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Pharmacodynamic Model of Topotecan-induced Time Course of Neutropenia¹

Program of Molecular Therapeutics and Drug Discovery [W. C. Z., B. J. D., N. M. K., M. J. E.] and Biostatistics Facility [D. M. P.], University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213; Department of Pharmaceutical Sciences, School of Pharmacy [W. C. Z.], University of Pittsburgh, Pittsburgh, Pennsylvania 15213; Departments of Medicine [W. C. Z., M. J. E.] and Pharmacology [M. J. E.], School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213; Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089 [D. Z. D.]; Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105 [C. F. S.]; Center for Pediatric Pharmacokinetics and Therapeutics, University of Tennessee, Memphis, Tennessee 38105 [C. F. S.]; Department of Pathology, University of Maryland, Baltimore, Maryland 21201 [T. M., A. M. F.]; and Department of Hematology Oncology, MD Anderson Cancer Center, Houston, Texas 77030 [D. T.]

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/m²/day without filgrastim (POG), and at 1.7, 2, and 2.4 mg/m²/day with filgrastim (POG+G). In NHPs, topotecan was administered at 5, 10, and 20 mg/m²/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.

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