title: A limited sampling model for estimation of total and unbound mycophenolic acid (MPA) area under the curve (AUC) in hematopoietic cell transplantation (HCT).
abstract: OBJECTIVE
  Renal transplant patients with suboptimal mycophenolic acid (MPA) areas under the curves (AUCs) are at greater risk of acute rejection. In hematopoietic cell transplantation, a low MPA AUC is also associated with a higher incidence of acute graft versus host disease. Therefore, a limited sampling model was developed and validated to simultaneously estimate total and unbound MPA AUC0-12 in hematopoietic cell transplantation patients.
  
  
  METHODS
  Intensive pharmacokinetic sampling was performed at steady state between days 3 to 7 posttransplant in 73 adult subjects while receiving prophylactic mycophenolate mofetil 1 g per 12 hours orally or intravenously plus cyclosporine. Total and unbound MPA plasma concentrations were measured, and total and unbound AUC0-12 was determined using noncompartmental analysis. Regression analysis was then performed to build IV and PO, total and unbound AUC0-12 models from the first 34 subjects. The predictive performance of these models was tested in the next 39 subjects.
  
  
  RESULTS
  Trough concentrations poorly estimate observed total and unbound AUC0-12 (r<0.48). A model with 3 concentrations (2-, 4-, and 6-hour post start of infusion) best estimated observed total and unbound AUC0-12 after IV dosing (r>0.99). Oral total and unbound AUC0-12 was more difficult to estimate and required at least 4 concentrations (0-, 1-, 2-, and 6-hour post dose) in the model (r>0.85). The predictive performance of the final models was good. Eighty-three percent of IV and 70% of PO AUC0-12 predictions fell within +/-20% of the observed values without significant bias.
  
  
  CONCLUSIONS
  Trough MPA concentrations do not accurately describe MPA AUC0-12. Three intravenous (2-, 4-, 6-hour post start of infusion) or 4 oral (0-, 1-, 2-, and 6-hour post dose) MPA plasma concentrations measured over a 12-hour dosing interval will estimate the total and unbound AUC0-12 nearly as well as intensive pharmacokinetic sampling with good precision and low bias. This approach simplifies AUC0-12 targeting of MPA post hematopoietic cell transplantation.
authors.affiliation: Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Juki
authors.initials: J
authors.lastname: Ng
authors.forename: John
authors.initials: J
authors.lastname: Rogosheske
authors.forename: Juliet
authors.initials: J
authors.lastname: Barker
authors.forename: Daniel
authors.initials: D
authors.lastname: Weisdorf
authors.forename: Pamala A
authors.initials: PA
authors.lastname: Jacobson
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000008:administration & dosage; D016903:Drug Monitoring / Q000379:methods*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008954:Models, Biological; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D013056:Spectrophotometry, Ultraviolet
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid