title: Pharmacokinetic and pharmacodynamic investigation of irinotecan hydrochloride in pediatric patients with recurrent or progressive solid tumors.
abstract: 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.
  
  
  METHODS
  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.
  
  
  RESULTS
  CPT-11 exhibited a mean clearance (CL) of 15.31 +/- 5.95 (l/h) (13.06 +/- 3.58 (l/hr/m(2))) and AUC(0-inf) 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 CL of CPT-11 (p < 0.001). The final model for CPT-11 are as follows: CL (l/h) = 1.31 x CBW(0.75) (omegaCL = 21.7%), Vss (l) = 2.66 x CBW (omegaVss = 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacy, Tokyo Women's Medical University Hospital Center, Tokyo, Japan. t.kimura@pha.twmu.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Kimura
authors.forename: S
authors.initials: S
authors.lastname: Kashiwase
authors.forename: A
authors.initials: A
authors.lastname: Makimoto
authors.forename: M
authors.initials: M
authors.lastname: Kumagai
authors.forename: T
authors.initials: T
authors.lastname: Taga
authors.forename: Y
authors.initials: Y
authors.lastname: Ishida
authors.forename: K
authors.initials: K
authors.lastname: Ida
authors.forename: Y
authors.initials: Y
authors.lastname: Nagatoshi
authors.forename: H
authors.initials: H
authors.lastname: Mugishima
authors.forename: M
authors.initials: M
authors.lastname: Kaneko
authors.forename: J S
authors.initials: JS
authors.lastname: Barrett
mesh_terms: D000293:Adolescent; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D019540:Area Under Curve; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D000077146:Irinotecan; D007958:Leukocyte Count; D008297:Male; D008954:Models, Biological; D009364:Neoplasm Recurrence, Local; D009369:Neoplasms / Q000188:drug therapy*; D009504:Neutrophils / Q000378:metabolism; D017711:Nonlinear Dynamics; D012044:Regression Analysis
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin