A Limited Sampling Model for Estimating Pharmacokinetics of CPT‐11 and Its Metabolite SN‐38

The objective of this study was to develop a limited sampling model (LSM) to estimate the area under the curve (AUC) of 7‐ethyl‐10‐[4‐(1‐piperidino)‐1‐piperidino]carbonyloxycamptothecin (CPT‐11) and that of 7‐ethyl‐10‐hydroxycamptothecin (SN‐38) as predictive pharmacokinetic variables for leukopenia and episodes of diarrhea induced by CPT‐11 administration. The model was developed with a training set consisting of pharmacokinetic studies in 36 patients who received a 90‐min i.v. infusion of CPT‐11 at a dose of 100 mg/m 2 . A multiple regression analysis of CPT‐11 or SN‐38 concentrations observed at each time point in the training set was used to predict the AUC of CPT‐11 or SN‐38. The final sampling models using only two time points were: AUC CPT‐11 =3.7891★C2.5+14.0479*C13.5+1.5463 AUC SN‐38 =0.5319★C2.5+19.1468*C13.5+72.7349 where C2.5 and C13.5 are the plasma concentration of CPT‐11 (μg/ml) or SN‐38 (ng/ml) at 2.5 and 13.5 h after the initiation of CPT‐11 infusion, respectively. The models were validated prospectively on a separate test data set of 12 patients receiving the same dose of CPT‐11 investigated in a previous study. Validation of the final LSM on the test data set gave values of root mean square error (RMSE) of 12.72% and 5.97% for the AUC of CPT‐11 and that of SN‐38, respectively. The model can be used to monitor the AUCs of both CPT‐11 and SN‐38 for the early prediction of toxicities and to establish a pharmacokinetically based dose modification strategy for safe administration of CPT‐11.