LIMITED SAMPLING MODELS FOR SIMULTANEOUS ESTIMATION OF THE PHARMACOKINETICS OF IRINOTECAN AND ITS ACTIVE METABOLITE SN-38

Irinotecan (CPT-11) is a novel topoisomerase I inhibitor with clinical activity in human malignancies. The objective of this study was to de velop efficient limited sampling models (LSMs) to estimate simultaneou sly the area under the plasma concentration versus time curves (AUG) f or both CPT-11 and its active metabolite SN-38. A total of 64 pharmaco kinetic sets (greater than or equal to 24-h sampling) were obtained in phase I studies at doses ranging from 50 to 750 mg/m(2) (0.5-h i.v. i nfusion). The patients were randomly assigned to a training data set ( n = 32) and a test set (n = 32). Multiple linear regression analyses w ere used to determine the optimal LSMs based on the correlation coeffi cient (r), bias (MPE%, percentage of mean prediction error), and preci sion (RMSE%, percentage of root mean squared prediction error). Of the se LSMs, the ones including maximal concentrations of CPT-11 (0.5 h, t he end of the i.v. infusion) and metabolite SN-38 (approximate to 1 h) were favored along with predictive precision and clinical constraints . Several bivariate models including a 6-h time point as the last samp ling time (or 7 h) were found to be highly predictive of either the CP T-11 AUC or the SN-38 AUG. The chosen sampling time points were the on es that allowed the best compromise between the accurate determination of either compound alone with the same sampling times. The simultaneo usly best prediction of both CPT-11 and SN-38 AUCs was obtained with s ampling time points harvested at 0.5, 1, and 6 h (or 7 h). With these sampling time points a trivariate model was selected for the determina tion of CPT-11 AUC namely, CPT-11 AUC (ng h ml(-1)) = 0.820 x C-0.5h 0.402 x C-1h + 15.47 x C-6h + 928, and a corresponding model was sele cted for the determination of metabolite AUG, i.e., SN-38 AUC (ng h ml (-1)) = 4.05 x C-0.5h -0.81 x C-1h + 23.01 x C-6h -69.78, where C(t) i s the concentration in nanograms per milliliter of either compound at a given time t. These models performed well with the test data sets fo r CPT-11 AUC (r = 0.98, MPE% = -1.4, RMSE% = 13.9) and for SN-38 AUC ( r = 0.95, MPE% = -6.5, RMSE% = 37.7). In addition to the determination of AUCs (and hence clearance), these models also allow the determinat ion of the maximal concentrations of both compounds, which might be ne eded for pharmacodynamics studies. Other bi- and trivariate models inc luding other time points are also presented. These LSMs not only will facilitate ongoing and future clinical trials by significantly reducin g the number of blood samples needed for pharmacokinetics studies but will hopefully contribute to a better knowledge of pharmacokinetic-pha rmacodynamic relationships for both CPT-11 and its active metabolite S N-38.