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Pharmacometric Models for Improved Prediction of Myelosuppression and Treatment Response in Oncology
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 144
Keyword [en]
pharmacometrics, oncology, myelosuppression, chemotherapy, pharmacokinetics, pharmacodynamics
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
URN: urn:nbn:se:uu:diva-150431ISBN: 978-91-554-8046-2OAI: oai:DiVA.org:uu-150431DiVA: diva2:407356
Public defence
2011-05-06, Room B41, Uppsala Biomedical Center, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2011-04-15 Created: 2011-03-30 Last updated: 2011-05-05Bibliographically approved
List of papers
1. A simultaneous analysis of the time-course of leukocytes and neutrophils following docetaxel administration using a semi-mechanistic myelosuppression model
Open this publication in new window or tab >>A simultaneous analysis of the time-course of leukocytes and neutrophils following docetaxel administration using a semi-mechanistic myelosuppression model
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.

Keyword
Docetaxel, NONMEM, Myelosuppression, Neutropenia, Population pharmacokineticpharmacodynamic modeling, Pharmacometrics
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-150427 (URN)10.1007/s10637-010-9603-3 (DOI)000300160800048 ()21153753 (PubMedID)
Available from: 2011-03-30 Created: 2011-03-30 Last updated: 2012-03-08Bibliographically approved
2. Simultaneous modeling of endogenous G‑CSF and neutrophil dynamics following chemotherapy in breast cancer patients
Open this publication in new window or tab >>Simultaneous modeling of endogenous G‑CSF and neutrophil dynamics following chemotherapy in breast cancer patients
(English)Manuscript (preprint) (Other academic)
Keyword
Docetaxel, 5-fluorouracil-epirubicin-cyclophosphamide, endogenous G‑CSF, neutropenia, population pharmacokinetic-pharmacodynamic modeling, Pharmacometrics, NONMEM
Identifiers
urn:nbn:se:uu:diva-150426 (URN)
Available from: 2011-03-30 Created: 2011-03-30 Last updated: 2011-05-03
3. A semi-mechanistic model of docetaxel-induced myelosuppression to support dosing recommendation in liver impaired patients.
Open this publication in new window or tab >>A semi-mechanistic model of docetaxel-induced myelosuppression to support dosing recommendation in liver impaired patients.
(English)Manuscript (preprint) (Other academic)
Keyword
Docetaxel, NONMEM, myelosuppression, neutropenia, population pharmacokinetic-pharmacodynamic modeling, Pharmacometrics
Identifiers
urn:nbn:se:uu:diva-150425 (URN)
Available from: 2011-03-30 Created: 2011-03-30 Last updated: 2011-05-03
4. Comparison between using continuous and categorical toxicity data for estimation of a model for continuous data.
Open this publication in new window or tab >>Comparison between using continuous and categorical toxicity data for estimation of a model for continuous data.
(English)Manuscript (preprint) (Other academic)
Keyword
NONMEM, pharmacometrics, population pharmacokinetic-pharmacodynamic model, myelosuppression model, neutropenia, categorical data
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-150421 (URN)
Available from: 2011-03-30 Created: 2011-03-30 Last updated: 2011-05-03
5. Inverse relationship between leukaemic cell burden and plasma concentrations of daunorubicin in patients with acute myeloidleukaemia
Open this publication in new window or tab >>Inverse relationship between leukaemic cell burden and plasma concentrations of daunorubicin in patients with acute myeloidleukaemia
Show others...
2011 (English)In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 71, no 4, 514-521 p.Article in journal (Refereed) Published
Abstract [en]

center dot In vitro studies show that daunorubicin (DNR) cytotoxicity decreases with increasing cell density because of a high cellular uptake and depletion of drug in the medium.

center dot It is not known whether such an effect also occurs in vivo.

WHAT THIS STUDY ADDS

center dot We have shown that a large leukaemic cell burden lowers the plasma concentration of DNR in patients with acute myeloid leukaemia.

center dot Our analysis supports that a large leukaemic cell burden increases the central volume of distribution for DNR.

center dot Our study indicates that a dose adjustment of DNR may be of importance in acute myeloid leukaemia patients with high white blood cell counts.

AIMS

It has been shown that the cellular uptake and cytotoxicity of anthracyclines decrease with increasing cell density in vitro, an event termed 'the inocculum effect'. It is not known whether such an effect occurs in vivo. In this study the relationships between white blood cell (WBC) count, plasma and cellular concentrations of daunorubicin (DNR) in patients with acute myeloid leukaemia were investigated.

METHODS

Plasma and mononuclear blood cells were isolated from peripheral blood from 40 patients with acute myeloid leukaemia at end of infusion (time 1 h), 5 and 24 h following the first DNR infusion. DNR concentrations were determined by high-pressure liquid chromatography and related to the WBC count at diagnosis. A population pharmacokinetic model was used to estimate the correlations between baseline WBC count, volume of distribution and clearance of DNR.

RESULTS

A clear but weak inverse relationship between the baseline WBC count and plasma concentrations of DNR (r2 = 0.11, P < 0.05) at time 1 was found. Furthermore, a clear relationship between baseline WBC count and DNR central volume of distribution using population pharmacokinetic modelling (dOFV 4.77, P < 0.05) was also noted. Analysis of plasma DNR and the metabolite daunorubicinol (DOL) concentrations in patients with a high WBC count support that the low DNR/DOL concentrations are due a distribution effect.

CONCLUSION

This study shows that the leukaemic cell burden influences the plasma concentrations of anthracyclines. Further studies are needed to explore if patients with high a WBC count may require higher doses of anthracyclines.

Keyword
acute myeloid leukaemia, anthracycline, daunorubicin, pharmacokinetics, plasma, tumour burden
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-150428 (URN)10.1111/j.1365-2125.2010.03894.x (DOI)000288249500006 ()21204910 (PubMedID)
Available from: 2011-03-30 Created: 2011-03-30 Last updated: 2011-05-03Bibliographically approved
6. Modeling of in vitro drug activity and prediction of clinical outcome in acute myeloid leukemia
Open this publication in new window or tab >>Modeling of in vitro drug activity and prediction of clinical outcome in acute myeloid leukemia
Show others...
2007 (English)In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 47, no 8, 1014-1021 p.Article in journal (Refereed) Published
Abstract [en]

The objectives of this study were to develop a population pharmacodynamic model describing the in vitro drug sensitivity of tumor cells and to relate in vitro parameters to clinical outcome. Cell samples from 179 patients with acute myelocytic leukemia were exposed to cytosine arabinoside and daunorubicin, and cytotoxicity was analyzed using the fluorometric microculture cytotoxicity assay. A sigmoid E(max)-model for daunorubicin and an E(max)-model for cytosine arabinoside described the data. The model predicted drug potency (EC(50)) adequately from 1 concentration measurement. A logistic regression on individual in vitro parameters of 46 patients treated with the daunorubicin plus cytosine arabinoside regimen showed that the probability of complete response was significantly (P < .05) related to the product of the E(max)/EC(50) ratio of the two drugs. The findings demonstrate the value of population pharmacodynamic modeling of in vitro drug sensitivity data and a significant relationship between the in vitro parameters and clinical outcome.

Keyword
Acute myelocytic leukemia, Cytosine arabinoside, Daunorubicin, Fluorometric microculture cytotoxicity assay, NONMEM
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-13509 (URN)10.1177/0091270007302563 (DOI)000248417000010 ()17660484 (PubMedID)
Available from: 2008-02-21 Created: 2008-02-21 Last updated: 2011-05-03Bibliographically approved

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