Pharmacokinetic and pharmacodynamic investigation of irinotecan hydrochloride in pediatric patients with recurrent or progressive solid tumors.

Objective: A multicenter Phase I/II study of Irinotecan hydrochloride (CPT-11; 40 - 45 mg/m 2 /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 (1/h) (13.06 ± 3.58 (1/hr/m 2 )) and AUC 0-∞ of 3547.0 ± 1406.5 (ng × 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 CL of CPT-11 (p < 0.001). The final model for CPT-11 are as follows: CL (1/h) = 1.31 × CBW 0.75 (ωCL = 21.7%), Vss (1) = 2.66 × CBW (ωVss = 21.2%), Vc (1) = 1.13 × CBW, inter-compartment CL (1/h) = 0.257 x CBW 0.75 . Percentage changes of leucocyte and neutrophil count within a first month treatment were significantly correlated with C max of SN-38 (r = 0.78 and r = 0.74) and AUC 0-2 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 CBW 0.75 would seem to provide a good index of dosage requirement of CPT-11 in pediatric patients.