Determinants of mycophenolic acid levels after renal transplantation.
There are data suggesting an association between mycophenolic acid (MPA) levels and acute rejection and toxicity in renal transplant recipients treated with mycophenolate mofetil (MMF), and therefore, knowledge of factors determining MPA levels may aid in accurate adjustment of MMF dosage. A total of 4970 samples taken 12 hours postdose were analyzed for MPA by immunoassay at regular intervals from the first week posttransplantation in 117 renal transplant patients immunosuppressed with MMF and tacrolimus in a steroid-sparing regimen (prednisolone for the first 7 days only). MPA levels rose in the first 3 months and stabilized thereafter; dose-normalized MPA levels rose throughout the first 12 months and subsequently stabilized. Multivariate analysis by means of a population-averaged linear regression showed positive associations between MPA level and total daily dose (P < 0.001) but not individual dose or total daily dose corrected for body weight. Positive associations were also seen with serum albumin (P = 0.01), tacrolimus trough level (P = 0.01), and female gender (P = 0.002). The association with tacrolimus levels diminished with time. Negative associations were seen between MPA level and higher estimated creatinine clearance (P < 0.001), and also with increasing alanine transaminase levels (P = 0.002), the use of oral antibiotics (P < 0.001), and infective diarrhea (P < 0.001). The latter findings may be related to changes in enterohepatic recirculation of MPA. Many clinical variables show associations with trough MPA levels. An understanding of these factors may aid therapeutic monitoring of MMF.
Borrows
Richard
R
Renal and Transplant Units, St. Mary's Hospital, Paddington, London W2 1NY, United Kingdom. richardborrows@doctors.org.uk
Chusney
Gary
G
James
Anthony
A
Stichbury
Jose
J
Van Tromp
Jen
J
Cairns
Tom
T
Griffith
Megan
M
Hakim
Nadey
N
McLean
Adam
A
Palmer
Andrew
A
Papalois
Vassilios
V
Taube
David
D
D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D019980:Amoxicillin-Potassium Clavulanate Combination / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D002939:Ciprofloxacin / Q000627:therapeutic use; D003404:Creatinine / Q000097:blood; D003967:Diarrhea / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D008795:Metronidazole / Q000627:therapeutic use; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011355:Prodrugs / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012709:Serum Albumin / Q000378:metabolism; D016559:Tacrolimus / Q000097:blood / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome
D015415:Biomarkers; D007166:Immunosuppressive Agents; D011355:Prodrugs; D012709:Serum Albumin; D008795:Metronidazole; D002939:Ciprofloxacin; D019980:Amoxicillin-Potassium Clavulanate Combination; D003404:Creatinine; D000410:Alanine Transaminase; D009173:Mycophenolic Acid; D016559:Tacrolimus