Pharmacokinetic and pharmacodynamic analysis of enteric-coated mycophenolate sodium: limited sampling strategies and clinical outcome in renal transplant patients.
OBJECTIVE
Pharmacokinetic (PK) and pharmacodynamic (PD) monitoring strategies and clinical outcome were evaluated in enteric-coated mycophenolate sodium (EC-MPS)-treated renal allograft recipients.


METHODS
PK [mycophenolic acid (MPA)] and PD [inosine monophosphate dehydrogenase (IMPDH) activity] data were analysed in 66 EC-MPS and ciclosporin A (CsA)-treated renal allograft recipients. Adverse events were considered in a follow-up period of 12 weeks.


RESULTS
Analyses confirmed a limited sampling strategy (LSS) consisting of PK and PD data at predose, 1, 2, 3 and 4 h after oral intake as an appropriate sampling method (MPA r(2)= 0.812; IMPDH r(2)= 0.833). MPA AUC(0-12) of patients with early biopsy-proven acute rejection was significantly lower compared with patients without a rejection (median MPA AUC(0-12) 28 microg*h ml(-1) (7-45) vs. 40 microg*h ml(-1) (16-130), P < 0.01), MPA AUC(0-12) of patients with recurrent infections was significantly higher compared with patients without infections (median MPA AUC(0-12) 65 microg*h ml(-1) (range 37-130) vs. 37 microg*h ml(-1) (range 7-120), P < 0.005). Low 12-h IMPDH enzyme activity curve (AEC(0-12)) was associated with an increased frequency of gastrointestinal side-effects (median IMPDH AEC(0-12) 43 nmol*h mg(-1) protein h(-1)[range 12-67) vs. 75 nmol*h mg(-1) protein h(-1) (range 15-371), P < 0.01].


CONCLUSIONS
Despite highly variable absorption data, an appropriate LSS might be estimated by MPA AUC(0-4) and IMPDH AEC(0-4) in renal transplant patients treated with EC-MPS and CsA. Regarding adverse events, the suggested MPA-target AUC(0-12) from 30 to 60 microg*h ml(-1) seems to be appropriate in renal allograft recipients.
Sommerer
Claudia
C
Department of Nephrology, University Hospital, Heidelberg, Germany. claudia.sommerer@med.uni-heidelberg.de <claudia.sommerer@med.uni-heidelberg.de>
Müller-Krebs
Sandra
S
Schaier
Matthias
M
Glander
Petra
P
Budde
Klemens
K
Schwenger
Vedat
V
Mikus
Gerd
G
Zeier
Martin
M
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D016572:Cyclosporine / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006084:Graft Rejection / Q000378:metabolism; D006801:Humans; D007168:IMP Dehydrogenase / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D016030:Kidney Transplantation; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology; D013608:Tablets, Enteric-Coated; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D013608:Tablets, Enteric-Coated; D016572:Cyclosporine; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid
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