uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
A simultaneous analysis of the time-course of leukocytes and neutrophils following docetaxel administration using a semi-mechanistic myelosuppression model
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2012 (English)In: Investigational new drugs, ISSN 0167-6997, E-ISSN 1573-0646, Vol. 30, no 2, 833-845 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: To improve the predictive capacity of a semi-mechanistic myelosuppression model for neutrophils as the model have shown to over-predict the nadir of neutrophils and, secondly, to develop a model describing the time-course of leukocytes and neutrophils simultaneously.

Experimental Design: The study included 601 cancer patients treated with a 1 h infusion of docetaxel in monotherapy. A total of 3,549 pairwise observations of leukocytes and neutrophils from one treatment cycle were analyzed simultaneously in NONMEM.

Results: A basic model was developed consisting of a neutrophil and a non-neutrophil model, each with the same structure as the semi-mechanistic myelosuppression model. The leukocytes were modeled as the sum of the predicted neutrophils and non-neutrophils. The model described the time-course of the leukocytes well, but was not able to capture the nadir of the neutrophils. Hence the model was further refined and the included modifications (p < 0.001) in the final model are a sigmoid Emax functions for the drug effect, feedback functions on the cell maturation time in bone-marrow and an optimized number of transit compartments for each of the two cell types.

Conclusions: A joint semi-mechanistic myelosuppression model describing the time-course of leukocytes and neutrophils following docetaxel administration was developed. The data supported a more complex model compared to the previous model developed by Friberg et al. (2002), and increased the model's capacity to accurately describe the time-course of neutrophils following docetaxel therapy. The combined model also illustrates the differences between the cell types and allows prediction of neutrophil counts from leukocyte measurements.

Place, publisher, year, edition, pages
2012. Vol. 30, no 2, 833-845 p.
Keyword [en]
Docetaxel, NONMEM, Myelosuppression, Neutropenia, Population pharmacokineticpharmacodynamic modeling, Pharmacometrics
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-150427DOI: 10.1007/s10637-010-9603-3ISI: 000300160800048PubMedID: 21153753OAI: oai:DiVA.org:uu-150427DiVA: diva2:407342
Available from: 2011-03-30 Created: 2011-03-30 Last updated: 2012-03-08Bibliographically approved
In thesis
1. Pharmacometric Models for Improved Prediction of Myelosuppression and Treatment Response in Oncology
Open this publication in new window or tab >>Pharmacometric Models for Improved Prediction of Myelosuppression and Treatment Response in Oncology
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Chemotherapy plays an important role in the treatment of cancer. However, these drugs also cause death of non-malignant cells, resulting in severe side-effects. In addition, drug resistance may exist. Predictive tools for dose and drug selection are therefore warranted. In this thesis predictive pharmacometric models were developed for the main dose-limiting side-effect, neutropenia, and for treatment response following chemotherapy.

Neutropenia is associated with a high risk for life-threatening infections and leads frequently to reduced dose delivery and thereby suboptimal treatment of the tumor. A better characterization of the dynamics of docetaxel induced neutropenia was obtained by simultaneous analysis of neutrophils and leukocytes. The fraction of neutrophils was shown to change over the time-course, hence leukocytes and neutrophil counts are not interchangeable biomarkers. Sometimes neutrophil count is reported as categorical severity of neutropenia (Grade 0-4). A method was developed that allowed analysis of these data closer to its true continuous nature. The main regulatory hormone of neutrophils is granulocyte colony stimulating factor (G-CSF). Although recombinant G-CSF is used as supportive therapy to prevent neutropenia, little is known of how the endogenous G-CSF concentrations vary in patients following chemotherapy. A prospective study was carried out and simultaneous analysis of endogenous G-CSF and neutrophils following chemotherapy enabled a more mechanistic model to be developed that also could verify the self-regulatory properties of the physiological system.

Patient characteristics were investigated using a pharmacokinetic-myelosuppression model for docetaxel in patients with normal and impaired liver function. The model was a useful tool in evaluating different dosing strategies and a reduced dosing scheme was suggested in patients with poor liver function, thereby enabling docetaxel treatment in this patient population which has previously been excluded. Treatment of acute myeloid leukemia with daunorubicin and cytarabine is associated with drug resistance and high variability in pharmacokinetics, which was partly explained for daunorubicin by peripheral leukocyte count. An integrated model of the in vitro drug sensitivity and treatment response showed that in vitro drug sensitivity was predictive for treatment outcome in this patient population and may therefore be used for choice of drug.

The developed pharmacometric models in this thesis may be useful in the optimization of treatments schedules for existing and new drugs as well as to assist in drug and dose selection to improve therapy in an individual patient. The models and methods presented may also facilitate pooled analysis of data and demonstrate principles which could be useful for the pharmacometric community.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 78 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 144
pharmacometrics, oncology, myelosuppression, chemotherapy, pharmacokinetics, pharmacodynamics
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
urn:nbn:se:uu:diva-150431 (URN)978-91-554-8046-2 (ISBN)
Public defence
2011-05-06, Room B41, Uppsala Biomedical Center, Husargatan 3, Uppsala, 13:15 (English)
Available from: 2011-04-15 Created: 2011-03-30 Last updated: 2011-05-05Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Quartino, AngelicaFriberg, Lena EKarlsson, Mats O
By organisation
Department of Pharmaceutical Biosciences
In the same journal
Investigational new drugs
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 245 hits
ReferencesLink to record
Permanent link

Direct link