title: Pharmacokinetic and pharmacodynamic analysis of enteric-coated mycophenolate sodium: limited sampling strategies and clinical outcome in renal transplant patients.
abstract: 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.
authors.affiliation: Department of Nephrology, University Hospital, Heidelberg, Germany. claudia.sommerer@med.uni-heidelberg.de <claudia.sommerer@med.uni-heidelberg.de>
authors.forename: Claudia
authors.initials: C
authors.lastname: Sommerer
authors.forename: Sandra
authors.initials: S
authors.lastname: Müller-Krebs
authors.forename: Matthias
authors.initials: M
authors.lastname: Schaier
authors.forename: Petra
authors.initials: P
authors.lastname: Glander
authors.forename: Klemens
authors.initials: K
authors.lastname: Budde
authors.forename: Vedat
authors.initials: V
authors.lastname: Schwenger
authors.forename: Gerd
authors.initials: G
authors.lastname: Mikus
authors.forename: Martin
authors.initials: M
authors.lastname: Zeier
mesh_terms: 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
chemical_list: D007166:Immunosuppressive Agents; D013608:Tablets, Enteric-Coated; D016572:Cyclosporine; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid
references.citation: Transplantation. 1996 Apr 15;61(7):1029-37
references.pmid: 8623181
references.citation: Am J Transplant. 2005 May;5(5):987-94
references.pmid: 15816878
references.citation: Clin Chem. 2002 Mar;48(3):517-25
references.pmid: 11861442
references.citation: Ther Drug Monit. 2006 Apr;28(2):145-54
references.pmid: 16628123
references.citation: Clin J Am Soc Nephrol. 2007 Nov;2(6):1147-55
references.pmid: 17928466
references.citation: J Clin Pharmacol. 1996 Apr;36(4):315-24
references.pmid: 8728345
references.citation: Transplantation. 2008 Jun 27;85(12):1675-85
references.pmid: 18580456
references.citation: Clin Chim Acta. 1995 Jul 14;238(2):169-78
references.pmid: 7586576
references.citation: Transplantation. 1996 Sep 15;62(5):666-72
references.pmid: 8830834
references.citation: N Engl J Med. 2002 Feb 21;346(8):580-90
references.pmid: 11856798
references.citation: Clin Biochem. 1998 Jul;31(5):317-22
references.pmid: 9721428
references.citation: Am J Transplant. 2006 Jan;6(1):121-8
references.pmid: 16433766
references.citation: Clin Pharmacol Ther. 1998 Dec;64(6):672-83
references.pmid: 9871432
references.citation: Ther Drug Monit. 2001 Dec;23(6):717-21
references.pmid: 11802109
references.citation: Am J Transplant. 2004 Feb;4(2):231-6
references.pmid: 14974944
references.citation: Transplantation. 1995 Aug 15;60(3):225-32
references.pmid: 7645033
references.citation: Ther Drug Monit. 2001 Apr;23(2):119-28
references.pmid: 11294511
references.citation: Clin Biochem. 2001 Oct;34(7):543-9
references.pmid: 11738390
references.citation: Am J Transplant. 2007 Apr;7(4):888-98
references.pmid: 17391132
references.citation: J Am Soc Nephrol. 2006 Mar;17(3):871-80
references.pmid: 16452491
references.citation: Transplantation. 2007 Feb 27;83(4):417-24
references.pmid: 17318074
references.citation: Ther Drug Monit. 2009 Oct;31(5):585-91
references.pmid: 19704401
references.citation: Am J Transplant. 2009 Jul;9(7):1607-19
references.pmid: 19459794
references.citation: Clin Chem. 2001 Jan;47(1):88-94
references.pmid: 11148182
references.citation: Transplantation. 1999 Jul 27;68(2):261-6
references.pmid: 10440399
references.citation: Transplantation. 2003 Apr 27;75(8):1341-6
references.pmid: 12717227
references.citation: Lancet. 1995 May 27;345(8961):1321-5
references.pmid: 7752752
references.citation: Am J Transplant. 2004 Jul;4(7):1079-83
references.pmid: 15196064
references.citation: J Am Soc Nephrol. 1993 Nov;4(5):1159-71
references.pmid: 8305642
references.citation: Am J Transplant. 2003 May;3(5):534-42
references.pmid: 12752309
references.citation: Am J Transplant. 2007 Nov;7(11):2496-503
references.pmid: 17908276
references.citation: Am J Transplant. 2007 Mar;7(3):518-26
references.pmid: 17352710
references.citation: Am J Transplant. 2004 Dec;4(12):2045-51
references.pmid: 15575908
references.citation: Clin Pharmacokinet. 2009;48(5):329-41
references.pmid: 19566116
references.citation: J Clin Pharmacol. 2007 Jul;47(7):850-9
references.pmid: 17526858
references.citation: Transplantation. 2006 Oct 27;82(8):1004-12
references.pmid: 17060847
references.citation: Clin J Am Soc Nephrol. 2007 Jan;2(1):184-91
references.pmid: 17699403
references.citation: Ther Drug Monit. 2007 Apr;29(2):141-9
references.pmid: 17417067
references.citation: Transplantation. 2008 Oct 27;86(8):1043-51
references.pmid: 18946341
references.citation: Clin Ther. 2008 Apr;30(4):673-83
references.pmid: 18498916