Limited sampling model for the area under the concentration versus time curve of irinotecan and its application to a multicentric phase II trial

We previously established a limited sampling model (LSM) for the area under the concentration versus time curve (AUC) of irinotecan (CPT-11). Using this LSM, we performed a pharmacokinetic-pharmacodynamic analysis of CPT-11 in a multicentric Phase II study for non-small cell lung cancer. Ten institutes participated in this study, 36 patients were registered, and 30 patients were evaluable for the pharmacokinetic-pharmacodynamic analysis. CPT-11 and etoposide were administered daily for three consecutive days, both at a dose of 60 mg/m2. Blood samples were obtained 4 and 8 h after infusion on days 1 and 3. When using the LSM, there is a significant possible source of error in the timing of these selected points. In this study, however, the sample timing error was small. Mean timing errors were 1.0-4.0 min at each point. The estimated CPT-11 AUCs were: Day 1 Day 2 Day 1 + 3 Mean +/- SD (mg.h/liter) 3.76+/-0.68 4.10+/-0.86 7.86+/-1.43 Range 2.01-5.03 2. 29-5.72 4.30-10.68 Max/min 2.50 2.45 2.48 High interpatient variability was observed in the AUC. The CPT-11 AUC correlated positively with the grade of emesis (P = 0.003) and the percent decreases in WBC count (P = 0.001) and absolute neutrophil count (P =0.0006), but it did not correlate with the grade of diarrhea or response. We concluded that the LSM was useful in estimating individual pharmacokinetic parameters in multicentric trials.