title: Pharmacokinetics and pharmacodynamics of mycophenolate sodium (EC-MPS) co-administered with cyclosporine in the early-phase post-kidney transplantation.
abstract: Mycophenolate drug levels are decreased by co-administration of cyclosporine. However, mycophenolate levels may be associated with insufficient immunosuppression. We investigated the pharmacokinetics of 720 mg mycophenolate sodium (EC-MPS) and inosine monophosphate dehydrogenase (IMPDH) activity under co-medication with cyclosporine and steroids within the first 30 d after kidney transplantation (n = 24). Blood samples were drawn at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 h after the morning dose. Plasma concentrations of mycophenolic acid, its glucuronide metabolites (MPAG; AcMPAG), and free MPA were determined using validated HPLC-DAD. IMPDH activity in leukocytes was analyzed chromatographically. Only six of 24 patients had an MPA-AUC(12h) within the putative therapeutic range of 40-60 mg/L·h. MPA clearance was high with 29 L/h. fMPA-AUC(12h) (r = -0.429, p = 0.04) and MPAG-AUC(12h) correlated significantly with the glomerular filtration rate, while total MPA did not. The MPAG-AUC(12h) was about 52-fold higher than the corresponding values for MPA, whereas the AcMPAG-AUC(12h) reached about 20.4% of the respective MPA-AUC(12h.) We found significant correlations between IMPDH inhibition and MPA concentration (r = -0.665; p < 0.0001), fMPA (r = -0.446; p = 0.003), and AcMPAG (r = -0.459; p = 0.002) but not with MPAG. Only 25% of the patients attained the therapeutic range for MPA-AUC under standard EC-MPS dose during the early-phase post-transplantation. We recommend that EC-MPS should be given in higher doses (3 × 720 mg) in the early post-transplant period when co-administered with cyclosporine.
authors.affiliation: Division of Nephrology, University Hospital, Greifswald, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Stracke
authors.forename: Maria
authors.initials: M
authors.lastname: Shipkova
authors.forename: Jens
authors.initials: J
authors.lastname: Mayer
authors.forename: Frieder
authors.initials: F
authors.lastname: Keller
authors.forename: Amir
authors.initials: A
authors.lastname: Zarghom
authors.forename: Liying
authors.initials: L
authors.lastname: Yang
authors.forename: Doris
authors.initials: D
authors.lastname: Henne-Bruns
authors.forename: Eberhard
authors.initials: E
authors.lastname: Wieland
mesh_terms: D000328:Adult; D000368:Aged; D016572:Cyclosporine / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005260:Female; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000188:drug therapy*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D011183:Postoperative Complications; D011379:Prognosis; D011446:Prospective Studies; D020123:Sirolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid; D020123:Sirolimus