Limited sampling strategy for the estimation of mycophenolic acid area under the plasma concentration-time curve in adult patients undergoing liver transplant

Mycophenolate mofetil (MMF), the oral prodrug of mycophenolic acid (IMPA), is increasingly used in liver transplantation and plays a central role in the immunosuppressive regimen in liver transplantation. To study pharmacokinetic-pharmacodynamic relationships and therapeutic drug monitoring of MPA in the clinical setting, limited sampling strategies have been investigated for the estimation of MPA areas under the curves (AUCs). Thirty-eight adult patients undergoing liver transplant (31 males, seven females) receiving 1.0 g MMF twice daily and concomitant tacrolimus provided a total of 72 pharmacokinetic profiles. Multiple stepwise regression analysis was used to determine the algorithms for limited sampling strategies. Twenty-eight one-, two-, three-, and four-sampling estimation models were fitted (r(2) = 0.288-0.964) to all the profiles using linear regression and were used to estimate MPA AUC(0-12h) comparing those estimates with the corresponding AUC(0-12h), values calculated with the linear trapezoidal rule, including all 10 timed MPA concentrations. The four-point estimates at C-1h, C-2h, C-6h, and C-8h resulted in the best correlation between estimated AUC and true AUC when using the formula AUC = 6.03 + 0.89C(1h) + 1.94C(2h) + 2.24C(6h) + 4.64C(8h) (r(2) = 0.911). Bland and Altman analysis revealed good agreement between estimated AUC and AUC from the full profile. This limited sampling strategy provides an effective approach for estimation of full MPA AUC(0-12h), in patients undergoing liver transplant receiving concomitant tacrolimus therapy.