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

Irinotecan (IRN), a topoisomerase I interactive agent, has significant antitumor activity in early Phase I studies in children with recurrent solid tumors. However, the disposition of IRN and its metabolites, SN-38 and APC, in 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/m² daily for 5 consecutive days for 2 weeks. Serial blood samples 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 simultaneously to the IRN, SN-38, and APC plasma concentration versus time data. Systemic clearance rate for IRN was 58.7 ± 18.8 liters/h/m² (mean ± SD). The mean ± SD ng/ml·h single-day lactone SN-38 area under the concentration-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/m², respectively. The relative extent of IRN conversion to SN-38 and metabolism to APC measured after dose 1 were 0.49 ± 0.33 and 0.29 ± 0.17 (mean ± SD). No statistically significant intrapatient difference was noted for SN-38 area under the concentration-time curve. Large interpatient variability in IRN and metabolite disposition was observed. The relative extent of conversion and the SN-38 systemic exposure achieved with this protracted schedule of administration were much greater than reported in adults or children receiving larger intermittent doses.