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Model of Chemotherapy-Induced Myelosuppression With Parameter Consistency Across Drugs
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
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2002 (English)In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 20, no 24, 4713-4721 p.Article in journal (Refereed) Published
Abstract [en]


To develop a semimechanistic pharmacokinetic-pharmacodynamic model describing chemotherapy-induced myelosuppression through drug-specific parameters and system-related parameters, which are common to all drugs.


Patient leukocyte and neutrophil data after administration of docetaxel, paclitaxel, and etoposide were used to develop the model, which was also applied to myelosuppression data from 2'-deoxy-2'-methylidenecytidine (DMDC), irinotecan (CPT-11), and vinflunine administrations. The model consisted of a proliferating compartment that was sensitive to drugs, three transit compartments that represented maturation, and a compartment of circulating blood cells. Three system-related parameters were estimated: baseline, mean transit time, and a feedback parameter. Drug concentration-time profiles affected the proliferation of sensitive cells by either an inhibitory linear model or an inhibitory E(max) model. To evaluate the model, system-related parameters were fixed to the same values for all drugs, which were based on the results from the estimations, and only drug-specific parameters were estimated. All modeling was performed using NONMEM software.


For all investigated drugs, the model successfully described myelosuppression. Consecutive courses and different schedules of administration were also well characterized. Similar system-related parameter estimates were obtained for the different drugs and also for leukocytes compared with neutrophils. In addition, when system-related parameters were fixed, the model well characterized chemotherapy-induced myelosuppression for the different drugs.


This model predicted myelosuppression after administration of one of several different chemotherapeutic drugs. In addition, with fixed system-related parameters to proposed values, and only drug-related parameters estimated, myelosuppression can be predicted. We propose that this model can be a useful tool in the development of anticancer drugs and therapies.

Place, publisher, year, edition, pages
2002. Vol. 20, no 24, 4713-4721 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-92977DOI: 10.1200/JCO.2002.02.140PubMedID: 12488418OAI: oai:DiVA.org:uu-92977DiVA: diva2:166314
Available from: 2005-04-29 Created: 2005-04-29 Last updated: 2011-11-30Bibliographically approved
In thesis
1. Mechanism-Based Pharmacokinetic and Pharmacodynamic Modelling of Paclitaxel
Open this publication in new window or tab >>Mechanism-Based Pharmacokinetic and Pharmacodynamic Modelling of Paclitaxel
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Paclitaxel (Taxol®) is now widely used against breast, ovarian and non-small-cell lung cancer. Anticancer agents generally have narrow therapeutic indices, often with myelosuppression (mainly neutropenia) as dose-limiting side effect. A further complicating factor is that paclitaxel when given as Taxol® has a nonlinear pharmacokinetic (PK) behaviour in plasma. Identifying risk groups more sensitive to chemotherapy due to either a PK or pharmacodynamic (PD) interindividual variability is of importance. The aim of the thesis was to develop predictive mechanism-based PK and PD models applicable for paclitaxel.

PK and PK/PD models were developed for patient data from studies with relatively frequent sampling or sparse sampling schedules. Population analyses were performed using the software NONMEM.

A pharmacokinetic model describing unbound, total plasma and blood concentrations of paclitaxel from known binding mechanisms was developed and validated. The nonlinear PK in plasma could to a large extent be explained by the micelle forming vehicle Cremophor EL (CrEL) and the unbound drug showed linear PK. Besides a binding component directly proportional to concentrations of CrEL, the model included both linear and nonlinear binding components in plasma and blood. Further, relations between the PK parameters and different demographic factors, including polymorphisms in the cytochrome P450s involved in paclitaxel metabolism, were investigated.

A semi-physiological PD model for chemotherapy-induced myelosuppression was developed and applied to different anticancer drugs. The model included a self-renewal for proliferating cells, transit compartments describing the delay in observed myelosuppression and a feedback parameter reflecting the effect on the bone marrow from growth factors that can result in an overshoot in white blood cells. The system-related parameters estimated showed consistency across drugs and the difference in the drug-related parameter reflected the relative bone marrow toxicity of the drugs. Relations between demographic factors and the PD parameters were identified.

The developed mechanism-based models promote a better understanding of paclitaxel PK and PD and may be used as tools in dosing individualisation and in development of dosing strategies for new administration forms and new drugs in the same area.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 72 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 10
Pharmacokinetics/Pharmacotherapy, Pharmacokinetics, Pharmacodynamics, Mechanism-based, Modelling, Myelosuppression, Paclitaxel, Cremophor EL, NONMEM, Farmakokinetik/Farmakoterapi
National Category
Pharmaceutical Sciences
urn:nbn:se:uu:diva-5772 (URN)91-554-6232-4 (ISBN)
Public defence
2005-05-20, Room B42, BMC, Husargatan 3, Uppsala, 09:15 (English)
Available from: 2005-04-29 Created: 2005-04-29 Last updated: 2011-07-05Bibliographically approved

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Friberg, Lena E.Karlsson, Mats O.
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