title: Pharmacodynamic model of topotecan-induced time course of neutropenia.
abstract: Pharmacodynamic measures of neutropenia, such as absolute neutrophil count at nadir and neutrophil survival fraction, may not reflect the overall time course of neutropenia. We developed a pharmacokinetic-pharmacodynamic model to describe and quantify the time course of neutropenia after administration of topotecan to children and to compare this with nonhuman primates (NHPs) as a potential preclinical model of neutropenia. Topotecan was administered as a 30-min infusion daily for 5 days, repeated every 21 days. As part of a Phase I Pediatric Oncology Group study, topotecan was administered at 1.4 and 1.7 mg/m(2)/day without filgrastim (POG), and at 1.7, 2, and 2.4 mg/m(2)/day with filgrastim (POG+G). In NHPs, topotecan was administered at 5, 10, and 20 mg/m(2)/day without filgrastim. A pharmacokinetic-pharmacodynamic model was fit to profiles of topotecan lactone plasma concentrations and neutrophil survival fraction from cycle 1 and used to calculate topotecan lactone area under the plasma concentration-versus-time curve from 0 to 120 h (AUC(LAC)) and the area between the baseline and treatment-related neutrophil survival fraction (ABC) from 0 to 700 h. The mean +/- SD neutrophil survival fraction at nadir for the POG, POG+G, and NHP groups was 0.12 +/- 0.09, 0.11 +/- 0.17, and 0.09 +/- 0.08, respectively (P > 0.05). The mean +/- SD for the ratio of ABC to AUC(LAC) for the POG and NHP groups was 1.02 +/- 0.38 and 0.16 +/- 0.09, respectively (P < 0.05). The model estimate of ABC and the ratio of ABC to AUC(LAC) in children and NHPs may better reflect sensitivity to chemotherapy-induced neutropenia.
authors.affiliation: Program of Molecular Therapeutics and Drug Discovery, University of Pittsburgh Cancer Institute, Biomedical Science Tower E-1040, 200 Lothrop Street, Pittsburgh, PA 15213, USA. zamboniwc@msx.upmc.edu
authors.forename: W C
authors.initials: WC
authors.lastname: Zamboni
authors.forename: D Z
authors.initials: DZ
authors.lastname: D'Argenio
authors.forename: C F
authors.initials: CF
authors.lastname: Stewart
authors.forename: T
authors.initials: T
authors.lastname: MacVittie
authors.forename: B J
authors.initials: BJ
authors.lastname: Delauter
authors.forename: A M
authors.initials: AM
authors.lastname: Farese
authors.forename: D M
authors.initials: DM
authors.lastname: Potter
authors.forename: N M
authors.initials: NM
authors.lastname: Kubat
authors.forename: D
authors.initials: D
authors.lastname: Tubergen
authors.forename: M J
authors.initials: MJ
authors.lastname: Egorin
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D017321:Clinical Trials, Phase I as Topic; D004195:Disease Models, Animal; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D009504:Neutrophils / Q000187:drug effects; D011994:Recombinant Proteins; D013997:Time Factors; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D011994:Recombinant Proteins; D059004:Topoisomerase I Inhibitors; D016179:Granulocyte Colony-Stimulating Factor; D019772:Topotecan; D000069585:Filgrastim