Limited sampling strategies drawn within 3 hours postdose poorly predict mycophenolic acid area-under-the-curve after enteric-coated mycophenolate sodium

Previous studies predicted that limited sampling strategies (LSS) for estimation of mycophenolic acid (MPA) area-under-the-curve (AUC(0-12)) after ingestion of enteric-coated mycophenolate sodium (EC-MPS) using a clinically feasible sampling scheme may have poor predictive performance. Failure of LSS was thought to be due to the slow absorption of MPA causing late and variable times of maximum MPA concentration and variable predose concentrations. The aim of this study was to formally test the performance of LSS by developing and validating LSS for estimation of MPA AUC(0-12) after EC-MPS administration. Pharmacokinetic data from 109 renal transplant recipients collected during the maintenance period after transplantation were analysed retrospectively. LSS were developed separately for renal transplant patients who concurrently used cyclosporine (n = 79) and for patients not concurrently treated with cyclosporine (n = 30). Data were split into an index and a validation data set. For clinical feasibility reasons, a LSS could consist of a maximum of 3 sampling time points with the latest sample drawn 2 hours after drug administration. LSS with the latest sample drawn 3 hours after drug administration or even later were also tested. The validation of the developed LSS showed that MPA AUC(0-12) for patients concurrently treated with cyclosporine was best estimated by AUC(0-12) (mg x h x L(-1)) = 36.536 + 1.642 x C0.5 + 0.569 x C1.5 + 0.905 x C2 (r2 = 0.33, bias = -1.0 mg x h x L(-1), precision = 24 mg x h x L(-1)), whereas AUC(0-12) [mg x h x L(-1)] = 19.801 + 1.827 x C0.5 + 1.111 x C1 + 1.429 x C2 was the best AUC(0-12) estimator for patients not cotreated with cyclosporine (r2 = 0.31, bias = 0.4 mg x h x L(-1), precision = 14.5 mg x h x L(-1)). Both LSS showed poor precision and overestimation of AUC(0-12) values below the therapeutic window and underestimation of AUC(0-12) values above the therapeutic window of MPA. Using C3 as latest sampling time point improved the fit slightly, but not satisfactory, with r2 still <0.40 and precision still >14.0 mg x h x L(-1). Estimation of MPA AUC(0-12) with LSS for EC-MPS drawn within 2 or 3 hours postdose in renal transplant recipients in the maintenance period is likely to result in biased and imprecise results