Population Pharmacokinetic-Pharmacodynamic Model for Neutropenia with Patient Subgroup Identification: Comparison across Anticancer Drugs
Open Access
- 15 September 2006
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 12 (18), 5481-5490
- https://doi.org/10.1158/1078-0432.ccr-06-0815
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 of patient-specific characteristics on the neutrophil concentration-time course, to identify patient subgroups, and to compare covariates on system-related pharmacodynamic variable between drugs. Experimental Design: Drug and neutrophil concentration, demographic, and clinical chemistry data of several trials with docetaxel (637 patients), paclitaxel (45 patients), etoposide (71 patients), or topotecan (191 patients) were included in the covariate analysis of a physiology-based pharmacokinetic-pharmacodynamic neutropenia model. Comparisons of covariate relations across drugs were made. Results: A population model incorporating four to five relevant patient factors for each drug to explain variability in the degree and duration of neutropenia has been developed. Sex, previous anticancer therapy, performance status, height, binding partners, or liver enzymes influenced system-related variables and α1-acid glycoprotein, albumin, bilirubin, concomitant cytotoxic agents, or administration route changed drug-specific variables. Overall, female and pretreated patients had a lower baseline neutrophil concentration. Across-drug comparison revealed that several covariates (e.g., age) had minor (clinically irrelevant) influences but consistently shifted the pharmacodynamic variable in the same direction. Conclusions: These mechanistic models, including patient characteristics that influence drug-specific parameters, form the rationale basis for more tailored dosing of individual patients or subgroups to minimize the risk of infection and thus might contribute to a more successful therapy. In addition, nonsignificant or clinically irrelevant relations on system-related parameters suggest that these covariates could be negligible in clinical trails and daily use.Keywords
This publication has 37 references indexed in Scilit:
- Model Describing the Relationship Between Pharmacokinetics and Hematologic Toxicity of the Epirubicin-Docetaxel Regimen in Breast Cancer PatientsJournal of Clinical Oncology, 2005
- Incidence and Predictors of Low Chemotherapy Dose-Intensity in Aggressive Non-Hodgkin's Lymphoma: A Nationwide StudyJournal of Clinical Oncology, 2004
- The role of topotecan for extending the platinum-free interval in recurrent ovarian cancer: an in vitro modelGynecologic Oncology, 2004
- Impact of Body-Size Measures on Irinotecan Clearance: Alternative Dosing RecommendationsJournal of Clinical Oncology, 2002
- Conventional Compared with Individualized Chemotherapy for Childhood Acute Lymphoblastic LeukemiaNew England Journal of Medicine, 1998
- Xpose—an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEMComputer Methods and Programs in Biomedicine, 1998
- Ethnic and sex differences in the total and differential white cell count and platelet count.Journal of Clinical Pathology, 1996
- Is Dose Normalization to Weight or Body Surface Area Useful in Adults?JNCI Journal of the National Cancer Institute, 1990
- Analysis of pharmacokinetic data using parametric models. III. Hypothesis tests and confidence intervalsJournal of Pharmacokinetics and Biopharmaceutics, 1986
- Normal haematological values: sex difference in neutrophil count.BMJ, 1975