Diffusion-limited binding explains binary dose response for local arterial and tumour drug delivery.
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.


OBJECTIVE
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, B(p), ratio of binding capacity to product of equilibrium dissociation constant and accessible tissue volume fraction. At low B(p) (< 1), drugs are predominantly free and transport scales linearly with concentration. At high B(p) (> 40), drug transport exhibits threshold dependence on applied surface concentration.


CONCLUSIONS
In this paradigm, drugs and antibodies with large B(p) 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.
Tzafriri
A R
AR
Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ramitz@mit.edu
Levin
A D
AD
Edelman
E R
ER
D001158:Arteries / Q000473:pathology; D004058:Diffusion; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D006801:Humans; D015552:Injections, Intralesional; D009369:Neoplasms / Q000188:drug therapy*