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 (L SM) to estimate the area under the curve (AUG) of 1-piperidino)-1-pipe ridino]carbonyloxycamptothecin (CPT-11) and that of 7-ethyl-10-hydroxy camptothecin (SN-38) as predictive pharmacokinetic variables for leuko penia and episodes of diarrhea induced by CPT-11 administration, The m odel was developed with a training set consisting of pharmacokinetic s tudies 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 + 14.047 9 C13.5 + 1.5463 AUC(SN.38) = 0.5319 * C2.5 + 19.1468 * C13.5 + 72.7 349 where C2.5 and C13.5 are the plasma concentration of CPT-11 (mu g/ 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 s eparate 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% a nd 5.97% for the AUC of CPT-11 and that of SN-38, respectively, The mo del can be used to monitor the AUCs of both CPT-11 and SN-38 for the e arly prediction of toxicities and to establish a pharmacokinetically b ased dose modification strategy for safe administration of CPT-11.