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

Direct link
Population Pharmacokinetic Model for Cremophor EL
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
Show others and affiliations
Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-92976OAI: oai:DiVA.org:uu-92976DiVA: diva2:166313
Available from: 2005-04-29 Created: 2005-04-29 Last updated: 2011-03-01
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

Open Access in DiVA

No full text

Search in DiVA

By author/editor
Karlsson, Mats O.
By organisation
Division of Pharmacokinetics and Drug Therapy

Search outside of DiVA

GoogleGoogle Scholar

Total: 209 hits
ReferencesLink to record
Permanent link

Direct link