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The shape of the myelosuppression time profile is related to the probability of developing neutropenic fever in patients with docetaxel-induced grade IV neutropenia
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Pharmacometrics Research Group)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Pharmacometrics Research Group)
2012 (English)In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 69, no 4, 881-890 p.Article in journal (Refereed) Published
Abstract [en]


Chemotherapy-induced neutropenia is associated with the risk of developing febrile neutropenia (FN). The aim was to describe the time course of myelosuppression in breast cancer patients treated with docetaxel and to investigate how the shape of the predicted myelosuppression time course and earlier proposed risk factors influence the probability of developing FN.


Neutrophil counts from 140 breast cancer patients with observed grade IV neutropenia during the first course of docetaxel treatment were included. Twenty-six of the patients (19%) experienced FN. The myelosuppression time course was described using a semi-mechanistic myelosuppression model in NONMEM. The individual myelosuppression model parameters [baseline neutrophil count, mean transit time (MTT) and drug effect parameter (EC50)], myelosuppression descriptors (nadir, duration of grade IV neutropenia) and earlier suggested risk factors (age, performance status, haemoglobin and liver function) were explored to be related to FN by logistic regression.


The neutrophil time course following docetaxel treatment was well described by the model. EC50 and MTT were both significantly related to the probability of developing FN where low parameter values result in a rapid decline, low nadir and an increased risk of FN. None of the evaluated risk factors or myelosuppression descriptors were significant.


The probability to develop FN in patients who experience grade IV neutropenia was dependent on the myelosuppression time profile. Patients with a rapid neutrophil decline and high drug sensitivity had a higher probability to develop FN. Model-based parameter estimates were superior predictors over descriptive values such as the nadir or duration of neutropenia.

Place, publisher, year, edition, pages
2012. Vol. 69, no 4, 881-890 p.
Keyword [en]
Oncology, Haematological toxicity, Febrile neutropenia, NONMEM
National Category
Cancer and Oncology
URN: urn:nbn:se:uu:diva-170733DOI: 10.1007/s00280-011-1769-7ISI: 000302327300004OAI: oai:DiVA.org:uu-170733DiVA: diva2:509446
Available from: 2012-03-12 Created: 2012-03-12 Last updated: 2012-05-09Bibliographically approved
In thesis
1. Pharmacometric Models for Biomarkers, Side Effects and Efficacy in Anticancer Drug Therapy
Open this publication in new window or tab >>Pharmacometric Models for Biomarkers, Side Effects and Efficacy in Anticancer Drug Therapy
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

New approaches quantifying the effect of treatment are needed in oncology to improve the drug development process and to enable treatment optimization for existing therapies. This thesis focuses on the development of pharmacometric models for biomarkers, side effects and efficacy in order to identify predictors of clinical response in anti-cancer drug therapy.

The variability in myelosuppression was characterized in six different cytotoxic anticancer treatments to evaluate a model-based dose individualization approach utilizing neutrophil counts as a biomarker. The estimated impact of inter-occasion variability was relatively low in relation to the inter-individual variability, indicating that myelosuppression is predictable from one treatment course to another. The approach may thereby be useful for dose optimization within an individual.

To further study and to identify predictors for the severe side effect febrile neutropenia (FN), the relationship between the shape of the myelosuppression time-course and the probability of FN was characterized. Patients with a rapid decline in neutrophil counts and high drug sensitivity were identified to have a higher probability of developing FN compared with other patients who experience grade 4 neutropenia.

Predictors of clinical response in patients receiving sunitinib for the treatment of gastro-intestinal stromal tumor (GIST) were identified by the development of an integrated modeling framework. Drug exposure, biomarkers, tumor dynamics, side effects and overall survival (OS) were linked in a unified structure, and univariate and multivariate exposure variables were tested for their predictive capacities. The soluble biomarker, sVEGFR-3 and tumor size at start of treatment were found to be promising predictors of overall survival, with decreased sVEGFR-3 levels and smaller baseline tumor size being predictive of longer OS. Also hypertension and neutropenia was identified as predictors of OS. The developed modeling framework may be useful to monitor clinical response, optimize dosing in sunitinib and to facilitate dose individualization.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 58 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 157
Pharmacokinetics, Pharmacodynamics, Oncology, Febrile Neutropenia, GIST, Sunitinib
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
urn:nbn:se:uu:diva-170738 (URN)978-91-554-8312-8 (ISBN)
Public defence
2012-05-04, B42, Uppsala Biomedical Center, Husargatan 3, Uppsala, 13:15 (English)
Available from: 2012-04-13 Created: 2012-03-12 Last updated: 2012-04-19Bibliographically approved

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