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Determination of drug effect on tumour cells, host animal toxicity and drug pharmacokinetics in a hollow-fibre model in rats
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
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2000 (English)In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 46, no 6, 493-500 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE

Based on the previously published hollow-fibre assay mainly used for early in vivo anticancer drug screening, we wanted to develop an extended hollow-fibre model in which antitumour activity, haematological toxicity and pharmacokinetics could be studied in the same animal.

METHOD

The breast cancer cell lines MDA-MB-231 and MCF-7 were cultured in semipermeable hollow fibres. The fibres were implanted subcutaneously into immunocompetent male Sprague Dawley rats, and the rats were treated with 5-fluorouracil (5-FU, 125 mg/kg), epirubicin (EPI, 10 mg/kg) or cyclophosphamide (CP, 120 mg/kg) intraperitoneally, the new cyanoguanidine CHS 828 (375 mg/kg or 75 mg/kg x 5) orally, or vehicle only. After 6 days the fibres were retrieved and the cell density was evaluated. Haematological parameters were monitored and two to four samples per animal were drawn to determine the pharmacokinetic parameters in NONMEM.

RESULTS

Drug treatment had generally low effects on the tumour cells. Of the standard drugs (5-FU, EPI and CP), only CP exerted a statistically significant antiproliferative effect. CHS 828 had only a minor effect as a single dose, but divided into five daily doses had a pronounced effect on both cell lines. 5-FU, EPI and CP all caused a marked decrease in leucocytes, platelets and haemoglobin, while CHS 828 did not seem to affect these parameters. The pharmacokinetics of 5-FU and EPI were in accordance with previously established pharmacokinetic models. The pharmacokinetics of CP and CHS 828 were both described by one-compartment models.

CONCLUSIONS

This study illustrates the possibility of measuring antitumour effect, haematological toxicity and pharmacokinetics in the same animal using the hollow-fibre model.

Place, publisher, year, edition, pages
2000. Vol. 46, no 6, 493-500 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-90237DOI: 10.1007/s002800000181PubMedID: 11138463OAI: oai:DiVA.org:uu-90237DiVA: diva2:162526
Available from: 2003-04-15 Created: 2003-04-15 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Pharmacokinetic-Pharmacodynamic Modelling of Anticancer Drugs: Haematological Toxicity and Tumour Response in Hollow Fibres
Open this publication in new window or tab >>Pharmacokinetic-Pharmacodynamic Modelling of Anticancer Drugs: Haematological Toxicity and Tumour Response in Hollow Fibres
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Established quantitative relationships between dose, plasma concentrations and response [pharmacokinetic-pharmacodynamic (PKPD) models] have a high potential in improving therapeutic indices of anticancer drug therapy and in increasing drug development efficiency. PKPD modelling is a helpful tool for characterising and understanding schedule dependence. The aim of this thesis was to develop PKPD models of anticancer drugs for tumour effects and haematological toxicity, which is the most frequent dose-limiting toxicity.

PK and haematological toxicity after several schedules were studied in rats and semi-physiological PKPD models for the whole time course of myelosuppression were developed from animal and patient data. The possibility to implant hollow fibres filled with tumour cells in immunocompetent rats was investigated for simultaneous assessment of PK, tumour response and haematological toxicity. Population data analyses were performed using the software NONMEM.

When all injections were administered within eight hours, fractionated schedules of 5-fluorouracil and epirubicin produced similar haematological toxicity in rats as a single dose, when the non-linear PK of 5-fluorouracil was accounted for. When the time interval was extended to two days for 5-fluorouracil, the fractionated regimens were more toxic.

The developed semi-physiological PKPD models included transit compartments that mimic maturation stages in bone marrow and explain the time lag. Feedback mechanisms characterised the rebound. The models successfully described myelosuppression in patients (DMDC) and rats (5-fluorouracil), after different administration schedules. Further developments made it possible to characterise the time course of myelosuppression after administration of each one of six different drugs, with parameters related to the haematopoietic system consistent across drugs.

The developed hollow fibre model in immunocompetent rats was successfully applied to monitor PK, toxicity and the time course of antitumour effects. PKPD modelling illustrated that the schedule dependence of the anticancer agent CHS 828 is partly due to dose-dependent bioavailability and partly due to a schedule-dependent PD effect.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. 71 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 286
Keyword
Pharmacokinetics/Pharmacotherapy, Farmakokinetik/Farmakoterapi
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-3370 (URN)91-554-5587-5 (ISBN)
Public defence
2003-05-09, B41, BMC, Uppsala, 09:15
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Supervisors
Available from: 2003-04-15 Created: 2003-04-15Bibliographically approved

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Friberg, Lena E.Karlsson, Mats O.

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