TY - JOUR
T1 - Pharmacokinetics of irinotecan and its metabolites SN-38 and APC in children with recurrent solid tumors after protracted low-dose irinotecan
AU - Ma, Margaret K.
AU - Zamboni, William C.
AU - Radomski, Kristine M.
AU - Furman, Wayne L.
AU - Santana, Victor M.
AU - Houghton, Peter J.
AU - Hanna, Suzan K.
AU - Smith, Audrey K.
AU - Stewart, Clinton F.
PY - 2000/3
Y1 - 2000/3
N2 - 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.
AB - 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.
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M3 - Article
C2 - 10741701
AN - SCOPUS:0034099228
SN - 1078-0432
VL - 6
SP - 813
EP - 819
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 3
ER -