Population Pharmacokinetic-Pharmacodynamic Model for Neutropenia with Patient Subgroup Identification: Comparison across Anticancer Drugs

• DOI: 10.1158/1078-0432.ccr-06-0815
• Publication Date: 2006-09-25T17:02:30Z
• Authors: Charlotte Kloft; Johan Wallin; Anja Henningsson; Etienne Chatelut; Mats O. Karlsson
• Keywords: Pharmacodynamics; Population Pharmacokinetics

Abstract Purpose: Cancer chemotherapy, although based on body surface area, often causes unpredictable myelosuppression, especially severe neutropenia. The aim of this study was to evaluate qualitatively and quantitatively the influence patient-specific characteristics neutrophil concentration-time course, identify patient subgroups, compare covariates system-related pharmacodynamic variable between drugs. Experimental Design: Drug concentration, demographic, clinical chemistry data several trials with docetaxel (637 patients), paclitaxel (45 etoposide (71 or topotecan (191 patients) were included in covariate analysis a physiology-based pharmacokinetic-pharmacodynamic neutropenia model. Comparisons relations across drugs made. Results: A population model incorporating four five relevant factors for each drug explain variability degree duration has been developed. Sex, previous anticancer therapy, performance status, height, binding partners, liver enzymes influenced variables α1-acid glycoprotein, albumin, bilirubin, concomitant cytotoxic agents, administration route changed drug-specific variables. Overall, female pretreated patients had lower baseline concentration. Across-drug comparison revealed that (e.g., age) minor (clinically irrelevant) influences but consistently shifted same direction. Conclusions: These mechanistic models, including parameters, form rationale basis more tailored dosing individual subgroups minimize risk infection thus might contribute successful therapy. In addition, nonsignificant clinically irrelevant parameters suggest these could be negligible trails daily use.