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Pharmacokinetic-Pharmacodynamic Modelling of Anticancer Drugs: Haematological Toxicity and Tumour Response in Hollow Fibres
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
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. , p. 71
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 286
Keywords [en]
Pharmacokinetics/Pharmacotherapy
Keywords [sv]
Farmakokinetik/Farmakoterapi
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
URN: urn:nbn:se:uu:diva-3370ISBN: 91-554-5587-5 (print)OAI: oai:DiVA.org:uu-3370DiVA, id: diva2:162528
Public defence
2003-05-09, B41, BMC, Uppsala, 09:15
Opponent
Supervisors
Available from: 2003-04-15 Created: 2003-04-15 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Haematological toxicity following different dosing schedules of 5-fluorouracil and epirubicin in rats
Open this publication in new window or tab >>Haematological toxicity following different dosing schedules of 5-fluorouracil and epirubicin in rats
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2000 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 20, no 3A, p. 1519-1525Article in journal (Refereed) Published
Abstract [en]

AIM

To study the effects of single and fractionated doses of 5-fluorouracil and epirubicin on the leukocyte counts in rats.

METHODS

Six different dosing patterns of each drug were injected within one day. The leukocytes were followed for 11-15 days. Pharmacokinetic models were developed using NONMEM. Quantitative and qualitative pharmacokinetic-pharmacodynamic relationships were investigated.

RESULTS

A one-compartment model with non-linear elimination described 5-fluorouracil pharmacokinetics and a three-compartment model described epirubicin concentration data. Sigmoidal or basic Emax-models quantified the relationships between individual AUCs and decreases in leukocytes, for both drugs. Similar relationships between AUC and toxicity were found, regardless of whether the drugs were given as single or fractionated doses.

CONCLUSION

Quantitative relationships between AUC and the effect on leukocytes were established for 5-fluorouracil and epirubicin. However, no schedule dependence was indicated for the schedules used in the study.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-90233 (URN)10928065 (PubMedID)
Available from: 2003-04-15 Created: 2003-04-15 Last updated: 2017-12-14Bibliographically approved
2.
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4. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs
Open this publication in new window or tab >>Model of chemotherapy-induced myelosuppression with parameter consistency across drugs
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2002 (English)In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 20, no 24, p. 4713-4721Article in journal (Refereed) Published
Abstract [en]

PURPOSE:

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.

PATIENTS AND METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-90236 (URN)10.1200/JCO.2002.02.140 (DOI)12488418 (PubMedID)
Available from: 2003-04-15 Created: 2003-04-15 Last updated: 2017-12-14Bibliographically approved
5. Determination of drug effect on tumour cells, host animal toxicity and drug pharmacokinetics in a hollow-fibre model in rats
Open this publication in new window or tab >>Determination of drug effect on tumour cells, host animal toxicity and drug pharmacokinetics in a hollow-fibre model in rats
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2000 (English)In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 46, no 6, p. 493-500Article 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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-90237 (URN)10.1007/s002800000181 (DOI)11138463 (PubMedID)
Available from: 2003-04-15 Created: 2003-04-15 Last updated: 2017-12-14Bibliographically approved
6. Pharmacokinetic-pharmacodynamic modeling of the schedule-dependent effect of CHS 828 in a rat hollow fiber model
Open this publication in new window or tab >>Pharmacokinetic-pharmacodynamic modeling of the schedule-dependent effect of CHS 828 in a rat hollow fiber model
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Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-90238 (URN)
Available from: 2003-04-15 Created: 2003-04-15 Last updated: 2011-03-01

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