Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Pharmacometric Models for Biomarkers, Side Effects and Efficacy in Anticancer Drug Therapy
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Pharmacometrics Research Group)
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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 157
Keyword [en]
Pharmacokinetics, Pharmacodynamics, Oncology, Febrile Neutropenia, GIST, Sunitinib
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
URN: urn:nbn:se:uu:diva-170738ISBN: 978-91-554-8312-8 (print)OAI: oai:DiVA.org:uu-170738DiVA: diva2:511112
Public defence
2012-05-04, B42, Uppsala Biomedical Center, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2012-04-13 Created: 2012-03-12 Last updated: 2012-04-19Bibliographically approved
List of papers
1. Limited inter-occasion variability in relation to inter-individual variability in chemotherapy-induced myelosuppression
Open this publication in new window or tab >>Limited inter-occasion variability in relation to inter-individual variability in chemotherapy-induced myelosuppression
Show others...
2010 (English)In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 65, no 5, 839-848 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: A previously developed semi-physiological model of chemotherapy-induced myelosuppression has shown consistent system-related parameter and inter-individual variability (IIV) estimates across drugs. A requirement for dose individualization to be useful is relatively low variability between treatment courses (IOV) in relation to IIV. The objective of this study was to evaluate and compare magnitudes of IOV and IIV in myelosuppression model parameters across six different anti-cancer drug treatments.Methods: Neutrophil counts from several treatment courses following therapy with docetaxel, paclitaxel, epirubicin-docetaxel, 5-fluorouracil-epirubicin-cyclophosphamide, topotecan and etoposide were included in the analysis. The myelosuppression model was fitted to the data using NONMEM VI. IOV in the model parameters baseline neutrophil counts (ANC0), mean transit time through the non-mitotic maturation chain (MTT) and the parameter describing the concentration-effect relationship (Slope) were evaluated for statistical significance (P < 0.001).Results: IOV in MTT was significant for all the investigated datasets, except for topotecan, and was of similar magnitude (8-16 CV %). IOV in Slope was significant for docetaxel, topotecan and etoposide (19-39 CV %). For all six investigated datasets the IOV in myelosuppression parameters was lower than the IIV. There was no indication of systematic shifts in the system- or drug sensitivity-related parameters over time across data sets.Conclusion: This study indicates that the semi-physiological model of chemotherapy-induced myelosuppression has potential to be used for prediction of the time-course of myelosuppression in future courses and is thereby a valuable step towards individually tailored anticancer drug therapy.

Keyword
Hematologic toxicity, pharmacodynamics, NONMEM, inter-occasion variability, anti-cancer drugs
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-100507 (URN)10.1007/s00280-009-1089-3 (DOI)000274655500004 ()19680655 (PubMedID)
Available from: 2009-04-02 Created: 2009-04-01 Last updated: 2017-12-13Bibliographically approved
2. The shape of the myelosuppression time profile is related to the probability of developing neutropenic fever in patients with docetaxel-induced grade IV neutropenia
Open this publication in new window or tab >>The shape of the myelosuppression time profile is related to the probability of developing neutropenic fever in patients with docetaxel-induced grade IV neutropenia
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]

Purpose  

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.

Methods  

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.

Results  

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.

Conclusion  

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.

Keyword
Oncology, Haematological toxicity, Febrile neutropenia, NONMEM
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-170733 (URN)10.1007/s00280-011-1769-7 (DOI)000302327300004 ()
Available from: 2012-03-12 Created: 2012-03-12 Last updated: 2017-12-07Bibliographically approved
3. Pharmacokinetic-Pharmacodynamic Modeling of VEGF, sVEGFR-2, -3 and sKIT as Predictors of Tumor Dynamics and Overall Survival Following Sunitinib Treatment in GIST
Open this publication in new window or tab >>Pharmacokinetic-Pharmacodynamic Modeling of VEGF, sVEGFR-2, -3 and sKIT as Predictors of Tumor Dynamics and Overall Survival Following Sunitinib Treatment in GIST
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-170736 (URN)
Available from: 2012-03-12 Created: 2012-03-12 Last updated: 2012-04-19
4. PKPD Modeling of Predictors for Side Effects and Overall Survival in Sunitinb Treated Patients with Gastro Intestinal Stromal Tumor
Open this publication in new window or tab >>PKPD Modeling of Predictors for Side Effects and Overall Survival in Sunitinb Treated Patients with Gastro Intestinal Stromal Tumor
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-170737 (URN)
Available from: 2012-03-12 Created: 2012-03-12 Last updated: 2012-04-19

Open Access in DiVA

fulltext(8156 kB)1761 downloads
File information
File name FULLTEXT01.pdfFile size 8156 kBChecksum SHA-512
a6754a2ba593c3804e7ef8ce2b484497b5bf35d5648328a6206cee8293217b7ca4cd4fc402b05aaf9823378ad8119f8327819b86ae89f8550bb3cab4e18f5e87
Type fulltextMimetype application/pdf