A mathematical model for comparison of bolus injection, continuous infusion, and liposomal delivery of doxorubicin to tumor cells

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Abstract

Determining the optimal mode of delivery for doxorubicin is important given the wide use of the drug against many tumor types. The relative performances of bolus injection, continuous infusion, liposomal and thermoliposomal delivery are not yet definitely established from clinical trials. Here, a mathematical model is used to compare bolus injection, continuous infusion for various durations, liposomal and thermoliposomal delivery of doxorubicin. Effects of the relatively slow rate, and saturability, of doxorubicin uptake by cells are included. Peak concentrations attained in tumor cells are predicted and used as a measure of antitumor effectiveness. To measure toxicity, plasma area under the curve (AUC) and peak plasma concentrations of free doxorubicin are computed. For continuous infusion, the duration of infusion significantly affects predicted outcome. The optimal infusion duration increases with dose, and is in the range 1 to 3 hours at typical doses. The simulations suggest that continuous infusion for optimal durations is superior to the other protocols. Nonthermosensitive liposomes approach the efficacy of continuous infusion only if they release drug at optimal rates. Predictions for thermosensitive liposomes indicate a potential advantage at some doses, but only if hyperthermia is applied locally so that the blood is not significantly heated.

Original languageEnglish (US)
Pages (from-to)325-338
Number of pages14
JournalNeoplasia
Volume2
Issue number4
StatePublished - 2000

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Doxorubicin
Theoretical Models
Injections
Liposomes
Neoplasms
Area Under Curve
Fever
Clinical Trials
liposomal doxorubicin
Pharmaceutical Preparations

Keywords

  • Continuous infusion
  • Doxorubicin
  • Drug delivery
  • Liposome
  • Tumor

ASJC Scopus subject areas

  • Cancer Research

Cite this

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abstract = "Determining the optimal mode of delivery for doxorubicin is important given the wide use of the drug against many tumor types. The relative performances of bolus injection, continuous infusion, liposomal and thermoliposomal delivery are not yet definitely established from clinical trials. Here, a mathematical model is used to compare bolus injection, continuous infusion for various durations, liposomal and thermoliposomal delivery of doxorubicin. Effects of the relatively slow rate, and saturability, of doxorubicin uptake by cells are included. Peak concentrations attained in tumor cells are predicted and used as a measure of antitumor effectiveness. To measure toxicity, plasma area under the curve (AUC) and peak plasma concentrations of free doxorubicin are computed. For continuous infusion, the duration of infusion significantly affects predicted outcome. The optimal infusion duration increases with dose, and is in the range 1 to 3 hours at typical doses. The simulations suggest that continuous infusion for optimal durations is superior to the other protocols. Nonthermosensitive liposomes approach the efficacy of continuous infusion only if they release drug at optimal rates. Predictions for thermosensitive liposomes indicate a potential advantage at some doses, but only if hyperthermia is applied locally so that the blood is not significantly heated.",
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N2 - Determining the optimal mode of delivery for doxorubicin is important given the wide use of the drug against many tumor types. The relative performances of bolus injection, continuous infusion, liposomal and thermoliposomal delivery are not yet definitely established from clinical trials. Here, a mathematical model is used to compare bolus injection, continuous infusion for various durations, liposomal and thermoliposomal delivery of doxorubicin. Effects of the relatively slow rate, and saturability, of doxorubicin uptake by cells are included. Peak concentrations attained in tumor cells are predicted and used as a measure of antitumor effectiveness. To measure toxicity, plasma area under the curve (AUC) and peak plasma concentrations of free doxorubicin are computed. For continuous infusion, the duration of infusion significantly affects predicted outcome. The optimal infusion duration increases with dose, and is in the range 1 to 3 hours at typical doses. The simulations suggest that continuous infusion for optimal durations is superior to the other protocols. Nonthermosensitive liposomes approach the efficacy of continuous infusion only if they release drug at optimal rates. Predictions for thermosensitive liposomes indicate a potential advantage at some doses, but only if hyperthermia is applied locally so that the blood is not significantly heated.

AB - Determining the optimal mode of delivery for doxorubicin is important given the wide use of the drug against many tumor types. The relative performances of bolus injection, continuous infusion, liposomal and thermoliposomal delivery are not yet definitely established from clinical trials. Here, a mathematical model is used to compare bolus injection, continuous infusion for various durations, liposomal and thermoliposomal delivery of doxorubicin. Effects of the relatively slow rate, and saturability, of doxorubicin uptake by cells are included. Peak concentrations attained in tumor cells are predicted and used as a measure of antitumor effectiveness. To measure toxicity, plasma area under the curve (AUC) and peak plasma concentrations of free doxorubicin are computed. For continuous infusion, the duration of infusion significantly affects predicted outcome. The optimal infusion duration increases with dose, and is in the range 1 to 3 hours at typical doses. The simulations suggest that continuous infusion for optimal durations is superior to the other protocols. Nonthermosensitive liposomes approach the efficacy of continuous infusion only if they release drug at optimal rates. Predictions for thermosensitive liposomes indicate a potential advantage at some doses, but only if hyperthermia is applied locally so that the blood is not significantly heated.

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