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Population pharmacokinetic-dynamic analysis of anticancer drug treatment

Objective

- Interpatient differences in the dose-response relationship for cytotoxic drug therapy in ovarian and breast cancer by applying a population PK-PD approach. Breast and ovarian cancer have been chosen as examples of common chemo sensitive yet often incurable tumours.
- Quantitative relationships between interpatient differences in the exposure to anticancer agents and toxicities of the therapy.
- Whether patients should benefit from individualized drug treatment.
- Subpopulations of patients for which anticancer therapy has a low likelihood of tumour response, using a panel of tumour related pharmacodynamic markers (p53, Her-2/neu ER/PR, EGFR, LRP).
- Subpopulations of patients which are particularly at risk; for the development of severe side effects.

Patients with locally advanced or metastatic solid tumours vary widely in their response and tolerance of systemic therapy with anticancer agents. The variability in the dose-response and dose-toxicity relationship is determined by both pharmacokinetic (PK) and pharmacodynamic (PD) (tumour and end-organ related factors respectively). Application of the 'population approach' for characterization of variability in dose-response and dose-toxicity relationships as well as new insights in mechanisms of anticancer drug resistance, form the basis for the current large scale clinical-pharmacologic studies in patients with solid tumours. The studies will be carried out within the framework of the PAMM and ECSG and IDBBC-group of the EORTC. The population approach offers the possibility of gaining integrated information on PK, PD and response from sparse observational data and allows analysis of a variety of unbalanced study designs. Recent in vitro and in vivo studies have revealed that estrogen/progesteron (ER/PR) receptor status and overexpression of lung resistance protein (LRP), epidermal growth factor receptor (EGFR) or (mutant) oncogenes, such as p53 and Her-2/neu may cause resistance to anticancer agents in breast or ovarian cancer. We propose to apply the population approach in phase III/IV studies in ovarian and breast cancer using NONMEM (nonlinear mixed effect models, USF, CA USA). We will implement procedures for crossvalidation of analytical and biologic methods to prevent methodological bias. We define the following covariates for population PK analysis body weight, WHO performance score, age, albumin, renal, liver and bone marrow function, comedication; and add tumour stage, differentiation, TNM classification and p53, Her-2/neu ER/PR, LRP and EGFR tumour status for population PK-PD analysis

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

Nederlands Kanker Instituut
Address
161,Plesmanlaan 121
1066 CX Amsterdam
Netherlands

Participants (20)

Academisch Ziekenhuis Rotterdam
Netherlands
Address
301,Groene Hilleayh 301
3075 EA Rotterdam
Akademisch Ziekenhuis Groningen
Netherlands
Address
59,Ooster Singel 59
9713 EZ Groningen
Centre Antoine Lacassagne
France
Address
33,Avenue De Valombrose 33
06189 Nice
Centre Claudius Regaud
France
Address
20,Rue Du Pont St Pierre 20
31052 Toulouse
Centre Léon Bérard
France
Address
28,Rue Laennec 28
69373 Lyon
Centre Rene Huguenin
France
Address
35,Rue Dailly 35
92210 Saint Cloud
European Organization for Research and Treatment of Cancer
Netherlands
Address
601,Amstelveenseweg 601
1081 JC Amsterdam
IMPERIAL CANCER RESEARCH FUND
United Kingdom
Address
John Radcliffe Hospital
OX3 9DS Oxford/headington
Institut Bergonié, Centre Régional deLutte contre le Cancer de Bordeaux etdu Sud-Ouest
France
Address
180,Rue De Saint-genès 180
33076 Bordeaux
Istituto Nazionale Tumori Centroeuropeo
Italy
Address
Via Pedemontana Occidentale 12
33081 Aviano
Katholieke Universiteit Leuven
Belgium
Address
35,Kapucijnenvoer 35
3000 Leuven
Slotervaart Ziekenhuis
Netherlands
Address
6,Louwesweg 6
1066 EC Amsterdam
UNIVERSITY OF BOLOGNA
Italy
Address
Viale Risorgimento 4
40136 Bologna
University of Aberdeen
United Kingdom
Address
Foresterhill
AB9 2ZD Aberdeen
University of Glasgow
United Kingdom
Address
University Avenue
G12 8QQ Glasgow
University of Ioannina
Greece
Address
1,Salamaga 1
45110 Ioannina
University of Newcastle upon Tyne
United Kingdom
Address
Framlington Place
NE2 4HH Newcastle Upon Tyne
Université Libre de Bruxelles
Belgium
Address
1,Rue Héger-bordet 1
1000 Bruxelles
Uppsala University
Sweden
Address
3,Husargatan 3
751 23 Uppsala
Vrije Universiteit Amsterdam
Netherlands
Address
1117,De Boelelaan 1117
1081 HV Amsterdam