Two-mechanism peak concentration model for cellular pharmacodynamics of doxorubicin

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

A mathematical model is presented for the cellular uptake and cytotoxicity of the anticancer drug doxorubicin. The model assumes sigmoidal, Hill-type dependence of cell survival on drug-induced damage. Experimental evidence indicates distinct intracellular and extracellular mechanisms of doxorubicin cytotoxicity. Drug-induced damage is therefore expressed as the sum of two terms, representing the peak values over time of concentrations of intracellular and extracellular drugs. Dependence of cell kill on peak values of concentration rather than on an integral over time is consistent with observations that dose-response curves for doxorubicin converge to a single curve as exposure time is increased. Drug uptake by cells is assumed to include both saturable and unsaturable components, consistent with experimental data. Overall, the model provides better fits to in vitro cytotoxicity data than previous models. It shows how saturation of cellular uptake or binding with concentration can result in plateaus in the dose-response curve at high concentrations and short exposure, as observed experimentally in some cases. The model provides a unified framework for analyzing doxorubicin cellular pharmacokinetic and pharmacodynamic data, and can be applied in mathematical models for tumor response and treatment optimization.

Original languageEnglish (US)
Pages (from-to)705-713
Number of pages9
JournalNeoplasia
Volume7
Issue number7
DOIs
StatePublished - Jul 2005

Fingerprint

Doxorubicin
Pharmaceutical Preparations
Theoretical Models
Cell Survival
Pharmacokinetics
Neoplasms

Keywords

  • Adriamycin
  • Cellular pharmacodynamics
  • Chemotherapy
  • Doxorubicin
  • Mathematical model

ASJC Scopus subject areas

  • Cancer Research

Cite this

Two-mechanism peak concentration model for cellular pharmacodynamics of doxorubicin. / Fox, Ardith El-Kareh; Secomb, Timothy W.

In: Neoplasia, Vol. 7, No. 7, 07.2005, p. 705-713.

Research output: Contribution to journalArticle

@article{7d8fe9c0ca58496a9b79c761dd988a09,
title = "Two-mechanism peak concentration model for cellular pharmacodynamics of doxorubicin",
abstract = "A mathematical model is presented for the cellular uptake and cytotoxicity of the anticancer drug doxorubicin. The model assumes sigmoidal, Hill-type dependence of cell survival on drug-induced damage. Experimental evidence indicates distinct intracellular and extracellular mechanisms of doxorubicin cytotoxicity. Drug-induced damage is therefore expressed as the sum of two terms, representing the peak values over time of concentrations of intracellular and extracellular drugs. Dependence of cell kill on peak values of concentration rather than on an integral over time is consistent with observations that dose-response curves for doxorubicin converge to a single curve as exposure time is increased. Drug uptake by cells is assumed to include both saturable and unsaturable components, consistent with experimental data. Overall, the model provides better fits to in vitro cytotoxicity data than previous models. It shows how saturation of cellular uptake or binding with concentration can result in plateaus in the dose-response curve at high concentrations and short exposure, as observed experimentally in some cases. The model provides a unified framework for analyzing doxorubicin cellular pharmacokinetic and pharmacodynamic data, and can be applied in mathematical models for tumor response and treatment optimization.",
keywords = "Adriamycin, Cellular pharmacodynamics, Chemotherapy, Doxorubicin, Mathematical model",
author = "Fox, {Ardith El-Kareh} and Secomb, {Timothy W}",
year = "2005",
month = "7",
doi = "10.1593/neo.05118",
language = "English (US)",
volume = "7",
pages = "705--713",
journal = "Neoplasia",
issn = "1522-8002",
publisher = "Elsevier Inc.",
number = "7",

}

TY - JOUR

T1 - Two-mechanism peak concentration model for cellular pharmacodynamics of doxorubicin

AU - Fox, Ardith El-Kareh

AU - Secomb, Timothy W

PY - 2005/7

Y1 - 2005/7

N2 - A mathematical model is presented for the cellular uptake and cytotoxicity of the anticancer drug doxorubicin. The model assumes sigmoidal, Hill-type dependence of cell survival on drug-induced damage. Experimental evidence indicates distinct intracellular and extracellular mechanisms of doxorubicin cytotoxicity. Drug-induced damage is therefore expressed as the sum of two terms, representing the peak values over time of concentrations of intracellular and extracellular drugs. Dependence of cell kill on peak values of concentration rather than on an integral over time is consistent with observations that dose-response curves for doxorubicin converge to a single curve as exposure time is increased. Drug uptake by cells is assumed to include both saturable and unsaturable components, consistent with experimental data. Overall, the model provides better fits to in vitro cytotoxicity data than previous models. It shows how saturation of cellular uptake or binding with concentration can result in plateaus in the dose-response curve at high concentrations and short exposure, as observed experimentally in some cases. The model provides a unified framework for analyzing doxorubicin cellular pharmacokinetic and pharmacodynamic data, and can be applied in mathematical models for tumor response and treatment optimization.

AB - A mathematical model is presented for the cellular uptake and cytotoxicity of the anticancer drug doxorubicin. The model assumes sigmoidal, Hill-type dependence of cell survival on drug-induced damage. Experimental evidence indicates distinct intracellular and extracellular mechanisms of doxorubicin cytotoxicity. Drug-induced damage is therefore expressed as the sum of two terms, representing the peak values over time of concentrations of intracellular and extracellular drugs. Dependence of cell kill on peak values of concentration rather than on an integral over time is consistent with observations that dose-response curves for doxorubicin converge to a single curve as exposure time is increased. Drug uptake by cells is assumed to include both saturable and unsaturable components, consistent with experimental data. Overall, the model provides better fits to in vitro cytotoxicity data than previous models. It shows how saturation of cellular uptake or binding with concentration can result in plateaus in the dose-response curve at high concentrations and short exposure, as observed experimentally in some cases. The model provides a unified framework for analyzing doxorubicin cellular pharmacokinetic and pharmacodynamic data, and can be applied in mathematical models for tumor response and treatment optimization.

KW - Adriamycin

KW - Cellular pharmacodynamics

KW - Chemotherapy

KW - Doxorubicin

KW - Mathematical model

UR - http://www.scopus.com/inward/record.url?scp=23244457368&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=23244457368&partnerID=8YFLogxK

U2 - 10.1593/neo.05118

DO - 10.1593/neo.05118

M3 - Article

VL - 7

SP - 705

EP - 713

JO - Neoplasia

JF - Neoplasia

SN - 1522-8002

IS - 7

ER -