/19 09:00 [medline]
PHST- 2008/05/24 09:00 [entrez]
AID - S0149-2918(08)00153-7 [pii]
AID - 10.1016/j.clinthera.2008.04.014 [doi]
PST - ppublish
SO  - Clin Ther. 2008 Apr;30(4):673-83. doi: 10.1016/j.clinthera.2008.04.014.