Diffusion-limited binding explains binary dose response for local arterial and tumour drug delivery
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Edelman_Diffusion-limited binding.pdf
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Author(s)
Tzafriri, A. R.
Levin, A. D.
Edelman, Elazer R.
Date Issued
March 2009
Journal
Cell Proliferation
Publisher
Wiley Blackwell
Citation
Tzafriri, A. R., A. D. Levin, and E. R. Edelman. “Diffusion-limited Binding Explains Binary Dose Response for Local Arterial and Tumour Drug Delivery.” Cell Proliferation 42.3 (2009): 348–363.
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Author's final manuscript
Abstract
Background: Local drug delivery has transformed medicine, yet it remains unclear how drug efficacy depends on physicochemical properties and delivery kinetics. Most therapies seek to prolong release, yet recent studies demonstrate sustained clinical benefit following local bolus endovascular delivery.
Objectives: The purpose of the current study was to examine interplay between drug dose, diffusion and binding in determining tissue penetration and effect. Methods: We introduce a quantitative framework that balances dose, saturable binding and diffusion, and measured the specific binding parameters of drugs to target tissues. Results: Model reduction techniques augmented by numerical simulations revealed that impact of saturable binding on drug transport and retention is determined by the magnitude of a binding potential, Bp, ratio of binding capacity to product of equilibrium dissociation constant and accessible tissue volume fraction. At low Bp (< 1), drugs are predominantly free and transport scales linearly with concentration. At high Bp (> 40), drug transport exhibits threshold dependence on applied surface concentration. Conclusions: In this paradigm, drugs and antibodies with large Bp penetrate faster and deeper into tissues when presented at high concentrations. Threshold dependence of tissue transport on applied surface concentration of paclitaxel and rapamycin may explain threshold dose dependence of in vivo biological efficacy of these drugs.
Objectives: The purpose of the current study was to examine interplay between drug dose, diffusion and binding in determining tissue penetration and effect. Methods: We introduce a quantitative framework that balances dose, saturable binding and diffusion, and measured the specific binding parameters of drugs to target tissues. Results: Model reduction techniques augmented by numerical simulations revealed that impact of saturable binding on drug transport and retention is determined by the magnitude of a binding potential, Bp, ratio of binding capacity to product of equilibrium dissociation constant and accessible tissue volume fraction. At low Bp (< 1), drugs are predominantly free and transport scales linearly with concentration. At high Bp (> 40), drug transport exhibits threshold dependence on applied surface concentration. Conclusions: In this paradigm, drugs and antibodies with large Bp penetrate faster and deeper into tissues when presented at high concentrations. Threshold dependence of tissue transport on applied surface concentration of paclitaxel and rapamycin may explain threshold dose dependence of in vivo biological efficacy of these drugs.
MIT Department
Harvard University--MIT Division of Health Sciences and Technology
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DOI of Published Version
https://doi.org/10.1111/j.1365-2184.2009.00602.x
