title: The pharmacokinetic-pharmacodynamic relationship for mycophenolate mofetil in renal transplantation.
abstract: BACKGROUND
  Mycophenolate mofetil, a pro-drug for mycophenolic acid, reduces the likelihood of allograft rejection after renal transplantation. We studied the relationship between mycophenolic acid pharmacokinetics and the likelihood of rejection in a randomized concentration-controlled trial.
  
  
  METHODS
  Under double-blind conditions, recipients of kidney transplants were followed for evidence of allograft rejection for 6 months. In addition to mycophenolate mofetil, patients received usual doses of cyclosporine (INN, ciclosporin) and corticosteroids. The dose of mycophenolate mofetil (given twice daily) was controlled by feedback, with mycophenolic acid area under the concentration-time curve (AUC) as the controlled variable. Patients were randomly assigned to 1 of 3 target AUC groups.
  
  
  RESULTS
  Logistic regression analysis showed a significant (P < .0001) relationship between mycophenolic acid AUC and the likelihood of rejection. High mycophenolic acid values were associated with a very low probability of rejection. An AUC of 15 micrograms.h/mL yielded 50% of maximal achievable efficacy with a 4% change of efficacy for a 1 microgram.h/mL change in AUC at the midpoint of the logistic curve. Exploratory analyses showed other variables (e.g., the maximum observed plasma concentration, predose plasma concentration, and drug dose) had poorer predictive power for the rejection outcome. Bivariate regression confirmed the importance of AUC as a highly predictive variable and showed low predictive value of other variables, once the contribution of AUC had been considered. The characteristic side effects of mycophenolate mofetil therapy appeared related to drug dose but not to mycophenolic acid concentration.
  
  
  CONCLUSIONS
  The AUC of mycophenolic acid is predictive of the likelihood of allograft rejection after renal transplantation in patients receiving mycophenolate mofetil.
authors.affiliation: Roche Global Development, Palo Alto, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Hale
authors.forename: A J
authors.initials: AJ
authors.lastname: Nicholls
authors.forename: R E
authors.initials: RE
authors.lastname: Bullingham
authors.forename: R
authors.initials: R
authors.lastname: Hené
authors.forename: A
authors.initials: A
authors.lastname: Hoitsma
authors.forename: J P
authors.initials: JP
authors.lastname: Squifflet
authors.forename: W
authors.initials: W
authors.lastname: Weimar
authors.forename: Y
authors.initials: Y
authors.lastname: Vanrenterghem
authors.forename: F J
authors.initials: FJ
authors.lastname: Van de Woude
authors.forename: G A
authors.initials: GA
authors.lastname: Verpooten
mesh_terms: D019540:Area Under Curve; D004311:Double-Blind Method; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D016030:Kidney Transplantation; D016015:Logistic Models; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D011237:Predictive Value of Tests; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid