title: Performance of the new mycophenolate assay based on IMPDH enzymatic activity for pharmacokinetic investigations and setup of Bayesian estimators in different populations of allograft recipients.
abstract: A new mycophenolate (MPA) assay based on the enzymatic activity of recombinant type II inosine monophosphate dehydrogenase (the pharmacological target of MPA) with excellent correlation with high-performance liquid chromatography has recently been released for the measurement of MPA plasma levels. This study aimed to (1) compare this new assay with liquid chromatography tandem mass spectrometry (LC-MS/MS) for MPA pharmacokinetic (PK) studies in different populations of allograft recipients given mycophenolate mofetil, (2) develop specific Bayesian estimators for this inhibition assay and test their accuracy, and (3) compare the resulting MPA area under the curve (AUC0-12h) estimates with those of Bayesian estimators developed based on the LC-MS/MS results. Sixty-four adult or pediatric, renal or lung transplant patients who were administered mycophenolate mofetil in association with cyclosporine, tacrolimus, or sirolimus at different post-transplant periods were enrolled as part of different PK studies. Eight hundred ninety-four patients' samples were analyzed in parallel with the enzymatic MPA assay and a reference LC-MS/MS method. Repeated analysis of quality control samples showed a mean difference of 6% between the 2 assays, whereas the results obtained in different populations of transplanted patients showed excellent correlation (r2 > 0.96) and small mean relative differences (2.0%-16.9%). The full profiles obtained with both assays were adequately fitted using either a 2-compartment model with 1 "gamma" absorption phase or a 1-compartment model with 2 gamma inputs. Several PK parameters were significantly affected by the analytical method used. Accurate Bayesian estimators could be specifically developed for the enzymatic MPA assay, using the same 3 concentration-time points (20 minutes, 1 hour, and 3 hours post dose) as with LC-MS/MS, with a median bias versus reference (trapezoidal) AUC0-12h values of -1.3% (range -45.2% to 40.4%), and 83% of the patients within +/-20% of the reference. These Bayesian estimates were significantly higher than those obtained with LC-MS/MS in patients on cyclosporine or sirolimus, but not in patients on tacrolimus.
authors: INSERM UMR-S850, University of Limoges, CHU Limoges, France. pierre.marquet@unilim.fr
authors: Pierre
authors: P
authors: Marquet
authors: Franck
authors: F
authors: Saint-Marcoux
authors: Aurélie
authors: A
authors: Prémaud
authors: François-Ludovic
authors: FL
authors: Sauvage
authors: Evelyne
authors: E
authors: Jaqz-Aigrain
authors: Christiane
authors: C
authors: Knoop
authors: Yvon
authors: Y
authors: Lebranchu
authors: Marco
authors: M
authors: Tiberi
authors: Ingrid
authors: I
authors: Domke
authors: Jean
authors: J
authors: Debord
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics; D002648:Child; D016572:Cyclosporine / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006085:Graft Survival / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D020123:Sirolimus / Q000493:pharmacokinetics; D016559:Tacrolimus / Q000493:pharmacokinetics*; D014184:Transplantation, Homologous
chemical_list: D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus