Defining Algorithms for Efficient Therapeutic Drug Monitoring of Mycophenolate Mofetil in Heart Transplant Recipients

Pharmacokinetics of mycophenolate mofetil (MMF) show large interindividual variability. Concentration-controlled dosing of MMF based on routine therapeutic drug monitoring, which requires area under the concentration-time curve (mycophenolic acid [MPA]-AUC0-12h) determinations, is uncommon. Dose adjustments are based on predose concentrations (C0h) or side effects. The aim of this study was to compare C0hwith postdose concentrations (C0.5h-C12h) and to develop practical methods for estimation of MPA-AUCs on the basis of a limited sampling strategy (LSS) in heart transplant recipients under MMF and tacrolimus maintenance immunosuppression. Full MPA-AUC0-12hprofiles were generated by high-performance liquid chromatography in 28 patients. Statistical analysis for MPA-AUC0-12hwas performed by a case resampling bootstrap method. Bland and Altmann analysis was performed to test agreement between “predicted AUC” and “measured AUC.” C1hprovided the highest coefficient of determination (r2= 0.57) among the concentrations determined during the 12-hour interval, which were correlated with AUC. All other MPA levels were better surrogates of the MPA-AUC0-12hwhen compared with C0h(r2= 0.14). The best estimation of MPA-AUC0-12hwas achieved with four sampling points with the algorithm AUC = 1.25*C1h+ 5.29*C4h+ 2.90*C8h+ 3.61*C10h(r2= 0.95). Since LSS with four time points appeared unpractical, the authors prefer models with three or two points. To optimize practicability, LSS with sample points within the first 2 hours were evaluated resulting in the algorithms: AUC = 1.09*C0.5h+ 1.19*C1h+ 3.60*C2h(r2= 0.84) and AUC = 1.65*C0.5h+ 4.74*C2h(r2= 0.75) for three and two sample points, respectively. The results provide strong evidence for the use of either LSS or the use of time points other than C0hfor therapeutic drug monitoring of MMF. Using the algorithms for the estimation of MPA-AUC0-12hbased on LSS within the first 2 hours after MMF dosing may help to optimize treatment with MMF by individualization of dosing.