Pharmacodynamic model of topotecan-induced time course of neutropenia

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 mode l to describe and quantify the time course of neutropenia after administrat ion of topotecan to children and to compare this with nonhuman primates (NH Ps) as a potential preclinical model of neutropenia. Topotecan was administ ered 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 m g/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-pharmacodyn amic model was fit to profiles of topotecan lactone plasma concentrations a nd neutrophil survival fraction from cycle 1 and used to calculate topoteca n lactone area under the plasma concentration-versus-time curve from 0 to 1 20 h (AUC(LAC)) and the area between the baseline and treatment-related neu trophil 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 s ensitivity to chemotherapy-induced neutropenia.