title: Population pharmacokinetics of unbound mycophenolic acid in adult allogeneic haematopoietic cell transplantation: effect of pharmacogenetic factors.
abstract: OBJECTIVE
  To evaluate pharmacogenetic factors as contributors to the variability of unbound mycophenolic acid (MPA) exposure in adult allogeneic haematopoietic cell transplantation (alloHCT) recipients.
  
  
  METHODS
  A population-based pharmacokinetic (PK) model of unbound MPA was developed using non-linear mixed-effects modelling (nonmem). Previously collected intensive unbound MPA PK data from 132 adult alloHCT recipients after oral and intravenous dosing of the prodrug mycophenolate mofetil (MMF) were used. In addition to clinical covariates, genetic polymorphisms in UGT1A8, UGT1A9, UGT2B7 and MRP2 were evaluated for their impact on unbound MPA PK.
  
  
  RESULTS
  Unbound MPA concentration-time data were well described by a two compartment model with first order absorption and linear elimination. For the typical patient (52 years of age, creatinine clearance 86 ml min(-1)), the median estimated values [coefficient of variation, %, (CV)] of systemic clearance, intercompartmental clearance, central and peripheral volumes of MPA were 1610 l h(-1) (37.4%), 541 l h(-1) (75.6%), 1230 l (37.5%), and 6140 l (120%), respectively. After oral dosing, bioavailability was low (0.56) and highly variable (CV 46%). No genetic polymorphisms tested significantly explained the variability among individuals. Creatinine clearance was a small but significant predictor of unbound MPA CL. No other clinical covariates impacted unbound MPA PK.
  
  
  CONCLUSIONS
  In adult alloHCT recipients, variability in unbound MPA AUC was large and remained largely unexplained even with the inclusion of pharmacogenetic information. Targeting unbound MPA AUC in a patient will require therapeutic drug monitoring.
authors: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143, USA.
authors: Adam
authors: A
authors: Frymoyer
authors: Davide
authors: D
authors: Verotta
authors: Pamala
authors: P
authors: Jacobson
authors: Janel
authors: J
authors: Long-Boyle
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001682:Biological Availability; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics; D017711:Nonlinear Dynamics; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D014184:Transplantation, Homologous; D055815:Young Adult
chemical_list: D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid