The pharmacokinetic-pharmacodynamic relationship for mycophenolate mofetilin renal transplantation

Background: Mycophenolate mofetil, a pro-drug for mycophenolic acid, reduce s the likelihood of allograft rejection after renal transplantation. We stu died the relationship between mycophenolic acid pharmacokinetics and the li kelihood of rejection in a randomized concentration-controlled trial. Methods: Under double-blind conditions, recipients of kidney transplants we re followed for evidence of allograft rejection for 6 months. In addition t o mycophenolate mofetil, patients received usual doses of cyclosporine (INN , ciclosporin) and corticosteroids, The dose of mycophenolate mofetil (give n twice daily) was controlled by feedback, with mycophenolic acid area unde r the concentration-time curve (AUC) as the controlled variable. Patients w ere randomly assigned to 1 of 3 target AUC groups. Results: Logistic regression analysis showed a significant (P < .0001) rela tionship between mycophenolic acid AUC and the likelihood of rejection. Hig h mycophenolic acid values were associated with a very low probability of r ejection. An AUC of 15 mu g.h/mL yielded 50% of maximal achievable efficacy with a 4% change of efficacy for a 1 mu g.h/mL change in AUC at the midpoi nt of the logistic curve. Exploratory analyses showed other variables (eg, the maximum observed plasma concentration, predose plasma concentration, an d drug dose) had poorer predictive power for the rejection outcome. Bivaria te regression confirmed the importance of AUC as a highly predictive variab le and showed low predictive value of other variables, once the contributio n of AUC had been considered. The characteristic side effects of mycophenol ate mofetil therapy appeared related to drug dose but not to mycophenolic a cid concentration. Conclusions The AUC of mycophenolic acid is predictive of the likelihood of allograft rejection after renal transplantation in patients receiving myco phenolate mofetil.