title: Mycophenolic mofetil optimized pharmacokinetic modelling, and exposure-effect associations in adult heart transplant recipients.
abstract: Mycophenolic acid (MPA) area under the curve (AUC) has been associated with graft outcome.
  
  
  OBJECTIVE
  (1) to develop pharmacokinetic tools to optimize MPA inter-dose AUC estimation in heart transplant patients; and (2) to investigate the relationships between acute allograft rejection and MPA AUC, trough level (C0) or mycophenolate mofetil (MMF) dose. Two independent modeling approaches (parametric and non parametric) were used to fit 56 rich MPA pharmacokinetic (PK) profiles collected from 40 adult heart transplant recipients enrolled in the PIGREC study, receiving MMF and a calcineurin inhibitor (CNI), in the first year post-transplantation. In addition, associations between drug exposure (MPA C0, AUC and MMF dose) and acute rejection or MMF adverse events were investigated using time-dependent Cox models with stratification on the type of calcineurin inhibitor. Exposure threshold values were investigated using ROC curve analysis. The 2 models developed fit adequately the data and the use of their combination yielded 100% consistency with the measured AUC in terms of strategy of dose adjustment (maintain, increase or decrease). MPA measured AUC adjusted on CNI exposure was significantly associated with rejection (per unit increase: HR [95% CI]=0.97 [0.95-0.99], p=0.0122), while no effect was shown for adverse events attributable to MMF. An AUC threshold of 50 mg×h/L was proposed (sensitivity=77%, specificity=25%) beyond which the risk of rejection was significantly increased (low vs. high: HR=3.48 [1.21-10.0], p=0.0204). The tools developed have already been made available to the heart transplant community on our ISBA website (https://pharmaco.chu-limoges.fr).
authors.affiliation: Department of Pharmacology and Toxicology, University Hospital of Limoges, France; UMR 850 INSERM, University of Limoges, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Woillard
authors.affiliation: Department of Pharmacology and Toxicology, University Hospital of Limoges, France; UMR 850 INSERM, University of Limoges, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Saint-Marcoux
authors.affiliation: Department of Pharmacology and Toxicology, University Hospital of Limoges, France; UMR 850 INSERM, University of Limoges, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Monchaud
authors.affiliation: Department of Pharmacology and Toxicology, University Hospital of Limoges, France.
authors.forename: Rym
authors.initials: R
authors.lastname: Youdarène
authors.affiliation: Department of Pharmacology and Toxicology, University Hospital of Limoges, France; UMR 850 INSERM, University of Limoges, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Pouche
authors.affiliation: Department of Pharmacology and Toxicology, University Hospital of Limoges, France; UMR 850 INSERM, University of Limoges, France. Electronic address: pierre.marquet@unilim.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Marquet
mesh_terms: D000328:Adult; D019540:Area Under Curve; D065095:Calcineurin Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D006084:Graft Rejection / Q000188:drug therapy*; D016027:Heart Transplantation / Q000379:methods; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D012372:ROC Curve; D055815:Young Adult
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid
keywords: Area under the curve; Graft rejection; Heart transplantation; Mycophenolate mofetil; Pharmacokinetics; Pharmacokinetics/pharmacodynamics