Pharmacokinetics of irinotecan and its metabolites SN-38 and ABC in children with recurrent solid tumors after protracted low-dose irinotecan

Irinotecan (IRN), a topoisomerase I interactive agent, has significant anti tumor activity in early Phase I studies in children with recurrent solid tu mors. However, the disposition of IRN and its metabolites, SN-38 and APC, i n children has not been reported. Children with solid tumors refractory to conventional therapy received IRN by a 1-h i.v. infusion at either 20, 24, or 29 mg/m(2) daily for 5 consecutive days for 2 weeks, Serial blood sample s were collected after doses 1 and 10 of the first course. IRN, SN-38, and APC lactone concentrations were determined by an isocratic high-performance liquid chromatography assay. A linear four-compartment model was fit simul taneously to the IRN, SN-38, and APC plasma concentration versus time data. Systemic clearance rate for IRN was 58.7 +/- 18.8 liters/h/m(2) (mean +/- SD). The mean +/- SD ng/ml.h single day lactone SN-38 area under the concen tration-time curve (AUC(0-->6)) was 90.9 +/- 96.4, 103.7 +/- 62.4, and 95.3 +/- 63.9 at IRN doses of 20, 24, and 29 mg/m(2), respectively, The relativ e extent of IRN conversion to SN-38 and metabolism to APC measured after do se 1 were 0.49 +/- 0.33 and 0.29 +/- 0.17 (mean +/- SD). No statistically s ignificant intrapatient difference was noted for SN-38 area under the conce ntration-time curve. Large interpatient variability in IRN and metabolite d isposition was observed. The relative extent of conversion and the SN-38 sy stemic exposure achieved with this protracted schedule of administration we re much greater than reported in adults or children receiving larger interm ittent doses.