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Nishi-Tokyo-shi, Japan

Kimura T.,Tokyo Womens Medical University | Kimura T.,Childrens Hospital of Philadelphia | Kashiwase S.,Tokyo Womens Medical University | Makimoto A.,National Cancer Hospital Center | And 8 more authors.
International Journal of Clinical Pharmacology and Therapeutics | Year: 2010

Objective: A multicenter Phase I/II study of Irinotecan hydrochloride (CPT-11; 40 - 45 mg/m2/dose) was conducted for the treatment of refractory pediatric solid tumors. The pharmacokinetics of CPT-11 and its metabolites were characterized using both traditional noncompartmental analysis and population pharmacokinetics using NONMEM VI; pharmacokinetic pharmacodynamic relationships of SN-38 with indices of toxicity were also evaluated. Method: 11 patients between 3 and 18 years were enrolled. Pharmacokinetic parameters and consideration of relevant covariates (performance status (PS), BSA, corrected body weight (CBW), exponent of 3/4 on weight, etc.) were evaluated. Relationships between pharmacokinetic parameters of SN-38 and percentage change from baseline in patient biochemical response data were investigated via regression analysis. Result: CPT-11 exhibited a mean clearance (CL) of 15.31 ± 5.95 (l/h) (13.06 ± 3.58 (l/hr/m2)) and AUC 0-∞ of 3547.0 ± 1406.5 (ng x h/ml); the AUC ratio of parent CPT-11 to SN-38 was 5.0%. Based on the population pharmacokinetic analysis, decreasing PS was significantly dependent on reduction in CLof CPT-11 (p < 0.001). The final model for CPT-11 are as follows: CL (l/h) = 1.31 x CBW0.75 (ωCL = 21.7%), Vss (l) = 2.66 x CBW (ωVss = 21.2%), Vc (l) = 1.13 x CBW, inter-compartment CL (l/h) = 0.257 x CBW 0.75. Percentage changes of leucocyte and neutrophil count within a first month treatment were significantly correlated with Cmax of SN-38 (r = 0.78 and r = 0.74) and AUC0-2 of SN-38 (r = 0.73 and r = 0.73). Conclusion: Pharmacokinetic parameters were similar to results published in several past reports. An allometric scaling of CBW0.75 would seem to provide a good index of dosage requirement of CPT-11 in pediatric patients. ©2010 Dustri-Verlag Dr. K. Feistle. Source

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